bims-medebr 2023-01-15 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023–01–15
29 papers selected by
Regina F. Fernández, Johns Hopkins University

Medium-chain fatty acids for the prevention or treatment of Alzheimer's disease: a systematic review and meta-analysis.
Analysis of cerebral glucose metabolism following experimental subarachnoid hemorrhage over 7 days.
Molecular insights into sex-specific metabolic alterations in Alzheimer's mouse brain using multi-omics approach.
Mitochondrial Ca2+ handling as a cell signaling hub: lessons from astrocyte function.
What Is the Evidence for Dietary-Induced DHA Deficiency in Human Brains?
The relationship between depletion of brain GM1 ganglioside and Parkinson's disease.
Contribution of ceramides metabolism in psychiatric disorders.
Functional Correlates of Striatal Dopamine Transporter Cerebrospinal Fluid Levels in Alzheimer's Disease: A Preliminary 18F-FDG PET/CT Study.
Impact of glucose metabolism on the developing brain.
Lipid peroxidation and sphingolipid alterations in the cerebral cortex and hypothalamus of rats fed a high-protein diet.
Mitochondrial dysfunction in a rat model and the related risk of metabolic disorders.
Mitochondrial dysfunction in cognitive neurodevelopmental disorders: Cause or effect?
Mitochondrial signalling and homeostasis: from cell biology to neurological disease.
GTP energy dependence of endocytosis and autophagy in the aging brain and Alzheimer's disease.
Multiple pathways of lipid dysregulation in amyotrophic lateral sclerosis.
Mutations in the transcriptional regulator MeCP2 severely impact key cellular and molecular signatures of human astrocytes during maturation.
Characterization of mitochondrial and metabolic alterations induced by trisomy 21 during neural differentiation.
Disrupted axon-glia communication leads to neurodegeneration in metabolic diseases.
Effects of postnatal glucocorticoids on brain structure in preterm infants, a scoping review.
Lipid profile variability in children at different ages measured in dried blood spots.
Establishment of a flow cytometry screening method for patients with glucose transporter 1 deficiency syndrome.
Artificial intelligence-driven meta-analysis of brain gene expression identifies novel gene candidates and a role for mitochondria in Alzheimer's disease.
Acute metabolic alterations in the hippocampus are associated with decreased acetylation after blast induced TBI.
Reversal of spatial memory impairment by phosphodiesterase 3 inhibitor cilostazol is associated with reduced neuroinflammation and increased cerebral glucose uptake in aged male mice.
Isolated neurological presentations of mevalonate kinase deficiency.
Loss of small GTPase Rab7 activation in prion infection negatively affects a feedback loop regulating neuronal cholesterol metabolism.
Astrocyte L-Lactate Signaling in the ACC Regulates Visceral Pain Aversive Memory in Rats.
Atp7b-dependent choroid plexus dysfunction Causes transient copper deficit and metabolic changes in the developing mouse brain.
Long-Term High-Fat Diet Consumption Induces Cognitive Decline Accompanied by Tau Hyper-Phosphorylation and Microglial Activation in Aging.

Nutr Rev. 2023 Jan 12. pii: nuac104. [Epub ahead of print]

Medium-chain fatty acids for the prevention or treatment of Alzheimer's disease: a systematic review and meta-analysis.

Carolina B Castro, Cintia B Dias, Heidi Hillebrandt, Hamid R Sohrabi, Pratishtha Chatterjee, Tejal M Shah, Stephanie J Fuller, Manohar L Garg, Ralph N Martins.

   CONTEXT: In preclinical Alzheimer's disease (AD), the brain gradually becomes insulin resistant. As a result, brain glucose utilization is compromised, causing a cellular energy deficit that leads to the accumulation of free radicals, which increases inflammation and damages neurons. When glucose utilization is impaired, ketone bodies offer an alternative energy source. Ketone bodies are synthesized from fats, obtained from either the diet or adipose tissue. Dietary medium-chain fatty acids (MCFAs), which are preferentially metabolized into ketone bodies, have the potential to supply the insulin-resistant brain with energy.
OBJECTIVE: This systematic review and meta-analysis aims to review the effect of MCFA supplements on circulating ketone bodies and cognition in individuals with subjective cognitive decline, mild cognitive impairment, and AD.
DATA SOURCES: A comprehensive search of electronic databases was performed on August 12, 2019, to retrieve all publications meeting the inclusion criteria. Alerts were then set to identify any publications after the search date up until January 31, 2021.
DATA EXTRACTION: Data were extracted by 2 authors and assessed by a third. In total, 410 publications were identified, of which 16 (n = 17 studies) met the inclusion criteria.
DATA ANALYSIS: All studies assessing change in levels of blood ketone bodies due to MCFA supplementation (n = 12) reported a significant increase. Cognition outcomes (measured in 13 studies), however, varied, ranging from no improvement (n = 4 studies) to improvement (n = 8 studies) or improvement only in apolipoprotein E allele 4 (APOE ε4) noncarriers (n = 2 studies). One study reported an increase in regional cerebral blood flow in APOE ε4 noncarriers and another reported an increase in energy metabolism in the brain.
CONCLUSION: MCFA supplementation increases circulating ketone body levels, resulting in increased brain energy metabolism. Further research is required to determine whether this MCFA-mediated increase in brain energy metabolism improves cognition.
SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42019146967.

Keywords:  Alzheimer’s; MCT oil; coconut oil; dementia; medium-chain fatty acids; nutrition; prevention

DOI:  https://doi.org/10.1093/nutrit/nuac104
Sci Rep. 2023 Jan 09. 13(1): 427

Analysis of cerebral glucose metabolism following experimental subarachnoid hemorrhage over 7 days.

Fabian Schadt, Ina Israel, Alexandra Beez, Kastriot Alushi, Judith Weiland, Ralf-Ingo Ernestus, Thomas Westermaier, Samuel Samnick, Nadine Lilla.

Little is known about changes in brain metabolism following SAH, possibly leading towards secondary brain damage. Despite sustained progress in the last decade, analysis of in vivo acquired data still remains challenging. The present interdisciplinary study uses a semi-automated data analysis tool analyzing imaging data independently from the administrated radiotracer. The uptake of 2-[18F]Fluoro-2-deoxy-glucose ([18F]FDG) was evaluated in different brain regions in 14 male Sprague-Dawley rats, randomized into two groups: (1) SAH induced by the endovascular filament model and (2) sham operated controls. Serial [18F]FDG-PET measurements were carried out. Quantitative image analysis was performed by uptake ratio using a self-developed MRI-template based data analysis tool. SAH animals showed significantly higher [18F]FDG accumulation in gray matter, neocortex and olfactory system as compared to animals of the sham group, while white matter and basal forebrain region showed significant reduced tracer accumulation in SAH animals. All significant metabolic changes were visualized from 3 h, over 24 h (day 1), day 4 and day 7 following SAH/sham operation. This [18F]FDG-PET study provides important insights into glucose metabolism alterations following SAH-for the first time in different brain regions and up to day 7 during course of disease.

DOI: https://doi.org/10.1038/s41598-022-26183-1
Alzheimers Res Ther. 2023 Jan 09. 15(1): 8

Molecular insights into sex-specific metabolic alterations in Alzheimer's mouse brain using multi-omics approach.

Abigail Strefeler, Maxime Jan, Manfredo Quadroni, Tony Teav, Nadia Rosenberg, Jean-Yves Chatton, Nicolas Guex, Hector Gallart-Ayala, Julijana Ivanisevic.

   BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by altered cellular metabolism in the brain. Several of these alterations have been found to be exacerbated in females, known to be disproportionately affected by AD. We aimed to unravel metabolic alterations in AD at the metabolic pathway level and evaluate whether they are sex-specific through integrative metabolomic, lipidomic, and proteomic analysis of mouse brain tissue.
METHODS: We analyzed male and female triple-transgenic mouse whole brain tissue by untargeted mass spectrometry-based methods to obtain a molecular signature consisting of polar metabolite, complex lipid, and protein data. These data were analyzed using multi-omics factor analysis. Pathway-level alterations were identified through joint pathway enrichment analysis or by separately evaluating lipid ontology and known proteins related to lipid metabolism.
RESULTS: Our analysis revealed significant AD-associated and in part sex-specific alterations across the molecular signature. Sex-dependent alterations were identified in GABA synthesis, arginine biosynthesis, and in alanine, aspartate, and glutamate metabolism. AD-associated alterations involving lipids were also found in the fatty acid elongation pathway and lysophospholipid metabolism, with a significant sex-specific effect for the latter.
CONCLUSIONS: Through multi-omics analysis, we report AD-associated and sex-specific metabolic alterations in the AD brain involving lysophospholipid and amino acid metabolism. These findings contribute to the characterization of the AD phenotype at the molecular level while considering the effect of sex, an overlooked yet determinant metabolic variable.

Keywords:  3xTg AD mouse; Alzheimer’s disease; Amino acids; Lipidomics; Lysophospholipids; Metabolomics; Multi-omics; Proteomics; Sex differences

DOI:  https://doi.org/10.1186/s13195-023-01162-4
Essays Biochem. 2023 Jan 13. pii: EBC20220094. [Epub ahead of print]

Mitochondrial Ca2+ handling as a cell signaling hub: lessons from astrocyte function.

João Victor Cabral-Costa, Alicia J Kowaltowski.

  Astrocytes are a heterogenous population of macroglial cells spread throughout the central nervous system with diverse functions, expression signatures, and intricate morphologies. Their subcellular compartments contain a distinct range of mitochondria, with functional microdomains exhibiting widespread activities, such as controlling local metabolism and Ca2+ signaling. Ca2+ is an ion of utmost importance, both physiologically and pathologically, and participates in critical central nervous system processes, including synaptic plasticity, neuron-astrocyte integration, excitotoxicity, and mitochondrial physiology and metabolism. The mitochondrial Ca2+ handling system is formed by the mitochondrial Ca2+ uniporter complex (MCUc), which mediates Ca2+ influx, and the mitochondrial Na+/Ca2+ exchanger (NCLX), responsible for most mitochondrial Ca2+ efflux, as well as additional components, including the mitochondrial permeability transition pore (mtPTP). Over the last decades, mitochondrial Ca2+ handling has been shown to be key for brain homeostasis, acting centrally in physiopathological processes such as astrogliosis, astrocyte-neuron activity integration, energy metabolism control, and neurodegeneration. In this review, we discuss the current state of knowledge regarding the mitochondrial Ca2+ handling system molecular composition, highlighting its impact on astrocytic homeostasis.

Keywords:  MCU; NCLX; astrocytes; calcium signalling; metabolism; mitochondria

DOI:  https://doi.org/10.1042/EBC20220094
Nutrients. 2022 Dec 29. pii: 161. [Epub ahead of print]15(1):

What Is the Evidence for Dietary-Induced DHA Deficiency in Human Brains?

Andrew J Sinclair, Yonghua Wang, Duo Li.

  Docosahexaenoic acid (DHA) is a major constituent of neural and visual membranes and is required for optimal neural and visual function. DHA is derived from food or by endogenous synthesis from α-linolenic acid (ALA), an essential fatty acid. Low blood levels of DHA in some westernised populations have led to speculations that child development disorders and various neurological conditions are associated with sub-optimal neural DHA levels, a proposition which has been supported by the supplement industry. This review searched for evidence of deficiency of DHA in human populations, based on elevated levels of the biochemical marker of n-3 deficiency, docosapentaenoic acid (22:5n-6). Three scenarios/situations were identified for the insufficient supply of DHA, namely in the brain of new-born infants fed with high-linoleic acid (LA), low-ALA formulas, in cord blood of women at birth who were vegetarians and in the milk of women from North Sudan. Twenty post-mortem brain studies from the developed world from adults with various neurological disorders revealed no evidence of raised levels of 22:5n-6, even in the samples with reduced DHA levels compared with control subjects. Human populations most likely at risk of n-3 deficiency are new-born and weanling infants, children and adolescents in areas of dryland agriculture, in famines, or are refugees, however, these populations have rarely been studied. This is an important topic for future research.

Keywords:  alpha-linolenic acid (ALA); brain; deficiency of ALA; deficiency of DHA; docosahexaenoic acid (DHA); docosapentaenoic acid (22:5n-6); human; vegan; vegetarian

DOI:  https://doi.org/10.3390/nu15010161
FEBS Open Bio. 2023 Jan 13.

The relationship between depletion of brain GM1 ganglioside and Parkinson's disease.

Sandro Sonnino.

  GM1 is one of the main gangliosides of the nervous system and it exerts neurotrophic and neuroprotective properties in neurons. It is involved in many processes necessary for the correct physiology of neuronal cells. In particular, it is necessary for the activity of neuronal receptors that control processes such as differentiation, survival, and mitochondrial activity. A shortage of GM1 in the substantia nigra is potentially responsible for the neurodegeneration present in Parkinson's disease patients. In this review, I report on the role played by GM1 in neurons and how its genetic shortage may be responsible for the onset of Parkinson's disease.

Keywords:  GFRα1-RET-GDNF signalling; GM1 ganglioside; Neurodegeneration; Parkinson's disease; TrkA-NGF signaling; α-synuclein

DOI:  https://doi.org/10.1002/2211-5463.13554
J Neurochem. 2023 Jan 11.

Contribution of ceramides metabolism in psychiatric disorders.

Sofía Bernal-Vega, Martín García-Juárez, Alberto Camacho-Morales.

  Psychiatric disorders affect 970 million people worldwide, representing a significant source of disability. Although the underlying neurobiological traits for these disorders are not fully understood, a complex interplay between psychological, environmental, and biological factors contributes to their outcomes. Recent advances in lipidomic analysis and artificial intelligence algorithms have improved the identification of selective lipid species modulating the susceptibility to mental disorders. Sphingolipids (SLs) and ceramides-related SLs are among the most abundant lipids species in the brain that support major key pathways during neurodevelopment and brain plasticity. High levels of ceramides in plasma and brain contribute to psychiatric illness susceptibility in humans and animal models. However, the neuropathological mechanism regarding the involvement of ceramides in these disorders remain inconclusive. The brain is highly susceptible to nutritional insults, which could lead to functional impairment and influence the development and progression of psychiatric disorders. While the brain relies on glucose metabolism to support its physiological needs, a selective nutrient formula appears to have greater effects on brain health than others. For instance, consumption of high-energy diets is associated with brain anatomical, physiological and metabolic changes, including ceramides metabolism. Herein, we will address the contribution of ceramides metabolism as a modulator of major psychiatric disorders such as depression, anxiety, bipolar disorder, schizophrenia and attention deficit-hyperactivity disorder. We will also describe molecular and cellular targets of ceramides metabolism assisting the maintenance and progression of psychiatric disorders and their modulation by dietary formulas as non-pharmacologic treatments.

Keywords:  Sphingolipids; ceramides; high-energy diets; inflammation; psychiatric disorders

DOI:  https://doi.org/10.1111/jnc.15759
Int J Mol Sci. 2023 Jan 01. pii: 751. [Epub ahead of print]24(1):

Functional Correlates of Striatal Dopamine Transporter Cerebrospinal Fluid Levels in Alzheimer's Disease: A Preliminary 18F-FDG PET/CT Study.

Riccardo Camedda, Chiara Giuseppina Bonomi, Martina Gaia Di Donna, Agostino Chiaravalloti.

  The aim of our study was to investigate regional glucose metabolism with 18F-FDG positron emission tomography/computed tomography in a population of patients with Alzheimer's disease (AD) in relation to cerebrospinal (CSF) levels of striatal dopamine transporter (DAT). All patients underwent lumbar puncture and received a biomarker-based diagnosis of AD. Differences in regional brain glucose metabolism were assessed by Statistical Parametric Mapping version 12 with the use of age, gender, and MMSE as covariates in the analysis. A positive correlation between CSF DAT levels and glucose metabolism at the level of two brain areas involved in the pathophysiological process of Alzheimer's disease, the substantia nigra and the posterior cingulate gyrus, has been highlighted. Results indicate that patients with higher CSF DAT levels have a better metabolic pattern in two key zones, suggesting less advanced disease status in patients with more conserved dopaminergic systems.

Keywords:  Alzheimer’s disease; DAT; FDG-PET; dementia; dopaminergic impairment

DOI:  https://doi.org/10.3390/ijms24010751
Front Endocrinol (Lausanne). 2022 ;13 1047545

Impact of glucose metabolism on the developing brain.

Marta Cacciatore, Eleonora Agata Grasso, Roberta Tripodi, Francesco Chiarelli.

  Glucose is the most important substrate for proper brain functioning and development, with an increased glucose consumption in relation to the need of creating new brain structures and connections. Therefore, alterations in glucose homeostasis will inevitably be associated with changes in the development of the Nervous System. Several studies demonstrated how the alteration of glucose homeostasis - both hyper and hypoglycemia- may interfere with the development of brain structures and cognitivity, including deficits in intelligence quotient, anomalies in learning and memory, as well as differences in the executive functions. Importantly, differences in brain structure and functionality were found after a single episode of diabetic ketoacidosis suggesting the importance of glycemic control and stressing the need of screening programs for type 1 diabetes to protect children from this dramatic condition. The exciting progresses of the neuroimaging techniques such as diffusion tensor imaging, has helped to improve the understanding of the effects, outcomes and mechanisms underlying brain changes following dysglycemia, and will lead to more insights on the physio-pathological mechanisms and related neurological consequences about hyper and hypoglycemia.

Keywords:  brain; glucose metabolism; hyperglycemia; hypoglycemia; type 1 diabetes

DOI:  https://doi.org/10.3389/fendo.2022.1047545
Nutrition. 2022 Dec 13. pii: S0899-9007(22)00354-9. [Epub ahead of print]107 111942

Lipid peroxidation and sphingolipid alterations in the cerebral cortex and hypothalamus of rats fed a high-protein diet.

Elżbieta Supruniuk, Ewa Żebrowska, Mateusz Maciejczyk, Anna Zalewska, Adrian Chabowski.

   OBJECTIVES: High-protein diets (HPDs) are widely accepted to enhance satiety and energy expenditure and thus have become a popular strategy to lose weight and facilitate muscle protein synthesis. However, long-term high-protein consumption could be linked with metabolic and clinical problems such as renal and liver dysfunctions. This study verified the effects of 8-wk high-protein ingestion on lipid peroxidation and sphingolipid metabolism in the plasma, cerebral cortex, and hypothalamus in rats.
METHODS: Immunoenzymatic and spectrophotometric methods were applied to assess oxidation-reduction (redox) biomarkers and neutral sphingomyelinase activity, whereas gas-liquid chromatography and high-performance liquid chromatography were used to examine sphingolipid levels.
RESULTS: The vast majority of HPD-related alterations was restricted to the hypothalamus. Specifically, an increased rate of lipid peroxidation (increased lipid hydroperoxides, 8-isoprostanes, and thiobarbituric acid reactive substances) associated with ceramide accumulation via the activation of de novo synthesis (decreased sphinganine), salvage pathway (decreased sphingosine), and sphingomyelin hydrolysis (decreased sphingomyelin and increased neutral sphingomyelinase activity) was noted.
CONCLUSIONS: This study showed that HPD substantially affected hypothalamic metabolic pathways, which potentially alter cerebral output signals to the peripheral tissues.

Keywords:  Cerebral cortex; High-protein diet; Hypothalamus; Lipid peroxidation; Oxidative stress; Sphingolipid metabolism

DOI:  https://doi.org/10.1016/j.nut.2022.111942
J Tradit Chin Med. 2023 Feb;43(1): 95-104

Mitochondrial dysfunction in a rat model and the related risk of metabolic disorders.

L I Han, Huang Xiaomin, Cai Haiyang, Herok George, H E Jing, S U Yixun, L I Weihong, Y I Chenju, Oliver Brian G, Chen Hui.

   OBJECTIVE: To explore whether kidney deficiency (KYD) is prone to metabolic disorders may be linked to impaired mitochondrial function in thermogenesis and metabolic tissues.
METHODS: A rat model of KYD was used, which was established using Sprague Dawley rat dams with warm preference subjected to herbal treatment that can improve kidney . The human relevance was confirmed by reduced serum corticosterone levels, and increased preference for warm location.
RESULTS: KYD Rats were underdeveloped. Adenosine-triphosphate (ATP) production was reduced in the brown fat, but increased in the muscle. However, oxidative phosphorylated complexes to generate ATP and mitochondrial biogenesis marker were reduced in both tissues. When the second insult of high-fat diet (HFD) was introduced, KYD rats gained less weight yet developed more severe lipid and glucose metabolic disorders. This may be driven by disregulated liver gluconeogenesis marker forkhead box protein O1 and lipid metabolic regulator cholesterol 7 alpha-hydroxylase.
CONCLUSION: KYD rats exhibited reduced mito-chondrial function in the brown fat, but were partially compensated by skeletal muscle, associated with the phenotype of warm preference and metabolic disorder, which was further exacerbated by additional HFD consumption. Future studies can focus on treatment targetting mitochondria function to reverse this phenotype.

Keywords:  DNA, mitochondrial; adenosine triphosphate; kidney deficiency; peroxisome proliferator-activated receptor gamma coactivator 1-alpha; thermogenesis

DOI:  https://doi.org/10.19852/j.cnki.jtcm.20221017.001
Mitochondrion. 2023 Jan 05. pii: S1567-7249(23)00002-8. [Epub ahead of print]

Mitochondrial dysfunction in cognitive neurodevelopmental disorders: Cause or effect?

Ayyappan Anitha, Ismail Thanseem, Mary Iype, Sanjeev V Thomas.

  Mitochondria have a crucial role in brain development and neurogenesis, both in embryonic and adult brains. Since the brain is the highest energy consuming organ, it is highly vulnerable to mitochondrial dysfunction. This has been implicated in a range of brain disorders including, neurodevelopmental conditions, psychiatric illnesses, and neurodegenerative diseases. Genetic variations in mitochondrial DNA (mtDNA), and nuclear DNA encoding mitochondrial proteins, have been associated with several cognitive disorders. However, it is not yet clear whether mitochondrial dysfunction is a primary cause of these conditions or a secondary effect. Our review article deals with this topic, and brings out recent advances in mitochondria-oriented therapies. Mitochondrial dysfunction could be involved in the pathogenesis of a subset of disorders involving cognitive impairment. In these patients, mitochondrial dysfunction could be the cause of the condition, rather than the consequence. There are vast areas in this topic that remains to be explored and elucidated.

Keywords:  Antioxidant therapy; Brain energetics; Cause or effect; Cognitive disorders; Cybrid; Mitochondria

DOI:  https://doi.org/10.1016/j.mito.2023.01.002
Trends Neurosci. 2023 Jan 10. pii: S0166-2236(22)00239-9. [Epub ahead of print]

Mitochondrial signalling and homeostasis: from cell biology to neurological disease.

Jack J Collier, Monika Oláhová, Thomas G McWilliams, Robert W Taylor.

  Efforts to understand how mitochondrial dysfunction contributes to neurodegeneration have primarily focussed on the role of mitochondria in neuronal energy metabolism. However, progress in understanding the etiological nature of emerging mitochondrial functions has yielded new ideas about the mitochondrial basis of neurological disease. Studies aimed at deciphering how mitochondria signal through interorganellar contacts, vesicular trafficking, and metabolic transmission have revealed that mitochondrial regulation of immunometabolism, cell death, organelle dynamics, and neuroimmune interplay are critical determinants of neural health. Moreover, the homeostatic mechanisms that exist to protect mitochondrial health through turnover via nanoscale proteostasis and lysosomal degradation have become integrated within mitochondrial signalling pathways to support metabolic plasticity and stress responses in the nervous system. This review highlights how these distinct mitochondrial pathways converge to influence neurological health and contribute to disease pathology.

Keywords:  immunity; inflammation; metabolism; mitochondrial-derived vesicles; mitochondria–lysosome axis; quality control

DOI:  https://doi.org/10.1016/j.tins.2022.12.001
Geroscience. 2023 Jan 09.

GTP energy dependence of endocytosis and autophagy in the aging brain and Alzheimer's disease.

Ricardo A Santana Martínez, Priyanka D Pinky, Benjamin A Harlan, Gregory J Brewer.

  Increased interest in the aging and Alzheimer's disease (AD)-related impairments in autophagy in the brain raise important questions about regulation and treatment. Since many steps in endocytosis and autophagy depend on GTPases, new measures of cellular GTP levels are needed to evaluate energy regulation in aging and AD. The recent development of ratiometric GTP sensors (GEVALS) and findings that GTP levels are not homogenous inside cells raise new issues of regulation of GTPases by the local availability of GTP. In this review, we highlight the metabolism of GTP in relation to the Rab GTPases involved in formation of early endosomes, late endosomes, and lysosomal transport to execute the autophagic degradation of damaged cargo. Specific GTPases control macroautophagy (mitophagy), microautophagy, and chaperone-mediated autophagy (CMA). By inference, local GTP levels would control autophagy, if not in excess. Additional levels of control are imposed by the redox state of the cell, including thioredoxin involvement. Throughout this review, we emphasize the age-related changes that could contribute to deficits in GTP and AD. We conclude with prospects for boosting GTP levels and reversing age-related oxidative redox shift to restore autophagy. Therefore, GTP levels could regulate the numerous GTPases involved in endocytosis, autophagy, and vesicular trafficking. In aging, metabolic adaptation to a sedentary lifestyle could impair mitochondrial function generating less GTP and redox energy for healthy management of amyloid and tau proteostasis, synaptic function, and inflammation.

Keywords:  Aging; Alzheimer’s; Autophagy; Endocytosis; Energetics; GTP; Lysosomes; Mitophagy

DOI:  https://doi.org/10.1007/s11357-022-00717-x
Brain Commun. 2023 ;5(1): fcac340

Multiple pathways of lipid dysregulation in amyotrophic lateral sclerosis.

Katherine Phan, Ying He, Surabhi Bhatia, Russell Pickford, Gordon McDonald, Srestha Mazumder, Hannah C Timmins, John R Hodges, Olivier Piguet, Nicolas Dzamko, Glenda M Halliday, Matthew C Kiernan, Woojin Scott Kim.

  Amyotrophic lateral sclerosis is a rapidly progressing neurodegenerative disease characterized by the degeneration of motor neurons and loss of various muscular functions. Dyslipidaemia is prevalent in amyotrophic lateral sclerosis with aberrant changes mainly in cholesterol ester and triglyceride. Despite this, little is known about global lipid changes in amyotrophic lateral sclerosis or in relation to disease progression. The present study incorporated a longitudinal lipidomic analysis of amyotrophic lateral sclerosis serum with a comparison with healthy controls using advanced liquid chromatography-mass spectrometry. The results established that diglyceride, the precursor of triglyceride, was enriched the most, while ceramide was depleted the most in amyotrophic lateral sclerosis compared with controls, with the diglyceride species (18:1/18:1) correlating significantly to neurofilament light levels. The prenol lipid CoQ8 was also decreased in amyotrophic lateral sclerosis and correlated to neurofilament light levels. Most interestingly, the phospholipid phosphatidylethanolamine and its three derivatives decreased with disease progression, in contrast to changes with normal ageing. Unsaturated lipids that are prone to lipid peroxidation were elevated with disease progression with increases in the formation of toxic lipid products. Furthermore, in vitro studies revealed that phosphatidylethanolamine synthesis modulated TARDBP expression in SH-SY5Y neuronal cells. Finally, diglyceride, cholesterol ester and ceramide were identified as potential lipid biomarkers for amyotrophic lateral sclerosis diagnosis and monitoring disease progression. In summary, this study represents a longitudinal lipidomics analysis of amyotrophic lateral sclerosis serum and has provided new insights into multiple pathways of lipid dysregulation in amyotrophic lateral sclerosis.

Keywords:  amyotrophic lateral sclerosis; biomarkers; lipidomics

DOI:  https://doi.org/10.1093/braincomms/fcac340
Cell Rep. 2023 Jan 04. pii: S2211-1247(22)01843-5. [Epub ahead of print]42(1): 111942

Mutations in the transcriptional regulator MeCP2 severely impact key cellular and molecular signatures of human astrocytes during maturation.

Jialin Sun, Sivan Osenberg, Austin Irwin, Li-Hua Ma, Nigel Lee, Yangfei Xiang, Feng Li, Ying-Wooi Wan, In-Hyun Park, Mirjana Maletic-Savatic, Nurit Ballas.

  Mutations in the MECP2 gene underlie a spectrum of neurodevelopmental disorders, most commonly Rett syndrome (RTT). We ask whether MECP2 mutations interfere with human astrocyte developmental maturation, thereby affecting their ability to support neurons. Using human-based models, we show that RTT-causing MECP2 mutations greatly impact the key role of astrocytes in regulating overall brain bioenergetics and that these metabolic aberrations are likely mediated by dysfunctional mitochondria. During post-natal maturation, astrocytes rely on neurons to induce their complex stellate morphology and transcriptional changes. While MECP2 mutations cause cell-intrinsic aberrations in the astrocyte transcriptional landscape, surprisingly, they do not affect the neuron-induced astrocyte gene expression. Notably, however, astrocytes are unable to develop complex mature morphology due to cell- and non-cell-autonomous aberrations caused by MECP2 mutations. Thus, MECP2 mutations critically impact key cellular and molecular features of human astrocytes and, hence, their ability to interact and support the structural and functional maturation of neurons.

Keywords:  CP: Neuroscience; MeCP2; Rett syndrome; energy metabolism; human astrocytes; human neurons; mitochondria; morphology; neurodevelopment; transcription

DOI:  https://doi.org/10.1016/j.celrep.2022.111942
Free Radic Biol Med. 2023 Jan 10. pii: S0891-5849(23)00010-2. [Epub ahead of print]

Characterization of mitochondrial and metabolic alterations induced by trisomy 21 during neural differentiation.

Kendra M Prutton, John O Marentette, Kenneth N Maclean, James R Roede.

Cellular redox state directs differentiation of induced pluripotent stem cells (iPSC) by energy metabolism control and ROS generation. As oxidative stress and mitochondrial dysfunction have been extensively reported in Down syndrome (DS), we evaluated mitochondrial phenotypes and energy metabolism during neural differentiation of DS iPSCs to neural progenitor cells (NPCs). Our results indicate early maturation of mitochondrial networks and elevated NADPH oxidase 4 (NOX4) expression in DS iPSCs. DS cells also fail to transition from glycolysis to oxidative phosphorylation during differentiation. Specifically, DS NPCs show an increased energetic demand that is limited in their mitochondrial and glycolytic response to mitochondrial distress. Additionally, DS iPSC and NPC non-mitochondrial oxygen consumption was significantly impacted by NOX inhibition. Together, these data build upon previous evidence of accelerated neural differentiation in DS that correlates with cellular redox state. We demonstrate the potential for mitochondrial and non-mitochondrial ROS sources to impact differentiation timing in the context of DS, which could contribute to developmental deficits in this condition.

DOI: https://doi.org/10.1016/j.freeradbiomed.2023.01.009
Neurobiol Dis. 2023 Jan 09. pii: S0969-9961(23)00008-6. [Epub ahead of print] 105994

Disrupted axon-glia communication leads to neurodegeneration in metabolic diseases.

Stacey A Sakowski, Masha G Savelieff, Eva L Feldman.



Keywords:  Alzheimer's disease; Astrocyte; Diabetes; Metabolic crosstalk; Metabolic syndrome; Neuron; Obesity; Oligodendrocyte; Schwann cell

DOI:  https://doi.org/10.1016/j.nbd.2023.105994
Neurosci Biobehav Rev. 2023 Jan 03. pii: S0149-7634(23)00003-9. [Epub ahead of print]145 105034

Effects of postnatal glucocorticoids on brain structure in preterm infants, a scoping review.

Isabella Robles, Margarita Alethea Eidsness, Katherine E Travis, Heidi M Feldman, Sarah E Dubner.

  Glucocorticoids (GC) are used in neonatal intensive care units to prevent or reduce the severity of chronic lung disease in preterm infants and have been implicated in impaired neurodevelopment. Our objective was to identify what is known about the effects of postnatal GC treatment in human preterm infants on structural brain development and to identify gaps in the literature. Following Arksey and O'Malley's scoping review methodological framework, we searched scientific literature databases for original research on human preterm infants, postnatal GCs, and brain structure. 11 studies assessed the effects of GCs on structural brain outcomes. 56 studies reported brain injury, but not structure. Dexamethasone was consistently associated with decreased total and regional brain volumes, including cerebellar volumes. Hydrocortisone was often, but not always associated with absence of brain volume differences. No studies examined the impact of inhaled GC on brain structure. Additional research on the effects of neonatal GCs after preterm birth on a variety of structural brain measures is required for understanding contributions to neurodevelopment and informing practice guidelines.

Keywords:  Brain; Glucocorticoids; Human; Imaging; Prematurity

DOI:  https://doi.org/10.1016/j.neubiorev.2023.105034
Mol Omics. 2023 Jan 10.

Lipid profile variability in children at different ages measured in dried blood spots.

Helena Beatriz Ferreira, Tânia Melo, Hugo Rocha, Artur Paiva, Pedro Domingues, M Rosário Domingues.

Dried blood spot (DBS) is a minimally invasive sampling technique that has several advantages over conventional venipuncture/arterial blood sampling. More recently, DBS has also been applied for lipidomics analysis, but this is an area that requires further research. The few works found in the literature on lipidomics of DBS samples performed the analysis in adult samples, leaving pediatric ages unmapped. The objective of this study was to assess the variability of the lipid profile (identified by high-resolution C18 RP-LC-MS/MS) of DBS at pediatric age (0-10 days, 2-18 months, and 3-13 years) and to identify age-related variations. The results revealed that the lipidomic signature of the three age groups is significantly different, especially for a few species of neutral lipids and phosphatidylcholines. The main contributors to the differentiation of the groups correspond to 3 carnitine (Car), 2 cholesteryl ester (CE), 2 diacylglycerol (DG), 2 triacylglycerol (TG), 3 phosphatidylcholine (PC), 1 ether-linked PC, 1 phosphatidylethanolamine (PE), 1 ether-linked PE and 1 phosphatidylinositol (PI) species, all with statistically significant differences. Additionally, lipid species containing linoleic acid (C18:2) were shown to have significantly lower levels in the 0-10 days group with a gradual increase in the 2-18 month, reaching the highest concentrations in the 3-13 year group. The results of this study highlighted the adaptations of the lipid profile at different pediatric ages. These results may help improve understanding of the evolution of lipid metabolism throughout childhood and should be investigated further.

DOI: https://doi.org/10.1039/d2mo00206j
Mol Genet Metab Rep. 2023 Mar;34 100954

Establishment of a flow cytometry screening method for patients with glucose transporter 1 deficiency syndrome.

Sachie Nakamura, Yasushi Ito, Hiroko Hayakawa, Shiho Aoki, Takanori Yamagata, Hitoshi Osaka.

   Objective: We assessed the usefulness of flow cytometry as a functional assay to measure glucose transporter 1 (GLUT1) levels on the surface of red blood cells (RBCs) from Japanese patients with glucose transporter 1 deficiency syndrome (Glut1DS).
Methods: We recruited 13 genetically confirmed Glut1DS patients with a solute carrier family 2 member 1 (SLC2A1) mutation (eight missense, one frameshift, two nonsense, and two deletion) and one clinically suspected Glut1DS-like patient without an SLC2A1 mutation, and collected whole blood with informed consent. We stained pelleted RBCs (1 μL) from the patients with a Glut1.RBD ligand and anti-glycophorin A antibody, which recognizes a human RBC membrane protein, and analyzed the cells using flow cytometry.
Results: Relative GLUT1 levels quantified by flow cytometry in 11 of 13 patients with definite Glut1DS were 90% below those of healthy controls. Relative GLUT1 levels were not reduced in two of 13 Glut1DS patients who had a missense mutation and no intellectual disability and one Glut1DS-like patient without an SLC2A1 mutation. Relative GLUT1 levels were significantly reduced in Glut1DS patients with an SLC2A1 mutation, more severe intellectual disability, and spasticity.
Conclusions: This method to detect GLUT1 levels on RBCs is simple and appears to be an appropriate screening assay to identify severe Glut1DS patients in the early stage before the development of irreversible neurologic damage caused by chronic hypoglycorrhachia.

Keywords:  Flow cytometry; GLUT1; Glucose transporter 1 deficiency syndrome (Glut1DS); SLC2A1; Screening method

DOI:  https://doi.org/10.1016/j.ymgmr.2022.100954
Comput Struct Biotechnol J. 2023 ;21 388-400

Artificial intelligence-driven meta-analysis of brain gene expression identifies novel gene candidates and a role for mitochondria in Alzheimer's disease.

Caitlin A Finney, Fabien Delerue, Wendy A Gold, David A Brown, Artur Shvetcov.

  Alzheimer's disease (AD) is the most common form of dementia. There is no treatment and AD models have focused on a small subset of genes identified in familial AD. Microarray studies have identified thousands of dysregulated genes in the brains of patients with AD yet identifying the best gene candidates to both model and treat AD remains a challenge. We performed a meta-analysis of microarray data from the frontal cortex (n = 697) and cerebellum (n = 230) of AD patients and healthy controls. A two-stage artificial intelligence approach, with both unsupervised and supervised machine learning, combined with a functional network analysis was used to identify functionally connected and biologically relevant novel gene candidates in AD. We found that in the frontal cortex, genes involved in mitochondrial energy, ATP, and oxidative phosphorylation, were the most significant dysregulated genes. In the cerebellum, dysregulated genes were involved in mitochondrial cellular biosynthesis (mitochondrial ribosomes). Although there was little overlap between dysregulated genes between the frontal cortex and cerebellum, machine learning models comprised of this overlap. A further functional network analysis of these genes identified that two downregulated genes, ATP5L and ATP5H, which both encode subunits of ATP synthase (mitochondrial complex V) may play a role in AD. Combined, our results suggest that mitochondrial dysfunction, particularly a deficit in energy homeostasis, may play an important role in AD.

Keywords:  Alzheimer’s disease; Gene expression; Machine learning; Microarray; Mitochondria

DOI:  https://doi.org/10.1016/j.csbj.2022.12.018
Metabolomics. 2023 Jan 12. 19(1): 5

Acute metabolic alterations in the hippocampus are associated with decreased acetylation after blast induced TBI.

Megha Kumari, Palkin Arora, Priyanka Sharma, Yasha Hasija, Poonam Rana, Maria M D'souza, Namas Chandra, Richa Trivedi.

   INTRODUCTION: Blast induced Traumatic brain injury (BI-TBI) is common among military personnels as well as war affected civilians. In the war zone, people can also encounter repeated exposure of blast wave, which may affect their cognition and metabolic alterations.
OBJECTIVE: In this study we assess the metabolic and histological changes in the hippocampus of rats at 24 h post injury.
METHOD: Rats were divided into four groups: (i) Sham; (ii) Mild TBI (mi); (iii) Moderate TBI (mo); and (iv) Repetitive mild TBI (rm TBI) and then subjected to different intensities of blast exposure. Hippocampal tissues were collected after 24 h of injury for proton nuclear magnetic resonance spectroscopy (1H NMR spectroscopy) and immunohistochemical (IHC) analysis.
RESULTS: The metabolic alterations were found in the hippocampal tissue samples and these alterations showed significant change in glutamate, N-Acetylaspartic acid (NAA), acetate, creatine, phosphoethanolamine (PE), ethanolamine and PC/choline concentrations in rmTBI rats only. IHC studies revealed that AH3 (Acetyl histone) positive cells were decreased in rm TBI tissue samples in comparison to other TBI groups and sham rats. This might reflect an epigenetic alteration due to repeated blast exposure at 24 h post injury. Additionally, astrogliosis was observed in miTBI and moTBI hippocampal tissue while no change was observed in rmTBI tissues.
CONCLUSION: The present study reports altered acetylation in the presence of altered metabolism in hippocampal tissue of blast induced rmTBI at 24 h post injury. Mechanistic understanding of these intertwined processes may help in the development of better therapeutic pathways and agents for blast induced TBI in near future.

Keywords:  Acetylation; Acute injury; Blast induced TBI; Hippocampus; Metabolomics

DOI:  https://doi.org/10.1007/s11306-022-01970-z
Front Pharmacol. 2022 ;13 1031637

Reversal of spatial memory impairment by phosphodiesterase 3 inhibitor cilostazol is associated with reduced neuroinflammation and increased cerebral glucose uptake in aged male mice.

Shuichi Yanai, Tetsuro Tago, Jun Toyohara, Tomoko Arasaki, Shogo Endo.

  The nucleotide second messenger 3', 5'-cyclic adenosine monophosphate (cAMP) and 3', 5'-cyclic guanosine monophosphate (cGMP) mediate fundamental functions of the brain, including learning and memory. Phosphodiesterase 3 (PDE3) can hydrolyze both cAMP and cGMP and appears to be involved in the regulation of their contents in cells. We previously demonstrated that long-term administration of cilostazol, a PDE3 inhibitor, maintained good memory performance in aging mice. Here, we report on studies aimed at determining whether cilostazol also reverses already-impaired memory in aged male mice. One month of oral 1.5% cilostazol administration in 22-month-old mice reversed age-related declines in hippocampus-dependent memory tasks, including the object recognition and the Morris water maze. Furthermore, cilostazol reduced neuroinflammation, as evidenced by immunohistochemical staining, and increased glucose uptake in the brain, as evidence by positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG). These results suggest that already-expressed memory impairment in aged male mice that depend on cyclic nucleotide signaling can be reversed by inhibition of PDE3. The reversal of age-related memory impairments may occur in the central nervous system, either through cilostazol-enhanced recall or strengthening of weak memories that otherwise may be resistant to recall.

Keywords:  [18F]FDG PET; aging; cilostazol; memory; neuroinflammation; phosphodiesterase 3 inhibitor

DOI:  https://doi.org/10.3389/fphar.2022.1031637
JIMD Rep. 2023 Jan;64(1): 53-56

Isolated neurological presentations of mevalonate kinase deficiency.

Eva M M Hoytema van Konijnenburg, Esmeralda Oussoren, Joost Frenkel, Peter M van Hasselt.

  Mevalonate kinase (MK) deficiency is a rare autosomal recessive metabolic disorder caused by pathogenic variants in the MVK gene with a broad phenotypic spectrum including autoinflammation, developmental delay and ataxia. Typically, neurological symptoms are considered to be part of the severe end of the phenotypical spectrum and are reported to be in addition to the autoinflammatory symptoms. Here, we describe a patient with MK deficiency with severe neurological symptoms but without autoinflammation and we found several similar patients in the literature. Possibly, the non-inflammatory phenotype is related to a specific genotype: the MVK p.(His20Pro)/p.(Ala334Thr) variant. There is probably an underdetection of the neurological MK deficient phenotype without inflammatory symptoms as clinicians may not test for MK deficiency when patients present with only neurological symptoms. In conclusion, although rare, neurological symptoms without hyperinflammation might be more common than expected in MK deficiency. It seems relevant to consider MK deficiency in patients with psychomotor delay and ataxia, even if there are no inflammatory symptoms.

Keywords:  ataxia; autoinflammation; mevalonate kinase deficiency; mevalonic acid; psychomotor delay

DOI:  https://doi.org/10.1002/jmd2.12348
J Biol Chem. 2023 Jan 06. pii: S0021-9258(23)00015-7. [Epub ahead of print] 102883

Loss of small GTPase Rab7 activation in prion infection negatively affects a feedback loop regulating neuronal cholesterol metabolism.

Pearl Cherry, Li Lu, Su Yeon Shim, Vincent Ebacher, Waqas Tahir, Hermann M Schatzl, Samia Hannaoui, Sabine Gilch.

  Prion diseases are fatal and infectious neurodegenerative diseases that occur in humans and animals. They are caused by the misfolding of the cellular prion protein PrPc into the infectious isoform PrPSc. PrPSc accumulates mostly in endo-lysosomal vesicles of prion-infected cells, eventually causing neurodegeneration. In response to prion infection, elevated cholesterol levels and a reduction in membrane-attached small GTPase Rab7 have been observed in neuronal cells. Here, we investigated the molecular events causing an impaired Rab7 membrane attachment and the potential mechanistic link with elevated cholesterol levels in prion infection. We demonstrate that prion infection is associated with reduced levels of active Rab7 (Rab7.GTP) in persistently prion-infected neuronal cell lines, primary cerebellar granular neurons, and neurons in the brain of mice with terminal prion disease. In primary cerebellar granular neurons, levels of active Rab7 were increased during the very early stages of the prion infection prior to a significant decrease concomitant with PrPSc accumulation. The reduced activation of Rab7 in prion-infected neuronal cell lines is also associated with its reduced ubiquitination status, decreased interaction with its effector RILP, and altered lysosomal positioning. Consequently, the Rab7-mediated trafficking of low-density lipoprotein (LDL) to lysosomes is delayed. This results in an impaired feedback regulation of cholesterol synthesis leading to an increase in cholesterol levels. Notably, transient over-expression of the constitutively active mutant of Rab7 rescues the delay in the LDL trafficking, hence reducing cholesterol levels and attenuating PrPSc propagation, demonstrating a mechanistic link between the loss of Rab7.GTP and elevated cholesterol levels.

Keywords:  Rab7; cholesterol metabolism; low-density lipoprotein (LDL); prion; ubiquitination

DOI:  https://doi.org/10.1016/j.jbc.2023.102883
Cells. 2022 Dec 21. pii: 26. [Epub ahead of print]12(1):

Astrocyte L-Lactate Signaling in the ACC Regulates Visceral Pain Aversive Memory in Rats.

Zafar Iqbal, Shu Liu, Zhuogui Lei, Aruna Surendran Ramkrishnan, Mastura Akter, Ying Li.

  Pain involves both sensory and affective elements. An aspect of the affective dimension of pain is its sustained unpleasantness, characterized by emotional feelings. Pain results from interactions between memory, attentional, and affective brain circuitry, and it has attracted enormous interest in pain research. However, the brain targets and signaling mechanism involved in pain remain elusive. Using a conditioned place avoidance (CPA) paradigm, we show that colorectal distention (CRD magnitude ≤ 35 mmHg, a subthreshold for pain) paired with a distinct environment can cause significant aversion to a location associated with pain-related insults in rats. We show a substantial increase in the L-lactate concentration in the anterior cingulate cortex (ACC) following CPA training. Local exogenous infusion of lactate into the ACC enhances aversive memory and induces the expression of the memory-related plasticity genes pCREB, CREB, and Erk1/2. The pharmacological experiments revealed that the glycogen phosphorylation inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) impairs memory consolidation. Furthermore, short-term Gi pathway activation of ACC astrocytes before CPA training significantly decreases the lactate level and suppresses pain-related aversive learning. The effects were reversed by the local infusion of lactate into the ACC. Our study demonstrates that lactate is released from astrocytes in vivo following visceral pain-related aversive learning and memory retrieval and induces the expression of the plasticity-related immediate early genes CREB, pCREB, and Erk1/2 in the ACC. Chronic visceral pain is an important factor in the pathophysiology of irritable bowel syndrome (IBS). The current study provides evidence that astrocytic activity in the ACC is required for visceral pain-related aversive learning and memory.

Keywords:  anterior cingulate cortex (ACC); astrocyte; aversion memory; chemogenetic; colorectal distension; conditioned place avoidance (CPA); lactate; optogenetic

DOI:  https://doi.org/10.3390/cells12010026
PLoS Genet. 2023 Jan 10. 19(1): e1010558

Atp7b-dependent choroid plexus dysfunction Causes transient copper deficit and metabolic changes in the developing mouse brain.

Clorissa L Washington-Hughes, Shubhrajit Roy, Herana Kamal Seneviratne, Senthilkumar S Karuppagounder, Yulemni Morel, Jace W Jones, Alex Zak, Tong Xiao, Tatiana N Boronina, Robert N Cole, Namandjé N Bumpus, Christopher J Chang, Ted M Dawson, Svetlana Lutsenko.

Copper (Cu) has a multifaceted role in brain development, function, and metabolism. Two homologous Cu transporters, Atp7a (Menkes disease protein) and Atp7b (Wilson disease protein), maintain Cu homeostasis in the tissue. Atp7a mediates Cu entry into the brain and activates Cu-dependent enzymes, whereas the role of Atp7b is less clear. We show that during postnatal development Atp7b is necessary for normal morphology and function of choroid plexus (ChPl). Inactivation of Atp7b causes reorganization of ChPl' cytoskeleton and cell-cell contacts, loss of Slc31a1 from the apical membrane, and a decrease in the length and number of microvilli and cilia. In ChPl lacking Atp7b, Atp7a is upregulated but remains intracellular, which limits Cu transport into the brain and results in significant Cu deficit, which is reversed only in older animals. Cu deficiency is associated with down-regulation of Atp7a in locus coeruleus and catecholamine imbalance, despite normal expression of dopamine-β-hydroxylase. In addition, there are notable changes in the brain lipidome, which can be attributed to inhibition of diacylglyceride-to-phosphatidylethanolamine conversion. These results identify the new role for Atp7b in developing brain and identify metabolic changes that could be exacerbated by Cu chelation therapy.

DOI: https://doi.org/10.1371/journal.pgen.1010558
Nutrients. 2023 Jan 03. pii: 250. [Epub ahead of print]15(1):

Long-Term High-Fat Diet Consumption Induces Cognitive Decline Accompanied by Tau Hyper-Phosphorylation and Microglial Activation in Aging.

Zheng Liang, Xiaokang Gong, Runjia Ye, Yang Zhao, Jin Yu, Yanna Zhao, Jian Bao.

  High-fat diet (HFD) intake is commonly related to a substantial risk of cognitive impairment for senior citizens over 65 years of age, which constitutes a profound global health burden with several economic and social consequences. It is critical to investigate the effects of long-term HFD consumption on cognitive function and to inspect the potential underlying mechanisms. In the present study, 9-month-old male C57BL/6 mice were randomly assigned to either a normal diet (ND, 10 kcal% fat) or an HFD diet (60 kcal% fat) for 10 months. Then a series of behavioral tests, and histological and biochemistry examinations of the hippocampus and cortex proceeded. We found that long-term HFD-fed aged mice exhibited cognitive function decline in the object place recognition test (OPR). Compared with the ND group, the HFD-fed mice showed Tau hyperphosphorylation at ps214 in the hippocampus and at ps422 and ps396 in the cortex, which was accompanied by GSK-3β activation. The higher activated phenotype of microglia in the brain of the HFD group was typically evidenced by an increased average area of the cell body and reduced complexity of microglial processes. Immunoblotting showed that long-term HFD intake augmented the levels of inflammatory cytokines IL-6 in the hippocampus. These findings indicate that long-term HFD intake deteriorates cognitive dysfunctions, accompanied by Tau hyperphosphorylation, microglial activation, and inflammatory cytokine expression, and that the modifiable lifestyle factor contributes to the cognitive decline of senior citizens.

Keywords:  Tau hyperphosphorylation; cognitive decline; high-fat diet; microglial activation

DOI:  https://doi.org/10.3390/nu15010250