bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2022‒02‒06
38 papers selected by
Regina F. Fernández
Johns Hopkins University
  1. Effects of hypercapnia / ischemia and dissection on the rat brain metabolome.
  2. Clozapine induces astrocyte-dependent FDG-PET hypometabolism.
  3. Estrogen transcriptomic regulation of brain bioenergetics and metabolism is cell-type-specific and estrogen-receptor-subtype-dependent.
  4. Encapsulation of Docosahexaenoic Acid Oil Substantially Improves the Oxylipin Profile of Rat Tissues.
  5. Allopregnanolone potentiates bioenergetic capacity and mitochondrial biogenesis in astrocytes.
  6. ApoE4 confers mitochondrial substrate oxidation defects that can be bioenergetically compensated by a ketogenic substrate beta-hydroxy butyrate (BHB).
  7. Fatty acid-binding protein 3 knockout mice exhibit astrocyte-mediated neuroinflammation and cognitive impairment.
  8. Clonidine and Brain Mitochondrial Energy Metabolism: Pharmacodynamic Insights Beyond Receptorial Effects.
  9. Cognitive Impairment and Metabolite Profile Alterations in the Hippocampus and Cortex of Male and Female Mice Exposed to a Fat and Sugar-Rich Diet are Normalized by Diet Reversal.
  10. Aberrant protein palmitoylation: A new route involved in Alzheimer's disease.
  11. Bitter brain: Hypoglycemia and the pathology of neurodegeneration and dementia.
  12. Minocycline as a therapeutic strategy against the brain dysfunctions induced by hypercholesterolemia.
  13. Effects of Chronic Arginase Inhibition with Norvaline on Tau Pathology and Brain Glucose Metabolism in Alzheimer's Disease Mice.
  14. Evidence of methylphenidate effect on mitochondria, redox homeostasis, and inflammatory aspects: Insights from animal studies.
  15. Ketone Ester Effects on Biomarkers of Brain Metabolism and Cognitive Performance in Cognitively Intact Adults ≥ 55 Years Old. A Study Protocol for a Double-Blinded Randomized Controlled Clinical Trial.
  16. Sex- and estrous-cycle dependent dorsal hippocampal phosphoproteomic changes induced by low-dose ketamine.
  17. Efficacy and Safety of Ketone Supplementation or Ketogenic Diets for Alzheimer's Disease: A Mini Review.
  18. The metabolic landscape of brain alterations in Alzheimer's disease.
  19. Human gray and white matter metabolomics to differentiate APOE-dependent metabolic changes in early and late Alzheimer's disease.
  20. Molecular effects of intranasal insulin in the rodent brain: Examination of insulin receptor signaling and the glutamatergic system.
  21. Neuroprotective Effects of a Small Mitochondrially-Targeted Tetrapeptide Elamipretide in Neurodegeneration.
  22. Mechanisms underlying cognitive impairment in a mouse model of familial hypercholesterolemia: Evidences of LDLr -/- mice.
  23. Brain H+ /CO2 sensing and control by glial cells.
  24. Inhibition of 15-hydroxyprostaglandin dehydrogenase protects a mouse model of Alzheimer's disease without affecting amyloid pathology.
  25. A mitochondria cluster at the proximal axon initial segment controls axodendritic TAU trafficking in rodent primary and human iPSC-derived neurons.
  26. Mitochondrial- and nuclear genome-controlled bioenergetic gene expression in Alzheimer's disease.
  27. Neuronal GPR81 regulates developmental brain angiogenesis and promotes brain recovery after a hypoxic ischemic insult.
  28. Specific small-molecule inhibition of PLD1 prevents ADRD-like memory deficits by preserving dendritic spine integrity driven by amyloidogenic proteins.
  29. Histone Acetylation Defects in Brain Precursor Cells: A Potential Pathogenic Mechanism Causing Proliferation and Differentiation Dysfunctions in Mitochondrial Aspartate-Glutamate Carrier Isoform 1 Deficiency.
  30. Effects of prenatal nutrient supplementation and early life exposures on neurodevelopment at age 10: a randomised controlled trial - the COPSYCH study protocol.
  31. Recent Neurotherapeutic Strategies to Promote Healthy Brain Aging: Are we there yet?
  32. Mitochondrial protein import determines lifespan through metabolic reprogramming and de novo serine biosynthesis.
  33. Could G6PD overexpression play a role in the prevention of Alzheimer's disease?
  34. Glucosylceramide synthase inhibition reduces ganglioside GM3 accumulation, alleviates amyloid neuropathology, and stabilizes remote contextual memory in a mouse model of Alzheimer's disease.
  35. High-dose triglyceride DHA supplementation increases plasma and cerebrospinal fluid phospholipid DHA species.
  36. Striking a balance: PIP2 and PIP3 signaling in neuronal health and disease.
  37. Synapses, Microglia, and Lipids in Alzheimer's Disease.
  38. Lipidome changes due to accumulation of cholesterol via APP-C99 alters neuronal permeability.
  1. Neurochem Int. 2022 Jan 29. pii: S0197-0186(22)00019-5. [Epub ahead of print] 105294
    Effects of hypercapnia / ischemia and dissection on the rat brain metabolome.
    Duncan A Sylvestre, Yurika Otoki, Adam H Metherel, Richard P Bazinet, Carolyn M Slupsky, Ameer Y Taha.
      It is known that brain energy metabolites such as ATP are quickly depleted during postmortem ischemia; however, a comprehensive assessment on the effects of preceding hypercapnia/ischemia and the dissection process on the larger brain metabolome remains lacking. This study sought to address this unknown by measuring aqueous metabolites impacted by hypercapnia/ischemia and brain dissection using Nuclear Magnetic Resonance. Metabolites were measured in rats subjected to 1) high energy head-focused microwave irradiation (control group); 2) CO2-induced hypercapnia/ischemia followed by immediate microwave irradiation; 3) CO2 followed by decapitation and then microwave irradiation ∼6.4 minutes later, to simulate a postmortem interval equivalent to typical dissection times; and 4) CO2-induced hypercapnia/ischemia followed by dissection within ∼6 minutes (no microwave fixation) to test the effects of brain dissection on the metabolome. Compared to microwave-irradiation, concentrations of high-energy phosphate metabolites and glucose were significantly reduced, while β-hydroxybutyrate and lactate were increased in rats subjected to all other treatments. Several amino acids and neurotransmitters (GABA) increased by hypercapnia/ischemia and dissection. Sugar donors involved in glycosylation decreased and nucleotides decreased or increased following hypercapnia/ischemia and dissection. sn-Glycero-3-phosphocholine decreased and choline increased in all groups relative to controls, indicating postmortem changes in lipid turnover. Antioxidants increased following hypercapnia/ischemia but decreased to control levels following dissection. This study demonstrates substantial post-mortem changes in brain energy and glycosylation pathways, as well as protein, nucleotide, neurotransmitter, lipid, and antioxidant turnover due to hypercapnia/ischemia and dissection. Changes in phosphate donors, glycosylation and amino acids reflect post-translational and protein degradation processes that persist post-mortem. Microwave irradiation is necessary for accurately capturing in vivo metabolite concentrations in brain.
    Keywords:  Dissection; Irradiation; Ischemia; Metabolomics; Microwave fixation
    DOI:  https://doi.org/10.1016/j.neuint.2022.105294
  2. Eur J Nucl Med Mol Imaging. 2022 Feb 05.
    Clozapine induces astrocyte-dependent FDG-PET hypometabolism.
    Andréia Rocha, Bruna Bellaver, Débora G Souza, Guilherme Schu, Igor C Fontana, Gianina T Venturin, Samuel Greggio, Fernanda U Fontella, Manoela L Schiavenin, Luiza S Machado, Diogo Miron, Jaderson C da Costa, Pedro Rosa-Neto, Diogo O Souza, Luc Pellerin, Eduardo R Zimmer.
      PURPOSE: Advances in functional imaging allowed us to visualize brain glucose metabolism in vivo and non-invasively with [18F]fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) imaging. In the past decades, FDG-PET has been instrumental in the understanding of brain function in health and disease. The source of the FDG-PET signal has been attributed to neuronal uptake, with hypometabolism being considered as a direct index of neuronal dysfunction or death. However, other brain cells are also metabolically active, including astrocytes. Based on the astrocyte-neuron lactate shuttle hypothesis, the activation of the glutamate transporter 1 (GLT-1) acts as a trigger for glucose uptake by astrocytes. With this in mind, we investigated glucose utilization changes after pharmacologically downregulating GLT-1 with clozapine (CLO), an anti-psychotic drug.METHODS: Adult male Wistar rats (control, n = 14; CLO, n = 12) received CLO (25/35 mg kg-1) for 6 weeks. CLO effects were evaluated in vivo with FDG-PET and cortical tissue was used to evaluate glutamate uptake and GLT-1 and GLAST levels. CLO treatment effects were also assessed in cortical astrocyte cultures (glucose and glutamate uptake, GLT-1 and GLAST levels) and in cortical neuronal cultures (glucose uptake).
    RESULTS: CLO markedly reduced in vivo brain glucose metabolism in several brain areas, especially in the cortex. Ex vivo analyses demonstrated decreased cortical glutamate transport along with GLT-1 mRNA and protein downregulation. In astrocyte cultures, CLO decreased GLT-1 density as well as glutamate and glucose uptake. By contrast, in cortical neuronal cultures, CLO did not affect glucose uptake.
    CONCLUSION: This work provides in vivo demonstration that GLT-1 downregulation induces astrocyte-dependent cortical FDG-PET hypometabolism-mimicking the hypometabolic signature seen in people developing dementia-and adds further evidence that astrocytes are key contributors of the FDG-PET signal.
    Keywords:  Astrocytes; Clozapine; FDG-PET; GLT-1; Glucose; Glutamate
    DOI:  https://doi.org/10.1007/s00259-022-05682-3
  3. Alzheimers Dement. 2021 Dec;17 Suppl 3 e055545
    Estrogen transcriptomic regulation of brain bioenergetics and metabolism is cell-type-specific and estrogen-receptor-subtype-dependent.
    Yiwei Wang, Yuan Shang, Fei Yin, Roberta Diaz Brinton.
      BACKGROUND: Late onset AD has an approximately 20-year prodromal period, which is characterized by brain glucose hypometabolism that can be detected in at risk groups and is predictive of disease progression. In females, this prodromal period coincides with the perimenopausal transition, during which loss of ovarian hormones is also associated with brain glucose hypometabolism. Further, in postmenopausal women, estrogen replacement therapy has demonstrated efficacy in improving brain glucose metabolism and recognition, supporting the role of estrogen (E2) as a master regulator of brain bioenergetics. Our previous studies demonstrated that in neurons, estrogen receptor beta (ERβ), not estrogen receptor alpha (ERα), co-localizes with mitochondria, and has a functional role in ATP production, indicating a cell type and ER subtype dependent regulation of brain bioenergetics. In this study, we investigated the differential transcriptomic response of key nodes involved in metabolism, nuclear-mitochondrial integration, energy sensing and redox sensing to E2 treatment.METHOD: To identify cell type-specific responses to estrogen treatment, rat embryonic primary neurons and enriched astrocytes were treated with 10nM E2 for 24 hours. To identify the contribution of ER subtypes, cells were treated with either ERα selective antagonist (MPP), or ERβ selective antagonist (PHTPP) prior to E2 treatment. Gene expression profiles for key regulators were determined by RNA-Seq.
    RESULT: Estrogen transcriptomic regulation of bioenergetics and metabolism, PI3K and AKT signaling, substrate transport, and redox sensing was evident in both cell types, with a stronger effect in neurons than in astrocytes. Estrogen transcriptomic regulation of key metabolic enzymes are further ER subtype specific. In neurons, both ERα and ERβ inhibition led to disruption of TCA cycle and activation of fatty acid and cholesterol metabolism compared to unopposed E2 treatment, whereas in astrocytes, ERα inhibition tended to activate ketone body metabolism while ERβ inhibition tended to activate fatty acid and cholesterol metabolism.
    CONCLUSION: Our analyses indicated that estrogen regulation of metabolism, nuclear-mitochondrial integration, energy sensing and redox sensing is cell type specific, with an overall stronger impact in neurons than in astrocytes. Further, neuronal vs astrocytic dependent responses to estrogen are ER subtype specific.
    DOI:  https://doi.org/10.1002/alz.055545
  4. Front Nutr. 2021 ;8 812119
    Encapsulation of Docosahexaenoic Acid Oil Substantially Improves the Oxylipin Profile of Rat Tissues.
    Jun Wang, Jordane Ossemond, Yann Le Gouar, Françoise Boissel, Didier Dupont, Frédérique Pédrono.
      Docosahexaenoic acid (DHA) is a major n-3 polyunsaturated fatty acid (PUFA) particularly involved in cognitive and cardiovascular functions. Due to the high unsaturation index, its dietary intake form has been considered to improve oxidation status and to favor bioaccessibility and bioavailability as well. This study aimed at investigating the effect of DHA encapsulated with natural whey protein. DHA was dietary provided as triacylglycerols to achieve 2.3% over total fatty acids. It was daily supplied to weanling rats for four weeks in omelet as food matrix, consecutively to a 6-hour fasting. First, when DHA oil was encapsulated, consumption of chow diet was enhanced leading to promote animal growth. Second, the brain exhibited a high accretion of 22.8% DHA, which was not improved by dietary supplementation of DHA. Encapsulation of DHA oil did not greatly affect the fatty acid proportions in tissues, but remarkably modified the profile of oxidized metabolites of fatty acids in plasma, heart, and even brain. Specific oxylipins derived from DHA were upgraded, such as Protectin Dx in heart and 14-HDoHE in brain, whereas those generated from n-6 PUFAs were mainly mitigated. This effect did not result from oxylipins measured in DHA oil since DHA and EPA derivatives were undetected after food processing. Collectively, these data suggested that dietary encapsulation of DHA oil triggered a more efficient absorption of DHA, the metabolism of which was enhanced more than its own accretion in our experimental conditions. Incorporating DHA oil in functional food may finally improve the global health status by generating precursors of protectins and maresins.
    Keywords:  DHA; brain; encapsulation; heart; oxylipin; rat
    DOI:  https://doi.org/10.3389/fnut.2021.812119
  5. Alzheimers Dement. 2021 Dec;17 Suppl 3 e056456
    Allopregnanolone potentiates bioenergetic capacity and mitochondrial biogenesis in astrocytes.
    Tian Wang, Shuhua Chen, Zisu Mao, Yuan Shang, Roberta Diaz Brinton.
      BACKGROUND: We reported previously that the neurosteroid allopregnanolone (Allo) promotes neural stem cell regeneration and differentiation, reverses neurogenic, metabolic and cognitive deficits and reduces Alzheimer's disease (AD) pathology in a mouse model of AD. To further investigate the cell-type specific mechanisms of Allo in regulating brain energy metabolism, we assessed the effect of Allo on mitochondrial bioenergetic profile and biogenesis in rat hippocampal astrocytes.METHOD: E18 rat hippocampal astrocyte were cultured for 10 days in DMEM:F12(1:1) with 10% FBS and then starved in 10% Charcoal stripped-FBS / DMEM:F12 for 24 hours before treatment with 100nM Allo or 0.001% Vehicle overnight. Upon completion of treatment, cells were subject to morphological, biochemical, metabolic and transcriptomic characterization of their mitochondrial phenotypes.
    RESULT: In primary hippocampal astrocytes, Allo significantly attenuates serum deprivation-induced bioenergetic deficits and oxidative stress by enhancing mitochondrial biogenesis and rebalancing mitochondrial dynamics. Allo treatment significantly enhances astrocytic mitochondrial biogenesis via Nrf1/Tfam signaling and reverses mitochondrial hyperfusion by elevating the ratio of mitochondrial fission protein Drp1 to the fusion protein Opa1. Functionally, Allo-induced improvement in bioenergetic function is coupled with reduced inflammasome activation in astrocytes.
    CONCLUSION: Outcomes of our findings further support the promising therapeutic effects of Allo against bioenergetic deficits that emerge in early phases of AD, with mitochondria being a major effector.
    DOI:  https://doi.org/10.1002/alz.056456
  6. Alzheimers Dement. 2021 Dec;17 Suppl 3 e054355
    ApoE4 confers mitochondrial substrate oxidation defects that can be bioenergetically compensated by a ketogenic substrate beta-hydroxy butyrate (BHB).
    Chase Garcia, Alexey Tomilov, Jose Sandoval, Gino A Cortopassi.
      BACKGROUND: Mitochondria are at the center of neural biogenergetics, and ApoE4 is the single most impactful risk factor for AD. We investigated the impact of ApoE on insulin sensitivity, on mitochondrial substrate utilization and bioenergetics. Persons with ApoE4 have reduced brain carbohydrate metabolism. To test for ApoE4 conferred neural mitochondrial metabolic differences, we constructed a novel stable-ApoE 2,3 and 4 N2a cell model, and tested ApoE's effects on Insulin sensitivity, and mitochondrial glucose, lipid and ketone oxidation.METHOD: Binding of ApoE isoforms E2, E3 and E4 to Insulin Receptor (IR) was measured by BLI and Co-IP, the impact of ApoE isoforms on mitochondrial glucose and lipid oxidation was measured by Seahorse.
    RESULT: ApoE3 was found to sensitize to insulin about 2-fold more potently than ApoE4. ApoE isoforms directly bind Insulin Receptor; the binding constants was in the range 200-300nM. Consistent with the previous insulin-sensitivity finding, ApoE3 caused a significant increase of the glycolytic rate and glucose oxidation relative to ApoE4. As there was no difference in oxidation of TCA cycle intermediates substrates in permeabilized cells, we infer ApoE3's glucose advantage is the result of increased insulin sensitivity. ApoE4 contributed a significant palmitate oxidation defect relative to ApoE2 and ApoE3. As this palmitate oxidation defect was observed in both mitochondria and cells it is likely to occur at or within mitochondria. We observed that the relative defect in ApoE4-dependent glucose and palmitate oxidation can be overcome by 5mM BHB. Thus, at the neural cell level, the metabolic defects contributed by ApoE 4 appear to be rescued by a ketogenic molecule, BHB, that requires neither insulin nor apolipoprotein particle to reach neural mitochondria and provide alternative metabolic support.
    CONCLUSION: ApoE4 confers 'double trouble' in mitochondrial glucose and lipid oxidation. ApoE4 confers a defect in mitochondrial lipid oxidation relative to all other isoforms. Simultaneously, ApoE4 lacks the benefit in glucose oxidation conferred by ApoE3, which appears to be driven by the reduced insulin sensitization potency of ApoE4. We also find that BHB can be an alternative source of neural bioenergy that enters mitochondria directly and thus is not affected by ApoE4 'double trouble'.
    DOI:  https://doi.org/10.1002/alz.054355
  7. Alzheimers Dement. 2021 Dec;17 Suppl 3 e049489
    Fatty acid-binding protein 3 knockout mice exhibit astrocyte-mediated neuroinflammation and cognitive impairment.
    Yijun Pan, Yoshiteru Kagawa, Yuji Owada, Joseph Nicolazzo.
      BACKGROUND: Fatty acid-binding protein 3 (FABP3) levels in the human cerebrospinal fluid elevate at early phases of Alzheimer's disease (AD), which is associated with reduced FABP3 levels in the brain and the onset of cognitive deterioration. However, it is unclear if reduced FABP3 levels in the brain can attribute to AD-like symptoms and pathology.METHOD: The cognitive function of FABP3 knockout (KO) and wildtype (WT) mice (15-week-old females) has been assessed using a battery of behavioural assessment tools, and the brain cytokines were subsequently assessed. Astrocytes were isolated from FABP3 KO and WT mice and cell metabolism and genes associated with metabolism and cytokines were examined.
    RESULT: FABP3 KO mice displayed deficits in short-term spatial memory (Fig 1A, 1B) and working memory (Fig 1C), which is associated with elevated IL-1β and TNF-α levels in the brain (Fig 1D). A significant decrease in glucose cellular uptake (Fig 2A) and metabolism (Fig 2B) and increase in fatty acid oxidation (Fig 2C) was demonstrated in FABP3 KO in relative to WT astrocytes. Genes responsible for fatty acid oxidation (carnitine palmitoyltransferase 1A) and transport (CD36) are upregulated in FABP3KO astrocytes (Fig 2D). In addition, IL-1β and TNFα mRNA in FABP3KO astrocytes increases by 3-fold and 4-fold, respectively (Fig 2D).
    CONCLUSION: This study demonstrates for the first time that FABP3 genetic knockout modifies astrocyte activities, which leads to AD-like pathology in mouse including elevated pro-inflammatory cytokine levels in the brain and cognitive dysfunction.
    DOI:  https://doi.org/10.1002/alz.049489
  8. Neurochem Res. 2022 Jan 31.
    Clonidine and Brain Mitochondrial Energy Metabolism: Pharmacodynamic Insights Beyond Receptorial Effects.
    Roberto Federico Villa, Antonella Gorini, Federica Ferrari.
      Clonidine is an anti-hypertensive drug that inhibits the release of norepinephrine from pre-synaptic terminals binding to pre-synaptic α2-adrenoreceptors. Some studies suggest that this drug decreases brain energy expenditure, particularly in hypoxic-ischemic injury. However, data about clonidine effects on the functional parameters regulating brain energy metabolism are lacking. In this study, the effects of acute clonidine treatment (5 μg×kg-1 i.p., 30 min) were evaluated on the catalytic activity of regulatory energy-linked enzymes of Krebs' cycle, Electron Transport Chain and glutamate metabolism of temporal cerebral cortex of 3-month-old male Sprague-Dawley rats. Enzyme activities were assayed on non-synaptic "free" mitochondria (FM) of neuronal perikaryon and partly of glial cells, and on intra-synaptic "light" (LM) and "heavy" mitochondria (HM), localized within synaptic terminals. This subcellular analysis differentiates clonidine effects on post-synaptic and pre-synaptic neuronal compartments. The results showed that clonidine increased citrate synthase, cytochrome oxidase and glutamate-oxaloacetate transaminase activities of FM. In LM, citrate synthase activity was decreased, while cytochrome oxidase and glutamate-oxaloacetate transaminase activities were increased; on the contrary, citrate synthase, cytochrome oxidase and glutamate dehydrogenase were all decreased in HM. Therefore, clonidine exerted different effects with respect to brain mitochondria, coherently with the in vivo energy requirements of each synaptic compartment: the drug increased energy-linked enzyme activities in post-synaptic compartment, while the metabolic variations were complex in the pre-synaptic one, being enzyme activities heterogeneously modified in LM and decreased in HM. This study highlights the relationships existing between the clonidine-induced neuroreceptorial effects and the energy metabolism in pre- and post- synaptic bioenergetics.
    Keywords:  Brain energy metabolism; Clonidine; Enzymes; Glutamate; Mitochondria; Neuroprotection
    DOI:  https://doi.org/10.1007/s11064-022-03541-z
  9. Aging Dis. 2022 Feb;13(1): 267-283
    Cognitive Impairment and Metabolite Profile Alterations in the Hippocampus and Cortex of Male and Female Mice Exposed to a Fat and Sugar-Rich Diet are Normalized by Diet Reversal.
    Alba M Garcia-Serrano, Adélaïde A Mohr, Juliette Philippe, Cecilia Skoug, Peter Spégel, João M N Duarte.
      Diabetes impacts on brain metabolism, structure, and function. Alterations in brain metabolism have been observed in obesity and diabetes models induced by exposure to diets rich in saturated fat and/or sugar and have been linked to memory impairment. However, it remains to be determined whether brain dysfunction induced by obesogenic diets results from permanent brain alterations. We tested the hypothesis that an obesogenic diet (high-fat and high-sucrose diet; HFHSD) causes reversible changes in hippocampus and cortex metabolism and alterations in behavior. Mice were exposed to HFHSD for 24 weeks or for 16 weeks followed by 8 weeks of diet normalization. Development of the metabolic syndrome, changes in behavior, and brain metabolite profiles by magnetic resonance spectroscopy (MRS) were assessed longitudinally. Control mice were fed an ingredient-matched low-fat and low-sugar diet. Mice fed the HFHSD developed obesity, glucose intolerance and insulin resistance, with a more severe phenotype in male than female mice. Relative to controls, both male and female HFHSD-fed mice showed increased anxiety-like behavior, impaired memory in object recognition tasks, but preserved working spatial memory as evaluated by spontaneous alternation in a Y-maze. Alterations in the metabolite profiles were observed both in the hippocampus and cortex but were more distinct in the hippocampus. HFHSD-induced metabolic changes included altered levels of lactate, glutamate, GABA, glutathione, taurine, N-acetylaspartate, total creatine and total choline. Notably, HFHSD-induced metabolic syndrome, anxiety, memory impairment, and brain metabolic alterations recovered upon diet normalization for 8 weeks. In conclusion, cortical and hippocampal derangements induced by long-term HFHSD consumption are reversible rather than being the result of permanent tissue damage.
    Keywords:  anxiety; brain metabolism; diabetes; high-fat; memory; obesity; sucrose
    DOI:  https://doi.org/10.14336/AD.2021.0720
  10. Alzheimers Dement. 2021 Dec;17 Suppl 3 e055478
    Aberrant protein palmitoylation: A new route involved in Alzheimer's disease.
    Salvatore Fusco, Francesca Natale, Walter Gulisano, Matteo Spinelli, Marco Rinaudo, Giuseppe Aceto, Francesco Greca, Daniela Puzzo, Claudio Grassi.
      BACKGROUND: Growing evidence points to altered metabolic signals as a risk factor for Alzheimer's disease (AD). The high fatty acid levels and brain insulin resistance (BIR) found in AD brains may impinge on protein palmitoylation (P-S-palm), a post-translational modification critically involved in the regulation of neuronal protein localization and synaptic function. Our previous findings highlighted the critical role of aberrant palmitoylation in BIR-dependent memory impairment (Spinelli et al., 2017).METHOD: We tested the effect of chronic intranasal injection of the palmitoylation inhibitor 2-bromopalmitate (2BP) on a large cohort of male and female 3xTg-AD mice, starting from 3 months of age, by performing cognitive (novel object recognition and object displacement tests), electrophysiological (LTP), immunohistochemical (Abeta deposition) and molecular analyses (Abeta measurement by ELISA). We also analyzed the palmitoyl-proteome (by acyl biotin exchange assay and mass-spectrometry) in the hippocampus of 9-month-old wild type, 3xTg-AD and 2BP-treated 3xTg-AD mice.
    RESULT: 2BP delayed the onset of memory deficits in both male and female 3xTg-AD mice. More importantly, 2BP significantly enhanced cognitive performances in 6-, 9- and 12-month-old animals. Accordingly, electrophysiological analyses on hippocampal brain slices from 2BP-treated 3xTg-AD mice revealed greater long-term potentiation at CA3-CA1 synapses. In addition, 2BP mice showed lower Abeta deposition in hippocampus. Finally, palmitoyl-proteome analysis revealed a large number of proteins involved in APP and tau metabolism, synaptic plasticity and brain metabolism aberrantly palmitoylated in the AD mouse model and reverted by 2BP.
    CONCLUSION: Our data indicate that aberrant palmitoylation plays a critical role in the onset and progression of AD and reveal novel targets of protein palmitoylation potentially involved in the development of neurodegeneration and dementia. This is also the first preclinical study on the effect of 2BP on AD-related cognitive decline.
    DOI:  https://doi.org/10.1002/alz.055478
  11. Alzheimers Dement. 2021 Dec;17 Suppl 3 e052401
    Bitter brain: Hypoglycemia and the pathology of neurodegeneration and dementia.
    Vyshnavy Balendra, Josephine C Esposto, Niklas Reich.
      BACKGROUND: Glucose poses the predominant energy source of the brain and its continuous uptake is vital for optimal brain function. Neurons metabolize glucose to generate adenosine triphosphate via glycolysis and the tricarboxylic acid cycle, whereas astrocytes utilize glucose both as an energy source and to generate glutamine - a neurotransmitter precursor- for neurons [Brekke et al., 2015]. Here, we prospectively examine the relationship between chronic hypoglycemia and the associated links between neurodegeneration and dementia. It is proposed that severe episodes or chronic hypoglycemia will induce an increased risk of dementia.METHODS: A complex and specific literature search was conducted across various scientific, international databases for English, peer-reviewed articles and reviews published in the last two decades using the following terms: diabetes, insulin, glucose metabolism, hypoglycemia, and Alzheimer's disease (AD). Case reports were excluded. The main objectives were predominantly focused on animal- or human-based studies.
    RESULTS: When blood glucose levels are <55 mg/dL, neurons in the cerebral cortex and hippocampus experience synaptic dysfunction, with neurons in the basal ganglia and thalamus affected in parallel [Mergenthaler et al., 2014]. Evidence shows that chronic hypoglycemia leads to severe neuronal death as well as a significant decline in cognitive performance, spatial learning and memory [Bree et al., 2009; Page et., 2009; Suh et al., 2007]. Hypoglycemia induces oxidative injury in hippocampal dendrites, resulting in impaired synaptic plasticity, reduced MAP2 intensity and thickness in the stratum radiatum of the hippocampal CA1 region and microgliosis in the hippocampus and cerebral cortex [Won, et al., 2012]. A population-based cross-sectional study showed chronic hypoglycemia to have a 2-fold increased risk for developing dementia with poor late-life cognition, independent of premorbid cognition[Yaffe et al., 2013].
    CONCLUSION: Recent evidence indicates that chronic hypoglycemia poses a risk factor for dementia, accelerating the progression of tau hyperphosphorylation, Aβ aggregation, cognitive dysfunction and AD. Understanding the pathologic mechanisms of hypoglycemia and monitoring the plasma glucose levels may be key factors in the prevention of AD and dementia.
    DOI:  https://doi.org/10.1002/alz.052401
  12. Alzheimers Dement. 2021 Dec;17 Suppl 3 e057493
    Minocycline as a therapeutic strategy against the brain dysfunctions induced by hypercholesterolemia.
    Julia Nostrani Martins, Matheus Scarpatto Rodrigues, Hemelin Resende Farias, Matheus Henrique Rossoni Fossá, Tainá Schons, Josiane Budni, Andreza Fabro de Bem, Jade de Oliveira.
      BACKGROUND: About 40% of adults have elevated plasma cholesterol levels, making hypercholesterolemia a critical health issue. Clinical and experimental evidence have shown that hypercholesterolemia contributes to the development of neuropathologies. Mechanisms such as blood-brain barrier dysfunction and neuroinflammation seem to connect hypercholesterolemia to brain changes related to these neuropathologies. Minocycline, an antibiotic compound of the tetracycline class, has shown significant neuroprotective effects in experimental studies, particularly on the inhibition of microglial activation. In this sense, we hypothesized that minocycline could display beneficial effects in the cognitive deficits related to hypercholesterolemia.METHOD: In this study, CF-1 male and female adult young (3 months old) mice were treated with either a standard diet or a high cholesterol diet (2.5% of cholesterol). After four weeks, the animals also received minocycline or 0.9% saline by oral gavage once a day for another four weeks, totaling eight weeks of the experimental period. Next, the animals were subjected to behavioral tests, such as object recognition, splash test, and cataleptic posture. After that, the glucose tolerance test was performed, and the plasma was collected for the further performance of the biochemical analysis.
    RESULT: Eight weeks of high cholesterol diet consumption caused an increase in the total plasma cholesterol levels of animals, which were reduced by the treatment with minocycline. Both diet and minocycline did not affect the plasma glucose levels and the glucose tolerance of animals. Also, hypercholesterolemic mice exhibited a higher body weight, weight gain, and adiposity index at the end of the experimental period. However, these parameters were not affected by the minocycline treatment. Regarding the behavioral tests, hypercholesterolemia in mice was related to a significant deficit in recognition memory and cataleptic posture, which were improved by minocycline treatment. In addition, hypercholesterolemia induced depressive-like behavior in mice, reflected by less grooming time on the splash test, which was not changed by the minocycline treatment.
    CONCLUSION: Therefore, our results show that administration of minocycline presented promising effects in ameliorating the cognitive and behavioral deficits related to hypercholesterolemia, demonstrating that microglial activation might play a role in the memory deficits induced by this metabolic disease.
    DOI:  https://doi.org/10.1002/alz.057493
  13. Neurochem Res. 2022 Jan 31.
    Effects of Chronic Arginase Inhibition with Norvaline on Tau Pathology and Brain Glucose Metabolism in Alzheimer's Disease Mice.
    Baruh Polis, Margherita Squillario, Vyacheslav Gurevich, Kolluru D Srikanth, Michael Assa, Abraham O Samson.
      Alzheimer's disease (AD) is an insidious neurodegenerative disorder representing a serious continuously escalating medico-social problem. The AD-associated progressive dementia is followed by gradual formation of amyloid plaques and neurofibrillary tangles in the brain. Though, converging evidence indicates apparent metabolic dysfunctions as key AD characteristic. In particular, late-onset AD possesses a clear metabolic signature. Considerable brain insulin signaling impairment and a decline in glucose metabolism are common AD attributes. Thus, positron emission tomography (PET) with glucose tracers is a reliable non-invasive tool for early AD diagnosis and treatment efficacy monitoring. Various approaches and agents have been trialed to modulate insulin signaling. Accumulating data point to arginase inhibition as a promising direction to treat AD via diverse molecular mechanisms involving, inter alia, the insulin pathway. Here, we use a transgenic AD mouse model, demonstrating age-dependent brain insulin signaling abnormalities, reduced brain insulin receptor levels, and substantial energy metabolism alterations, to evaluate the effects of arginase inhibition with Norvaline on glucose metabolism. We utilize fluorodeoxyglucose whole-body micro-PET to reveal a significant treatment-associated increase in glucose uptake by the brain tissue in-vivo. Additionally, we apply advanced molecular biology and bioinformatics methods to explore the mechanisms underlying the effects of Norvaline on glucose metabolism. We demonstrate that treatment-associated improvement in glucose utilization is followed by significantly elevated levels of insulin receptor and glucose transporter-3 expression in the mice hippocampi. Additionally, Norvaline diminishes the rate of Tau protein phosphorylation. Our results suggest that Norvaline interferes with AD pathogenesis. These findings open new avenues for clinical evaluation and innovative drug development.
    Keywords:  Energy metabolism; Functional brain imaging; GLUT3; Glucose uptake; Insulin receptor; Tau protein
    DOI:  https://doi.org/10.1007/s11064-021-03519-3
  14. Prog Neuropsychopharmacol Biol Psychiatry. 2022 Jan 29. pii: S0278-5846(22)00010-0. [Epub ahead of print]116 110518
    Evidence of methylphenidate effect on mitochondria, redox homeostasis, and inflammatory aspects: Insights from animal studies.
    Luiza N Foschiera, Felipe Schmitz, Angela T S Wyse.
      Methylphenidate (MPH) is a central nervous system (CNS) stimulant known for its effectiveness in the treatment of Attention Deficit Hyperactivity Disorder (ADHD), a neuropsychiatric condition that has a high incidence in childhood and affects behavior and cognition. However, the increase in its use among individuals who do not present all the diagnostic criteria for ADHD has become a serious public health problem since the neurological and psychiatric consequences of this unrestricted use are not widely known. In addition, since childhood is a critical period for the maturation of the CNS, the high prescription of MPH for preschool children also raises several concerns. This review brings new perspectives on how MPH (in different doses, routes of administration and ages) affects the CNS, focusing on animal studies that evaluated changes in mitochondrial (bioenergetics), redox balance and apoptosis, as well as inflammatory parameters. MPH alters brain energy homeostasis, increasing glucose consumption and impairing the activity of enzymes in the Krebs cycle and electron transport chain, as well as ATP levels and Na+,K+-ATPase activity. MPH induces oxidative stress, increasing the levels of reactive oxygen and nitrogen species and altering enzymatic and non-enzymatic antioxidant defenses, which, consequently, is related to damage to proteins, lipids, and DNA. Among the harmful effects of MPH, studies also demonstrate its ability to induce inflammation as well as alter the apoptosis pathway. It is important to highlight that age, treatment time, administration route, and dose are factors that can influence MPH effects. However, young animals seem to be more susceptible to damage caused by MPH. It is possible that changes in mitochondrial function and markers of status oxidative, apoptosis and inflammation may be exerting important mechanisms associated with MPH toxicity and, therefore, the unrestricted use of this drug can cause brain damage.
    Keywords:  Apoptosis; Inflammation; Methylphenidate; Mitochondrial dysfunction; Oxidative stress
    DOI:  https://doi.org/10.1016/j.pnpbp.2022.110518
  15. J Prev Alzheimers Dis. 2022 ;9(1): 54-66
    Ketone Ester Effects on Biomarkers of Brain Metabolism and Cognitive Performance in Cognitively Intact Adults ≥ 55 Years Old. A Study Protocol for a Double-Blinded Randomized Controlled Clinical Trial.
    K I Avgerinos, R J Mullins, J M Egan, D Kapogiannis.
      BACKGROUND: Ketone bodies have been proposed as an "energy rescue" for the Alzheimer's disease (AD) brain, which underutilizes glucose. Prior research has shown that oral ketone monoester (KME) safely induces robust ketosis in humans and has demonstrated cognitive-enhancing and pathology-reducing properties in animal models of AD. However, human evidence that KME may enhance brain ketone metabolism, improve cognitive performance and engage AD pathogenic cascades is scarce.OBJECTIVES: To investigate the effects of ketone monoester (KME) on brain metabolism, cognitive performance and AD pathogenic cascades in cognitively normal older adults with metabolic syndrome and therefore at higher risk for AD.
    DESIGN: Double-blinded randomized placebo-controlled clinical trial.
    SETTING: Clinical Unit of the National Institute on Aging, Baltimore, US.
    PARTICIPANTS: Fifty cognitively intact adults ≥ 55 years old, with metabolic syndrome.
    INTERVENTION: Drinks containing 25 g of KME or isocaloric placebo consumed three times daily for 28 days.
    OUTCOMES: Primary: concentration of beta-hydroxybutyrate (BHB) in precuneus measured with Magnetic Resonance Spectroscopy (MRS). Exploratory: plasma and urine BHB, multiple brain and muscle metabolites detected with MRS, cognition assessed with the PACC and NIH toolbox, biomarkers of AD and metabolic mediators in plasma extracellular vesicles, and stool microbiome.
    DISCUSSION: This is the first study to investigate the AD-biomarker and cognitive effects of KME in humans. Ketone monoester is safe, tolerable, induces robust ketosis, and animal studies indicate that it can modify AD pathology. By conducting a study of KME in a population at risk for AD, we hope to bridge the existing gap between pre-clinical evidence and the potential for brain-metabolic, pro-cognitive, and anti-Alzheimer's effects in humans.
    Keywords:  Alzheimer’s disease; Ketosis; cognition; extracellular vesicles; ketone ester; magnetic resonance spectroscopy; metabolic syndrome
    DOI:  https://doi.org/10.14283/jpad.2022.3
  16. Sci Rep. 2022 Feb 02. 12(1): 1820
    Sex- and estrous-cycle dependent dorsal hippocampal phosphoproteomic changes induced by low-dose ketamine.
    Samantha K Saland, Kathrin Wilczak, Edward Voss, TuKiet T Lam, Mohamed Kabbaj.
      Numerous emotional and cognitive processes mediated by the hippocampus present differences between sexes and can be markedly influenced by hormonal status in males and females of several species. In rodents, the dorsal hippocampus (dHPC) is known to contribute to the rapid antidepressant actions of the NMDA receptor antagonist ketamine. We and others have demonstrated a greater sensitivity to the fast-acting antidepressant ketamine in female versus male rats that is estrogen- and progesterone-dependent. However, the underlying mechanisms remain unclear. Using an acute low dose (2.5 mg/kg) of ketamine that is behaviorally effective in female but not male rats, a label-free phosphoproteomics approach was employed to identify ketamine-induced changes in signaling pathway activation and phosphoprotein abundance within the dHPC of intact adult male rats and female rats in either diestrus or proestrus. At baseline, males and females showed striking dissimilarities in the dHPC proteome and phosphoproteome related to synaptic signaling and mitochondrial function-differences also strongly influenced by cycle stage in female rats. Notably, phosphoproteins enriched in PKA signaling emerged as being both significantly sex-dependent at baseline and also the primary target of ketamine-induced protein phosphorylation selectively in female rats, regardless of cycle stage. Reduced phosphoprotein abundance within this pathway was observed in males, suggesting bi-directional effects of low-dose ketamine between sexes. These findings present biological sex and hormonal milieu as critical modulators of ketamine's rapid actions within this brain region and provide greater insight into potential translational and post-translational processes underlying sex- and hormone-dependent modulation of ketamine's therapeutic effects.
    DOI:  https://doi.org/10.1038/s41598-022-05937-x
  17. Front Nutr. 2021 ;8 807970
    Efficacy and Safety of Ketone Supplementation or Ketogenic Diets for Alzheimer's Disease: A Mini Review.
    Matthieu Lilamand, François Mouton-Liger, Emmanuelle Di Valentin, Marta Sànchez Ortiz, Claire Paquet.
      Alzheimer's disease (AD) is the most frequent age-related neurodegenerative disorder, with no curative treatment available so far. Alongside the brain deposition of β-amyloid peptide and hyperphosphorylated tau, neuroinflammation triggered by the innate immune response in the central nervous system, plays a central role in the pathogenesis of AD. Glucose usually represents the main fuel for the brain. Glucose metabolism has been related to neuroinflammation, but also with AD lesions. Hyperglycemia promotes oxidative stress and neurodegeneration. Insulinoresistance (e.g., in type 2 diabetes) or low IGF-1 levels are associated with increased β-amyloid production. However, in the absence of glucose, the brain may use another fuel: ketone bodies (KB) produced by oxidation of fatty acids. Over the last decade, ketogenic interventions i.e., ketogenic diets (KD) with very low carbohydrate intake or ketogenic supplementation (KS) based on medium-chain triglycerides (MCT) consumption, have been studied in AD animal models, as well as in AD patients. These interventional studies reported interesting clinical improvements in animals and decrease in neuroinflammation, β-amyloid and tau accumulation. In clinical studies, KS and KD were associated with better cognition, but also improved brain metabolism and AD biomarkers. This review summarizes the available evidence regarding KS/KD as therapeutic options for individuals with AD. We also discuss the current issues and potential adverse effects associated with these nutritional interventions. Finally, we propose an overview of ongoing and future registered trials in this promising field.
    Keywords:  Alzheimer's disease; ketogenic diet; ketone bodies; medium chain triglycerides; nutrition
    DOI:  https://doi.org/10.3389/fnut.2021.807970
  18. Alzheimers Dement. 2021 Dec;17 Suppl 3 e054793
    The metabolic landscape of brain alterations in Alzheimer's disease.
    Richa Batra, Matthias Arnold, Gabi Kastenmüller, Mariet Allen, Xue Wang, David A Bennett, Nilüfer Ertekin-Taner, Rima F Kaddurah-Daouk, Jan Krumsiek.
      BACKGROUND: Impairment of brain glucose metabolism has been frequently described in Alzheimer's disease (AD). Moreover, the strongest predictor of the lifetime incidence of AD is the ε4 allele of APOE, a protein involved in lipid metabolism. These connections between AD and metabolism provide motivation to perform an in-depth metabolic profiling of human brain tissue for different stages of AD pathophysiology.METHOD: Brain tissue samples were obtained from the Religious Orders Study and Memory and Aging Project (ROS/MAP) at the Rush Alzheimer's Disease Center. Furthermore, ROS/MAP collects extensive phenotyping of the participants' cognitive trajectories as well as postmortem pathology. Metabolic profiling was performed on Metabolon's untargeted platform, yielding 1,055 quantified metabolites. Generalized linear models with appropriate linkage functions for continuous or categorical AD-related phenotypes were used to discover the association of metabolic profiles with AD-related phenotypes, such as amount of amyloid and tangles in brain, global burden of pathology, NIA-Reagan score, diagnosis (derived from Braak and CERAD scores), clinical diagnosis at the time of death, global cognition assessed during the visit before death, estimated decline of global cognition over lifetime. The models included confounder correction for age, gender, body mass index, years of education, post mortem interval, number of APOEε4 alleles, and medications.
    RESULT: We found 263 metabolites to be significantly associated (adjusted p-value <0.05) with one of the AD phenotypes. 137 of these metabolites were significantly associated with three or more phenotypes. Of these, nine could be replicated using an independent autopsy cohort from Mayo Clinic, five could also be replicated using a published study based on Baltimore Longitudinal Study of Aging cohort. The associated metabolites are involved in various metabolic processes known to be involved in AD pathogenesis, such as amino acid metabolism, urea cycle, and polyamine metabolism. In addition, we have identified several novel associations that could uncover the interdependence of different AD-associated metabolic processes.
    CONCLUSION: We have generated a comprehensive landscape of AD-associated metabolites and associated processes. These will be instrumental to fill the gap in our understanding of the metabolic components of AD pathophysiology.
    DOI:  https://doi.org/10.1002/alz.054793
  19. Alzheimers Dement. 2021 Dec;17 Suppl 3 e054326
    Human gray and white matter metabolomics to differentiate APOE-dependent metabolic changes in early and late Alzheimer's disease.
    Tyler C Hammond, Stephanie Ham, Lucille M Yanckello, Arnold Stromberg, Peter T Nelson, Ai-Ling Lin.
      BACKGROUND: Many have suggested that irregularities in metabolism play an underlying role in the progression of Alzheimer's Disease (AD). A detailed knowledge of the biochemical composition of AD brain tissue vs normal brain tissue will be key in understanding the metabolic processes underlying AD, especially as they relate to APOE genotype. Here we perform a metabolomics analysis on the brain tissue of a large cohort of community-based participants in the UK-ADC brain bank to characterize the biochemical profiles of brains with and without Alzheimer's disease and other mixed pathologies based on APOE genotype and disease stage.METHOD: The global biochemical profiles of post-mortem human brain tissue from the gray matter of Brodmann area 9 was determined using mass spectroscopy. Brain tissue from 158 community-based older adult volunteers was analyzed. Metabolites were quantified using global untargeted metabolomics (HD4) and compared between cohorts using Welch's two-sample t-test to approximate fold change of metabolites between disease stage and APOE genotype. Random forest was used to rank metabolites in order of importance for predicting AD presence in tissue.
    RESULT: Late stage disease in the APOE E4 genotype has decreases in lysophospholipids, long chain polyunsaturated fatty acids, endocannabinoids, and branched fatty acids as well as N-acetylserine in the gray matter. Late stage disease in the APOE E4 genotype has increases in phospholipid metabolism and decreases in amino acid metabolism and Vitamin B6. The APOE E4 genotype is associated with increases in gamma-glutamyl amino acids, lysophospholipid, and amino acid metabolism and decreases in urea cycle, sterol, stachydrine, and benzoate metabolism during early stages of disease, but that there are few metabolic differences between genotypes in later disease. Alzheimer's disease has increases in phospholipid metabolism and decreases in amino acid metabolism compared to normal.
    CONCLUSION: Early stage disease showed many metabolic differences between genotypes and late stage tissues looked remarkably similar across genotype. This suggests there may be metabolically distinct pathways that each genotype takes to produce a tissue with common endpoint of disease characterized by an AD biochemical profile. Further studies are needed to examine whether these metabolites are consistently altered in Alzheimer's disease.
    DOI:  https://doi.org/10.1002/alz.054326
  20. Alzheimers Dement. 2021 Dec;17 Suppl 3 e054236
    Molecular effects of intranasal insulin in the rodent brain: Examination of insulin receptor signaling and the glutamatergic system.
    Jennifer M Erichsen, Jennifer L Woodruff, Claudia A Grillo, Lawrence P Reagan, James R Fadel.
      BACKGROUND: As brain insulin resistance has been identified as a pathological feature of age-related cognitive decline (ARCD), intranasal insulin (INI) is being explored as a potential treatment for patients with ARCD. Previous studies have demonstrated that INI enhances memory, but the underlying mechanisms remain unclear. To investigate the mechanistic basis for the pro-cognitive effects of INI, insulin receptor (IR) signaling and the expression of glutamate receptors and transporters, due to the role of the glutamatergic system in hippocampal synaptic transmission, was examined.METHOD: Adult male Sprague-Dawley rats received bilateral hippocampal injections of a control lentiviral vector (LV-Con) or a lentivirus containing a selective insulin receptor antisense sequence (LV-IRAS) to induce hippocampal-specific insulin resistance. Seven months later, these animals were administered INI 30 minutes before euthanasia. In a separate cohort of Fischer 344 x Brown Norway F1 hybrid male rats (no virus) we investigated the effects of acute and chronic (10 days) INI dosing paradigms in young (3 months old) and aged (26 months old) rats, with a final INI administration 30 minutes before euthanasia. In both experiments, the hippocampus was processed for immunoblot analysis to assess changes in central IR signaling and phosphorylation/expression of glutamate receptor subunits and transporters.
    RESULT: We previously observed that LV-IRAS injection selectively downregulated hippocampal IR expression and insulin-stimulated IR phosphorylation without affecting peripheral insulin sensitivity. Additionally, LV-IRAS animals showed reduced hippocampal basal glutamate levels and decreased phosphorylation/expression of glutamate receptor subunits. In this study, vesicular glutamate transporter 2 (vGluT2) expression, but not vGluT1, was significantly decreased in the hippocampus of LV-IRAS animals after INI administration. In the other cohort, age- and dosing paradigm-dependent effects were observed vis-à-vis IR signaling and glutamate receptor phosphorylation/expression.
    CONCLUSION: More studies are needed to fully understand the mechanistic changes following INI and to determine the most effective treatment strategies, but these data indicate that INI may improve cognition through the enhancement of IR signaling in the brain and/or through exerting synaptic effects on glutamate neurotransmission. It is important to understand the mechanism of action, as INI could eventually be used in the broader clinical setting to treat ARCD.
    DOI:  https://doi.org/10.1002/alz.054236
  21. Front Integr Neurosci. 2021 ;15 747901
    Neuroprotective Effects of a Small Mitochondrially-Targeted Tetrapeptide Elamipretide in Neurodegeneration.
    Nguyen Thanh Nhu, Shu-Yun Xiao, Yijie Liu, V Bharath Kumar, Zhen-Yang Cui, Shin-Da Lee.
      Neural mitochondrial dysfunction, neural oxidative stress, chronic neuroinflammation, toxic protein accumulation, and neural apoptosis are common causes of neurodegeneration. Elamipretide, a small mitochondrially-targeted tetrapeptide, exhibits therapeutic effects and safety in several mitochondria-related diseases. In neurodegeneration, extensive studies have shown that elamipretide enhanced mitochondrial respiration, activated neural mitochondrial biogenesis via mitochondrial biogenesis regulators (PCG-1α and TFAM) and the translocate factors (TOM-20), enhanced mitochondrial fusion (MNF-1, MNF-2, and OPA1), inhibited mitochondrial fission (Fis-1 and Drp-1), as well as increased mitophagy (autophagy of mitochondria). In addition, elamipretide has been shown to attenuate neural oxidative stress (hydrogen peroxide, lipid peroxidation, and ROS), neuroinflammation (TNF, IL-6, COX-2, iNOS, NLRP3, cleaved caspase-1, IL-1β, and IL-18), and toxic protein accumulation (Aβ). Consequently, elamipretide could prevent neural apoptosis (cytochrome c, Bax, caspase 9, and caspase 3) and enhance neural pro-survival (Bcl2, BDNF, and TrkB) in neurodegeneration. These findings suggest that elamipretide may prevent the progressive development of neurodegenerative diseases via enhancing mitochondrial respiration, mitochondrial biogenesis, mitochondrial fusion, and neural pro-survival pathway, as well as inhibiting mitochondrial fission, oxidative stress, neuroinflammation, toxic protein accumulation, and neural apoptosis. Elamipretide or mitochondrially-targeted peptide might be a targeted agent to attenuate neurodegenerative progression.
    Keywords:  Bendavia; MTP-31; SS-31; brain; mitochondrial; neurodegeneration
    DOI:  https://doi.org/10.3389/fnint.2021.747901
  22. Alzheimers Dement. 2021 Dec;17 Suppl 3 e051539
    Mechanisms underlying cognitive impairment in a mouse model of familial hypercholesterolemia: Evidences of LDLr -/- mice.
    Matheus Scarpatto Rodrigues, Jade de Oliveira, Daiane F Engel, Gabriela C de Paula, Helen M Melo, Samantha C Lopes, Camila T Ribeiro, Alessandra Gonçalves Machado, Rachel Kss Bast, José Claudio F Moreira, Daniel P Gelain, Rui D Prediger, Eduardo Lg Moreira, Sergio Teixeira Ferreira, Andreza Fabro de Bem.
      BACKGROUND: Familial hypercholesterolemia (FH) is a genetic disorder caused by low-density lipoprotein receptor (LDLr) dysfunction, resulting in elevated plasma cholesterol levels. Previous reports have shown an interplay between LDLr and amyloid-β (Aβ) metabolism, a peptide linked to Alzheimer's disease. Indeed, LDLr-/- mice are more vulnerable to the deleterious memory impact induced by Aβ. Here, we investigated whether the gene expression of proteins involved in Aβ metabolism and Aβ content is altered in adult or middle-aged LDLr-/- mice brains. Also, we investigated neuroinflammation as well as neuronal and synaptic damage.METHOD: Young adult (3-month-old) and middle-aged (14-month-old) male C57BL/6 wild-type (WT) and LDLr-/- mice were first submitted to the Morris water maze test. After spatial memory assessment, the Aβ1-42 levels and gene expression of proteins involved in Aβ synthesis were evaluated in the prefrontal cortex (PFC) and hippocampus of 3 and 14-months-old WT and LDLr-/- mice. We also assessed the apoptosis signaling, levels of synaptic proteins, and Iba-1 immunoreactivity (a marker for microglia) in the experimental groups' brain structures.
    RESULT: LDLr-/- mice presented spatial memory impairment, which was more severe in middle-aged animals, which was not associated with altered expression of proteins involved in Aβ processing and Aβ1-42 levels in either hippocampus or PFC. We further found that the expression of the apoptotic protein Bax was increased in both the PFC and hippocampus of 3- and 14-month-old LDLr-/- mice. LDLr-/- mice presented increased immunoreactivity for activated caspase-3 in the neurons of the PFC and hippocampus. We also observed a reduction in immunocontent of PSD 95 in the hippocampus of 3-month-old LDLr-/- mice. Moreover, synaptophysin immunocontent was decreased in the middle-age LDLr-/- mice hippocampi. In addition, we observed that LDLr-/- mice displayed increased immunoreactivity for Iba-1 in the PFC already at 3 months of age and in the hippocampus at middle-age. Finally, we found that LDLr -/- at middle-age exhibited microglial morphological changes related to their activated state in the PFC.
    CONCLUSION: Cognitive impairments in LDLr-/- mice were associated with exacerbation of neuronal apoptosis, synaptic dysfunction, and microglial activation in brain regions related to memory formation, but not with significant changes in Aβ processing or levels.
    DOI:  https://doi.org/10.1002/alz.051539
  23. Glia. 2022 Feb 01.
    Brain H+ /CO2 sensing and control by glial cells.
    Alexander V Gourine, Nicholas Dale.
      Maintenance of constant brain pH is critically important to support the activity of individual neurons, effective communication within the neuronal circuits, and, thus, efficient processing of information by the brain. This review article focuses on how glial cells detect and respond to changes in brain tissue pH and concentration of CO2 , and then trigger systemic and local adaptive mechanisms that ensure a stable milieu for the operation of brain circuits. We give a detailed account of the cellular and molecular mechanisms underlying sensitivity of glial cells to H+ and CO2 and discuss the role of glial chemosensitivity and signaling in operation of three key mechanisms that work in concert to keep the brain pH constant. We discuss evidence suggesting that astrocytes and marginal glial cells of the brainstem are critically important for central respiratory CO2 chemoreception-a fundamental physiological mechanism that regulates breathing in accord with changes in blood and brain pH and partial pressure of CO2 in order to maintain systemic pH homeostasis. We review evidence suggesting that astrocytes are also responsible for the maintenance of local brain tissue extracellular pH in conditions of variable acid loads associated with changes in the neuronal activity and metabolism, and discuss potential role of these glial cells in mediating the effects of CO2 on cerebral vasculature.
    Keywords:  acid-base balance; carbon dioxide; pH; respiratory circuits
    DOI:  https://doi.org/10.1002/glia.24152
  24. Alzheimers Dement. 2021 Dec;17 Suppl 3 e052500
    Inhibition of 15-hydroxyprostaglandin dehydrogenase protects a mouse model of Alzheimer's disease without affecting amyloid pathology.
    Min-Kyoo Shin, Yeojung Koh, Edwin Vázquez-Rosa, Coral Cintrón-Pérez, Sanford Markowitz, Andrew A Pieper.
      BACKGROUND: The 15-hydroxyprostaglandin dehydrogenase (15-PGDH) enzyme inactivates the lipid signaling molecule prostaglandin E2 (PGE2) by oxidizing it to 15-keto PGE2. We have previously shown that genetic elimination or pharmacologic inhibition of 15-PGDH (via the small molecule (+)-SW033291) protects peripheral organs by potentiating PGE2-mediated stem cell responses (1). Here, we investigate whether 15-PGDH expression in the brain is related to pathology in the 5xFAD mouse model of Alzheimer's disease, and if so then whether this might provide a novel route for therapy.METHOD: Two month old 5xFAD mice and WT littermates received intraperitoneal injections of vehicle or (+)-SW033291 (5mg/kg twice daily) for 4 months. At 6 months of age, Morris water maze test was conducted to evaluate cognitive function, and then mice were sacrificed for immunohistochemical determination of neuronal cell survival in the hippocampus and amyloid plaque deposition. Blood-brain barrier structure was also examined by electron microscopy.
    RESULT: Six-month-old 5xFAD mice display higher 15-PGDH activity in the brain than WT littermates. Treatment with (+)-SW033291 reduced 15-PGDH activity and protected 5xFAD mice from cognitive deficits in the Morris water maze test. This treatment also increased survival of adult-born young hippocampal neurons, as measured through bromodeoxyuridine labeling. Lastly, (+)-SW033291 treatment protected 5xFAD mice from developing blood-brain barrier disruption, as measured by the number of empty spaces around the vessel and astrocytic end-feet disruption. Notably, (+)-SW033291 treatment did not alter amyloid plaque formation in 5xFAD mice.
    CONCLUSION: An important element for discovering and developing disease-modifying therapies for Alzheimer's disease is diversification of targets, complementing and moving beyond the amyloid hypothesis. Pharmacologic inhibition of 15-PGDH in the brain, such as we have achieved here through treating mice with (+)-SW033291, may be an effective amyloid-independent therapeutic approach for patients.
    DOI:  https://doi.org/10.1002/alz.052500
  25. Cell Mol Life Sci. 2022 Feb 04. 79(2): 120
    A mitochondria cluster at the proximal axon initial segment controls axodendritic TAU trafficking in rodent primary and human iPSC-derived neurons.
    Noah Tjiang, Hans Zempel.
      Loss of neuronal polarity and missorting of the axonal microtubule-associated-protein TAU are hallmarks of Alzheimer's disease (AD) and related tauopathies. Impairment of mitochondrial function is causative for various mitochondriopathies, but the role of mitochondria in tauopathies and in axonal TAU-sorting is unclear. The axon-initial-segment (AIS) is vital for maintaining neuronal polarity, action potential generation, and-here important-TAU-sorting. Here, we investigate the role of mitochondria in the AIS for maintenance of TAU cellular polarity. Using not only global and local mitochondria impairment via inhibitors of the respiratory chain and a locally activatable protonophore/uncoupler, but also live-cell-imaging and photoconversion methods, we specifically tracked and selectively impaired mitochondria in the AIS in primary mouse and human iPSC-derived forebrain/cortical neurons, and assessed somatic presence of TAU. Global application of mitochondrial toxins efficiently induced tauopathy-like TAU-missorting, indicating involvement of mitochondria in TAU-polarity. Mitochondria show a biased distribution within the AIS, with a proximal cluster and relative absence in the central AIS. The mitochondria of this cluster are largely immobile and only sparsely participate in axonal mitochondria-trafficking. Locally constricted impairment of the AIS-mitochondria-cluster leads to detectable increases of somatic TAU, reminiscent of AD-like TAU-missorting. Mechanistically, mitochondrial impairment sufficient to induce TAU-missorting results in decreases of calcium oscillation but increases in baseline calcium, yet chelating intracellular calcium did not prevent mitochondrial impairment-induced TAU-missorting. Stabilizing microtubules via taxol prevented TAU-missorting, hinting towards a role for impaired microtubule dynamics in mitochondrial-dysfunction-induced TAU-missorting. We provide evidence that the mitochondrial distribution within the proximal axon is biased towards the proximal AIS and that proper function of this newly described mitochondrial cluster may be essential for the maintenance of TAU polarity. Mitochondrial impairment may be an upstream event in and therapeutic target for AD/tauopathy.
    Keywords:  Alzheimer's disease; Axon initial segment/AIS; Live-cell-imaging; Microtubule; Mitochondria; Mitochondriopathy; Neuron; Neuronal cell polarity; TAU; Tauopathy
    DOI:  https://doi.org/10.1007/s00018-022-04150-3
  26. Alzheimers Dement. 2021 Dec;17 Suppl 3 e054460
    Mitochondrial- and nuclear genome-controlled bioenergetic gene expression in Alzheimer's disease.
    Yuan Shang, Fei Yin, Roberta Diaz Brinton.
      BACKGROUND: Mitochondrial dysfunction is a hallmark of brain aging and particularly accentuated in neurodegenerative diseases including Alzheimer's disease (AD), yet the regulation of mitochondrial DNA (mtDNA) versus nuclear DNA (nDNA)-encoded genes in the aging- and AD brains is largely unknown.METHOD: Transcriptome datasets (ROSMAP, Mayo, and MSBB) and proteome dataset (ROSMAP) from cognitively normal and AD brains were analyzed. Linear regression models were applied to evaluate the association between mtDNA-encoded and nDNA-encoded genes at transcript and protein levels. Further, pathway analysis was performed to identify biological processes correlated with mtDNA-encoded gene expression.
    RESULT: At transcript level, mtDNA encoded genes were uniformly regulated (average R2 ranging from 0.43 to 0.92) across all datasets analyzed. While mtDNA encoded and nDNA encoded oxidative phosphorylation (OXPHOS) genes were positively correlated at protein level, they were differentially regulated at transcript level. Compared to control brains, both genesets were downregulated in AD brains at protein level whereas at the transcript level, mtDNA transcript number was higher vs nDNA transcript number was lower. In addition, transcriptional correlations between nDNA OXPHOS genes and mtDNA genes were reduced in AD brains. In both normal and AD brains, mtDNA transcripts were consistently correlated with Alzheimer's related pathways, including a positive correlation with notch signaling module and negative correlations with synapse, mitochondrial, translation, and ubiquitin mediated protein clearance modules. Across brain cell types, neuronal cell markers were negatively correlated with mtDNA transcripts whereas markers for oligodendrocyte, astrocyte and endothelial cells exhibited positive correlations.
    CONCLUSION: Outcomes of these analyses suggest an underappreciated correlation between mitochondrial gene expression with the development of AD, in particular the coordinated transcriptional regulation across both the mitochondrial- and nuclear genomes. While mitochondria are a promising therapeutic target for Alzheimer's disease, the findings reported herein indicate that restoring optimal mitochondrial function to prevent or treat Alzheimer's remains a complex challenge. This work was supported by National Institute on Aging grants P01-AG026572, R01 AG057931, and R01 AG059093 to RDB.
    DOI:  https://doi.org/10.1002/alz.054460
  27. J Cereb Blood Flow Metab. 2022 Feb 02. 271678X221077499
    Neuronal GPR81 regulates developmental brain angiogenesis and promotes brain recovery after a hypoxic ischemic insult.
    Prabhas Chaudhari, Ankush Madaan, José Carlos Rivera, Iness Charfi, Tiffany Habelrih, Xin Hou, Mohammad Nezhady, Gregory Lodygensky, Graciela Pineyro, Thierry Muanza, Sylvain Chemtob.
      Perinatal hypoxic/ischemic (HI) brain injury is a major clinical problem with devastating neurodevelopmental outcomes in neonates. During HI brain injury, dysregulated factor production contributes to microvascular impairment. Glycolysis-derived lactate accumulated during ischemia has been proposed to protect against ischemic injury, but its mechanism of action is poorly understood. Herein, we hypothesize that lactate via its G-protein coupled receptor (GPR81) controls postnatal brain angiogenesis and plays a protective role after HI injury. We show that GPR81 is predominantly expressed in neurons of the cerebral cortex and hippocampus. GPR81-null mice displayed a delay in cerebral microvascular development linked to reduced levels of various major angiogenic factors and augmented expression of anti-angiogenic Thrombospondin-1 (TSP-1) in comparison to their WT littermates. Coherently, lactate stimulation induced an increase in growth factors (VEGF, Ang1 and 2, PDGF) and reduced TSP-1 expression in neurons, which contributed to accelerating angiogenesis. HI injury in GPR81-null animals curtailed vascular density and consequently increased infarct size compared to changes seen in WT mice; conversely intracerebroventricular lactate injection increased vascular density and diminished infarct size in WT but not in GPR81-null mice. Collectively, we show that lactate acting via GPR81 participates in developmental brain angiogenesis, and attenuates HI injury by restoring compromised microvasculature.
    Keywords:  GPR81; Neonatal hypoxia-ischemia; TSP-1; VEGF; brain microvasculature; lactate; neurons
    DOI:  https://doi.org/10.1177/0271678X221077499
  28. Alzheimers Dement. 2021 Dec;17 Suppl 3 e056065
    Specific small-molecule inhibition of PLD1 prevents ADRD-like memory deficits by preserving dendritic spine integrity driven by amyloidogenic proteins.
    Chandramouli Natarajan, Krystyn Z Bourne, Ranidhanagomathi Chandrasekaran, Charles M Cook, Balaji Krishnan.
      BACKGROUND: Phosphatidyl choline phospholipase D (PC-PLD), a lipolytic enzyme that breaks down membrane phospholipids via two isoforms - a constitutively expressed PLD2 and an inducible PLD1 isoform - are also involved in developmentally important signaling mechanisms that regulate synaptic function. We were the first to propose and present a systematic study that established PLD1 as the aberrantly elevated isoform in AD and related dementia using human clinical samples and provided functional proof using mouse models to demonstrate the underlying synaptic dysfunction and memory deficits.METHOD: Synaptosomal Western blot analysis on 12 month 3xTg-AD mice hippocampi were used to investigate neuronal PLD1 expression and function. Long term potentiation of PLD1 dependent changes using pharmacological approaches in ex vivo slice preparations from wildtype and transgenic mouse models were used to assess synaptic perturbations that were first studied using the novel object recognition memory (NOR) and fear conditioning (FC) paradigms. Chronic PLD1 small molecule inhibitor treatment was assessed to ascertain the efficacy against Aβ and tau-driven AD-like memory deficit progression. Lastly, brain tissues from these animals were subjected to Western Blot analyses, Golgi analysis, immunohistochemical analysis to ascertain the potential signaling mechanism(s) that is/are perturbed/altered by overexpression of PLD1 in such diseased states.
    RESULT: Chronic PLD1 inhibition ameliorates the synaptic dysfunction and underlying memory deficits in the 3xTg-AD mouse model by specific action on preserving mushroom spine dendritic spine integrity. Further analysis using Western Blots revealed an underlying mechanism.
    CONCLUSION: Using chronic administration of a well-tolerated halopemide derivative of the specific PLD1 isoform inhibitor in the preclinical mouse models of synaptic dysfunction and memory deficits associated with amyloidogenic effects of Aβ and tau, we demonstrated neuroprotective aspects involving changes in the dendritic spine integrity that contributes to the preservation of memory.
    DOI:  https://doi.org/10.1002/alz.056065
  29. Front Cell Neurosci. 2021 ;15 773709
    Histone Acetylation Defects in Brain Precursor Cells: A Potential Pathogenic Mechanism Causing Proliferation and Differentiation Dysfunctions in Mitochondrial Aspartate-Glutamate Carrier Isoform 1 Deficiency.
    Eleonora Poeta, Sabrina Petralla, Giorgia Babini, Brunaldo Renzi, Luigi Celauro, Maria Chiara Magnifico, Simona Nicole Barile, Martina Masotti, Francesca De Chirico, Francesca Massenzio, Luigi Viggiano, Luigi Palmieri, Marco Virgili, Francesco Massimo Lasorsa, Barbara Monti.
      Mitochondrial aspartate-glutamate carrier isoform 1 (AGC1) deficiency is an ultra-rare genetic disease characterized by global hypomyelination and brain atrophy, caused by mutations in the SLC25A12 gene leading to a reduction in AGC1 activity. In both neuronal precursor cells and oligodendrocytes precursor cells (NPCs and OPCs), the AGC1 determines reduced proliferation with an accelerated differentiation of OPCs, both associated with gene expression dysregulation. Epigenetic regulation of gene expression through histone acetylation plays a crucial role in the proliferation/differentiation of both NPCs and OPCs and is modulated by mitochondrial metabolism. In AGC1 deficiency models, both OPCs and NPCs show an altered expression of transcription factors involved in the proliferation/differentiation of brain precursor cells (BPCs) as well as a reduction in histone acetylation with a parallel alteration in the expression and activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs). In this study, histone acetylation dysfunctions have been dissected in in vitro models of AGC1 deficiency OPCs (Oli-Neu cells) and NPCs (neurospheres), in physiological conditions and following pharmacological treatments. The inhibition of HATs by curcumin arrests the proliferation of OPCs leading to their differentiation, while the inhibition of HDACs by suberanilohydroxamic acid (SAHA) has only a limited effect on proliferation, but it significantly stimulates the differentiation of OPCs. In NPCs, both treatments determine an alteration in the commitment toward glial cells. These data contribute to clarifying the molecular and epigenetic mechanisms regulating the proliferation/differentiation of OPCs and NPCs. This will help to identify potential targets for new therapeutic approaches that are able to increase the OPCs pool and to sustain their differentiation toward oligodendrocytes and to myelination/remyelination processes in AGC1 deficiency, as well as in other white matter neuropathologies.
    Keywords:  SLC25A12/aralar1/AGC1 deficiency; epigenetics; mitochondria; neurons; oligodendrocytes; white matter disorder
    DOI:  https://doi.org/10.3389/fncel.2021.773709
  30. BMJ Open. 2022 Feb 01. 12(2): e047706
    Effects of prenatal nutrient supplementation and early life exposures on neurodevelopment at age 10: a randomised controlled trial - the COPSYCH study protocol.
    Parisa Mohammadzadeh, Julie Bøjstrup Rosenberg, Rebecca Vinding, Jens Richardt Møllegaard Jepsen, Ulrich Lindberg, Nilo Følsgaard, Mikkel Erlang Sørensen, Daban Sulaiman, Niels Bilenberg, Jayachandra Mitta Raghava, Birgitte Fagerlund, Mark Vestergaard, Christos Pantelis, Jakob Stokholm, Bo Chawes, Henrik Larsson, Birte Yding Glenthøj, Klaus Bønnelykke, Bjørn H Ebdrup, Hans Bisgaard.
      INTRODUCTION: Nutrient deficiency and immune and inflammatory disturbances in early life may compromise neurodevelopment and be implicated in the aetiology of psychiatric disorders. However, current evidence is limited by its predominantly observational nature. COpenhagen Prospective Study on Neuro-PSYCHiatric Development (COPSYCH) is a research alliance between Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) and Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research with the overall aim to investigate effects of prenatal and early life exposures on neurodevelopment at 10 years. COPSYCH will investigate the impact of prenatal n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) and high-dose vitamin D supplementation on neurodevelopment reflected by brain development, neurocognition and psychopathology. Moreover, the neurodevelopmental impact of early life exposures such as infections, low grade inflammation and the gut microbiome will be scrutinised.METHODS AND ANALYSIS: COPSYCH is based on the prospective and ongoing COPSAC2010 birth cohort of 700 mother-child pairs. Randomised controlled trials of supplementation with n-3 LCPUFA and/or high-dose vitamin D or placebo in the third trimester were embedded in a factorial 2×2 design (ClinicalTrials.gov: NCT01233297 and NCT00856947). This unique cohort provides deep phenotyping data from 14 previous clinical follow-up visits and exposure assessments since birth. The ongoing 10-year visit is a 2-day visit. Day 1 includes a comprehensive neurocognitive examination, and assessment of psychopathological dimensions, and assessment of categorical psychopathology. Day 2 includes acquisition of brain structural, diffusion and functional sequences using 3 Tesla MRI. Study outcomes are neurocognitive, psychopathological and MRI measures.
    ETHICS AND DISSEMINATION: This study has been approved by the Danish National Committee on Health Research Ethics and The Danish Data Protection Agency. The study is conducted in accordance with the guiding principles of the Declaration of Helsinki. Parents gave written informed consent before enrolment.
    Keywords:  child & adolescent psychiatry; mental health; paediatric infectious disease & immunisation; paediatric radiology
    DOI:  https://doi.org/10.1136/bmjopen-2020-047706
  31. Aging Dis. 2022 Feb;13(1): 175-214
    Recent Neurotherapeutic Strategies to Promote Healthy Brain Aging: Are we there yet?
    Chul-Kyu Kim, Perminder S Sachdev, Nady Braidy.
      Owing to the global exponential increase in population ageing, there is an urgent unmet need to develop reliable strategies to slow down and delay the ageing process. Age-related neurodegenerative diseases are among the main causes of morbidity and mortality in our contemporary society and represent a major socio-economic burden. There are several controversial factors that are thought to play a causal role in brain ageing which are continuously being examined in experimental models. Among them are oxidative stress and brain inflammation which are empirical to brain ageing. Although some candidate drugs have been developed which reduce the ageing phenotype, their clinical translation is limited. There are several strategies currently in development to improve brain ageing. These include strategies such as caloric restriction, ketogenic diet, promotion of cellular nicotinamide adenine dinucleotide (NAD+) levels, removal of senescent cells, 'young blood' transfusions, enhancement of adult neurogenesis, stem cell therapy, vascular risk reduction, and non-pharmacological lifestyle strategies. Several studies have shown that these strategies can not only improve brain ageing by attenuating age-related neurodegenerative disease mechanisms, but also maintain cognitive function in a variety of pre-clinical experimental murine models. However, clinical evidence is limited and many of these strategies are awaiting findings from large-scale clinical trials which are nascent in the current literature. Further studies are needed to determine their long-term efficacy and lack of adverse effects in various tissues and organs to gain a greater understanding of their potential beneficial effects on brain ageing and health span in humans.
    Keywords:  NAD+; anti-ageing; brain health; caloric restriction; cellular energetics
    DOI:  https://doi.org/10.14336/AD.2021.0705
  32. Nat Commun. 2022 Feb 03. 13(1): 651
    Mitochondrial protein import determines lifespan through metabolic reprogramming and de novo serine biosynthesis.
    Eirini Lionaki, Ilias Gkikas, Ioanna Daskalaki, Maria-Konstantina Ioannidi, Maria I Klapa, Nektarios Tavernarakis.
      Sustained mitochondrial fitness relies on coordinated biogenesis and clearance. Both processes are regulated by constant targeting of proteins into the organelle. Thus, mitochondrial protein import sets the pace for mitochondrial abundance and function. However, our understanding of mitochondrial protein translocation as a regulator of longevity remains enigmatic. Here, we targeted the main protein import translocases and assessed their contribution to mitochondrial abundance and organismal physiology. We find that reduction in cellular mitochondrial load through mitochondrial protein import system suppression, referred to as MitoMISS, elicits a distinct longevity paradigm. We show that MitoMISS triggers the mitochondrial unfolded protein response, orchestrating an adaptive reprogramming of metabolism. Glycolysis and de novo serine biosynthesis are causatively linked to longevity, whilst mitochondrial chaperone induction is dispensable for lifespan extension. Our findings extent the pro-longevity role of UPRmt and provide insight, relevant to the metabolic alterations that promote or undermine survival and longevity.
    DOI:  https://doi.org/10.1038/s41467-022-28272-1
  33. Alzheimers Dement. 2021 Dec;17 Suppl 3 e054322
    Could G6PD overexpression play a role in the prevention of Alzheimer's disease?
    Ángela García Correas, Aitor Carretero, Fernando Millán, Esther García Domínguez, Gloria Olaso González, Mari Carmen Gómez Cabrera, José Viña Ribes.
      BACKGROUND: Alzheimer's Disease (AD) is a neurodegenerative disorder and the most common type of dementia in the elderly. AD is characterized by the beta-amyloid (Aβ) peptide and neurofibrillary tangles accumulation in the brain, accompanied by a progressive neuronal dysfunction and neurodegeneration. Along with these phenomena, it should be noticed that alterations in energy metabolism and an increased production of free radicals leading to an increased in the oxidative stress, are also characteristics of AD. Against these reactive oxygen species (ROS), the cellular antioxidant defences use NADPH as reducing agent, mainly produced by glucose-6-phosphate dehydrogenase (G6PD) enzyme. The proposal of this study was to look into if G6PD overexpression had any effect on the onset of AD. To this end, we used three mouse cohorts: wild-type (WT) mice, double APPswe/PSEN1dE9 transgenic (2xTg) mice and a new triple APPswe/PSEN1dE9/G6PD transgenic (3xTg) mice that we generated by crossing between simple G6PD transgenic mice and the AD-like pathology model (2xTg mice). We compared the three groups at a functional, cognitive, biochemical and metabolic level.METHOD: We compare a 3xTg mouse cohort (n=12 males, 14 females) with a WT mouse cohort (n=9 males, 13 females) and a 2xTg mouse cohort (n= 13 males, 11 females). We evaluated different functional parameters (grip strength, motor coordination and endurance) through grip strength test, rotarod test and incremental-speed test on a treadmill; cognitive parameters (implicit memory, learning) through passive avoidance test and Hebb Williams mazes; biochemical measurements (G6PD activity, oxidative stress markers such as malondialdehyde, protein carbonylation); and metabolic changes through indirect calorimetry. All tests were performed in 12-14-month-old mice.
    RESULT: 3xTg female mice showed a better functional performance than WT and 2xTg females, while male mice showed no significant differences between the three groups of mice. The 3xTg mouse cohort also exhibited significant improvements in cognitive skills over 2xTg and WT groups. Preliminary results show a significantly higher respiratory quotient (RQ) in 3xTg females compared to 2xTg females. At the biochemical level, we did not find differences in the oxidative state between the 3 genotypes.
    CONCLUSION: G6PD overexpression could play a role in the onset delay of Alzheimer's disease in murine models.
    DOI:  https://doi.org/10.1002/alz.054322
  34. Alzheimers Res Ther. 2022 Feb 01. 14(1): 19
    Glucosylceramide synthase inhibition reduces ganglioside GM3 accumulation, alleviates amyloid neuropathology, and stabilizes remote contextual memory in a mouse model of Alzheimer's disease.
    James C Dodge, Thomas J Tamsett, Christopher M Treleaven, Tatyana V Taksir, Peter Piepenhagen, S Pablo Sardi, Seng H Cheng, Lamya S Shihabuddin.
      BACKGROUND: Gangliosides are highly enriched in the brain and are critical for its normal development and function. However, in some rare neurometabolic diseases, a deficiency in lysosomal ganglioside hydrolysis is pathogenic and leads to early-onset neurodegeneration, neuroinflammation, demyelination, and dementia. Increasing evidence also suggests that more subtle ganglioside accumulation contributes to the pathogenesis of more common neurological disorders including Alzheimer's disease (AD). Notably, ganglioside GM3 levels are elevated in the brains of AD patients and in several mouse models of AD, and plasma GM3 levels positively correlate with disease severity in AD patients.METHODS: Tg2576 AD model mice were fed chow formulated with a small molecule inhibitor of glucosylceramide synthase (GCSi) to determine whether reducing glycosphingolipid synthesis affected aberrant GM3 accumulation, amyloid burden, and disease manifestations in cognitive impairment. GM3 was measured with LC-MS, amyloid burden with ELISA and amyloid red staining, and memory was assessed using the contextual fear chamber test.
    RESULTS: GCSi mitigated soluble Aβ42 accumulation in the brains of AD model mice when treatment was started prophylactically. Remarkably, GCSi treatment also reduced soluble Aβ42 levels and amyloid plaque burden in aged (i.e., 70 weeks old) AD mice with preexisting neuropathology. Our analysis of contextual memory in Tg2576 mice showed that impairments in remote (cortical-dependent) memory consolidation preceded deficits in short-term (hippocampal-dependent) contextual memory, which was consistent with soluble Aβ42 accumulation occurring more rapidly in the cortex of AD mice compared to the hippocampus. Notably, GCSi treatment significantly stabilized remote memory consolidation in AD mice-especially in mice with enhanced cognitive training. This finding was consistent with GCSi treatment lowering aberrant GM3 accumulation in the cortex of AD mice.
    CONCLUSIONS: Collectively, our results indicate that glycosphingolipids regulated by GCS are important modulators of Aβ neuropathology and that glycosphingolipid homeostasis plays a critical role in the consolidation of remote memories.
    Keywords:  Amygdala; Cortex; Dementia; Glucosylceramide; Glycosphingolipids; Hippocampus
    DOI:  https://doi.org/10.1186/s13195-022-00966-0
  35. Alzheimers Dement. 2021 Dec;17 Suppl 3 e055544
    High-dose triglyceride DHA supplementation increases plasma and cerebrospinal fluid phospholipid DHA species.
    Victoria A Solomon, Xulei He, Michael G Harrington, Alfred N Fonteh, Hussein N Yassine.
      BACKGROUND: It is not clear whether triglyceride DHA-based formulations (TG-DHA) can sufficiently enrich brain DHA. Animal studies suggest that phosphatidylcholine (PC) and lyso-phosphatidylcholine (LPC) lipids might be preferred brain DHA substrates. The goal of this study is to assess the effect of high-dose TG-DHA supplementation on DHA-containing PC (PC-DHA) and LPC (LPC-DHA) lipid species in plasma and total cerebrospinal fluid (CSF) DHA as a surrogate for brain DHA incorporation.METHOD: We conducted a randomized clinical trial stratified by DHA treatment (n=14) and placebo (n=14) status in non-demented older participants (CDR ≤ 0.5, age ³ 55 years old). Participants were provided 2,040 mg DHA daily in the form of TG-DHA for six months. Plasma and CSF were obtained at baseline and after supplementation. Participants were also stratified by ApoE ε4 status, an allele known to increase Alzheimer's disease (AD) risk. PC and LPC lipid species from plasma and CSF were isolated and examined by LC/MS-MS. Total fatty acids in CSF were measured via GC/MS-MS.
    RESULT: Among all participants, PC-DHA represented 39% of total DHA in plasma, while LPC-DHA represented 1.8% of total DHA. PC-DHA increased by 69% and 19% in plasma and CSF, respectively, following supplementation compared to placebo (p<0.0001 for both). Plasma LPC-DHA increased by 140% in the treatment group compared to placebo (p<0.0001). Increases in plasma PC-DHA and LPC-DHA were both significantly correlated to changes in total DHA in CSF (R=0.8 and 0.57, respectively, p<0.003 for both). A trend toward greater increases in PC-DHA in non-ApoE ε4 carriers compared to carriers were also observed.
    CONCLUSION: Our data indicate that high-dose TG-DHA supplementation effectively increases DHA phospholipid incorporation in plasma and CSF. We acknowledge that CSF may not exactly reflect brain lipid uptake but provides useful information on brain DHA bioavailability. Our findings support that high-dose TG DHA supplementation are brain penetrant and can help answer whether enriching brain DHA can slow down cognitive decline in patients at risk of AD.
    DOI:  https://doi.org/10.1002/alz.055544
  36. Explor Neuroprotective Ther. 2021 ;1 86-100
    Striking a balance: PIP2 and PIP3 signaling in neuronal health and disease.
    Kamran Tariq, Bryan W Luikart.
      Phosphoinositides are membrane phospholipids involved in a variety of cellular processes like growth, development, metabolism, and transport. This review focuses on the maintenance of cellular homeostasis of phosphatidylinositol 4,5-bisphosphate (PIP2), and phosphatidylinositol 3,4,5-trisphosphate (PIP3). The critical balance of these PIPs is crucial for regulation of neuronal form and function. The activity of PIP2 and PIP3 can be regulated through kinases, phosphatases, phospholipases and cholesterol microdomains. PIP2 and PIP3 carry out their functions either indirectly through their effectors activating integral signaling pathways, or through direct regulation of membrane channels, transporters, and cytoskeletal proteins. Any perturbations to the balance between PIP2 and PIP3 signaling result in neurodevelopmental and neurodegenerative disorders. This review will discuss the upstream modulators and downstream effectors of the PIP2 and PIP3 signaling, in the context of neuronal health and disease.
    Keywords:  AKT; Alzheimer’s; Phosphoinositides; autism; cholesterol; cytoskeleton; ion channels; mammalian target of rapamycin
    DOI:  https://doi.org/10.37349/ent.2021.00008
  37. Front Neurosci. 2021 ;15 778822
    Synapses, Microglia, and Lipids in Alzheimer's Disease.
    Patrick J Paasila, Jason A Aramideh, Greg T Sutherland, Manuel B Graeber.
      Alzheimer's disease (AD) is characterised by synaptic dysfunction accompanied by the microscopically visible accumulation of pathological protein deposits and cellular dystrophy involving both neurons and glia. Late-stage AD shows pronounced loss of synapses and neurons across several differentially affected brain regions. Recent studies of advanced AD using post-mortem brain samples have demonstrated the direct involvement of microglia in synaptic changes. Variants of the Apolipoprotein E and Triggering Receptors Expressed on Myeloid Cells gene represent important determinants of microglial activity but also of lipid metabolism in cells of the central nervous system. Here we review evidence that may help to explain how abnormal lipid metabolism, microglial activation, and synaptic pathophysiology are inter-related in AD.
    Keywords:  APOE; Alzheimer’s disease; TREM2; lipids; microglia; synapses
    DOI:  https://doi.org/10.3389/fnins.2021.778822
  38. Alzheimers Dement. 2021 Dec;17 Suppl 3 e051164
    Lipidome changes due to accumulation of cholesterol via APP-C99 alters neuronal permeability.
    Jorge Montesinos, Estela Area-Gomez.
      BACKGROUND: γ-secretase activity is enriched at mitochondria-associated ER membranes (MAMs),a lipid-raft subdomain of the ER, where APP fragment C99 is delivered for its cleavage. Moreover, γ-secretase activity deficiency linked to AD mutations causes C99 accumulation at MAM, resulting in the upregulation of MAM activities such as sphingomyelin turnover and cholesterol esterification. We now explore whether the interaction of C99 with cholesterol could explain the link between C99 accumulation at MAM and the lipid abnormalities found in AD.METHOD: Using cellular models of C99 accumulation versus a cholesterol-binding deficient C99, we assessed cholesterol uptake dynamics and sub-cellular distribution along with MAM-regulated functionalities. Also, we used a photo click activable cholesterol analog to study the proteins interacting with cholesterol at MAM in both conditions. Finally, we compare membrane permeability dynamics in neuronal models of Alzheimer's disease.
    RESULT: C99 accumulation at MAM caused an increase in cholesterol uptake, cholesterol esterification, phospholipid synthesis and sphingomyelinase activity accompanied by a sub cellular redistribution of cholesterol to endolysosomes and ER, while C99-defective in cholesterol binding showed no changes in these activities. Moreover, when the cholesterol-interacting proteome of both conditions was compared, C99 caused a huge change/recruitment at MAM, especially of enzymes involved in lipid metabolism. ACSL4 (Acyl-CoA Synthetase Long Chain Family Member 4) activation was detected as an important player in the lipidome changes associated with C99 accumulation that led to membrane permeability alterations CONCLUSION: We report that the lipid alterations caused by pathogenic C99 accumulation are a consequence of an exacerbated uptake of extracellular cholesterol and mobilization towards MAM. The increase content of cholesterol at MAM driven by C99 might be responsible of the persistent activation of MAM and a subsequent alteration of the lipid metabolism since a cholesterol-binding deficient C99 fails to increase MAM activities and cholesterol trafficking. We also point to ACSL4 activation as a possible molecular switch for the permeability changes found in cellular models of AD.
    DOI:  https://doi.org/10.1002/alz.051164
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