bims-medebr 2022-01-02 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2022–01–02
27 papers selected by
Regina F. Fernández, Johns Hopkins University

The role of SLC transporters for brain health and disease.
Choline Supplementation Partially Restores Dendrite Structural Complexity in Developing Iron-Deficient Mouse Hippocampal Neurons.
Nutrients to Improve Mitochondrial Function to Reduce Brain Energy Deficit and Oxidative Stress in Migraine.
Effects of Simultaneous Exposure to a Western Diet and Wheel-Running Training on Brain Energy Metabolism in Female Rats.
Current and potential new treatment strategies for creatine deficiency syndromes.
Decreased O-GlcNAcylation and mitochondrial dysfunction are involving in low glucose induced Alzheimer's disease-like phenotype in induced pluripotent stem cell-derived neurons.
Role of ketone bodies in diabetes-induced dementia: sirtuins, insulin resistance, synaptic plasticity, mitochondrial dysfunction, and neurotransmitter.
Sexually Dimorphic Effects of a Western Diet on Brain Mitochondrial Bioenergetics and Neurocognitive Function.
Exercise-induced metabolic changes in astrocytes in the 5xFAD mouse model of Alzheimer's Disease.
Spinal cord injury chronically depresses glucose uptake in the rodent model.
Exposure to 3'Sialyllactose-Poor Milk during Lactation Impairs Cognitive Capabilities in Adulthood.
Modeling AD-related metabolic impairments in the TgF344-AD rat model.
Interfering with mitochondrial dynamics sensitizes glioblastoma multiforme to temozolomide chemotherapy.
Neurometabolite correlates with personality and stress in healthy emerging adults: A focus on sex differences.
Mitochondrial changes caused by LDL in hippocampal neurons.
Activation of vitamin D receptor inhibits Tau phosphorylation is associated with reduction of iron accumulation in APP/PS1 transgenic mice.
Lack of association between cortical amyloid deposition and glucose metabolism in early stage Alzheimer´s disease patients.
Long-term light and moderate exercise intervention similarly prevent both hippocampal and glycemic dysfunction in pre-symptomatic type 2 diabetic rats.
Mitochondrial Function and Parkinson's Disease: From the Perspective of the Electron Transport Chain.
Alzheimer's disease: A potential diabetes type 3.
Mitochondrial phenotypes in iPSC AD models.
1H NMR metabolomic profiling of human cerebrospinal fluid in aging process.
Neuromonitoring in Rare Disorders of Metabolism.
Late-Onset Calorie Restriction Worsens Cognitive Performances and Increases Frailty Level in Female Wistar Rats.
Impact of GAD65 and/or GAD67 deficiency on perinatal development in rats.
Astrocytic GLUT1 ablation improves systemic glucose metabolism and promotes cognition.
Neonatal GALT gene replacement offers metabolic and phenotypic correction through early adulthood in a rat model of classic galactosemia.

Cell Mol Life Sci. 2021 Dec 31. 79(1): 20

The role of SLC transporters for brain health and disease.

Yen T K Nguyen, Hoa T T Ha, Tra H Nguyen, Long N Nguyen.

  The brain exchanges nutrients and small molecules with blood via the blood-brain barrier (BBB). Approximately 20% energy intake for the body is consumed by the brain. Glucose is known for its critical roles for energy production and provides substrates for biogenesis in neurons. The brain takes up glucose via glucose transporters GLUT1 and 3, which are expressed in several neural cell types. The brain is also equipped with various transport systems for acquiring amino acids, lactate, ketone bodies, lipids, and cofactors for neuronal functions. Unraveling the mechanisms by which the brain takes up and metabolizes these nutrients will be key in understanding the nutritional requirements in the brain. This could also offer opportunities for therapeutic interventions in several neurological disorders. For instance, emerging evidence suggests a critical role of lactate as an alternative energy source for neurons. Neuronal cells express monocarboxylic transporters to acquire lactate. As such, treatment of GLUT1-deficient patients with ketogenic diets to provide the brain with alternative sources of energy has been shown to improve the health of the patients. Many transporters are present in the brain, but only a small number has been characterized. In this review, we will discuss about the roles of solute carrier (SLC) transporters at the blood brain barrier (BBB) and neural cells, in transport of nutrients and metabolites in the brain.

Keywords:  Blood-brain barrier; GLUT1; MCT1; Mfsd2a; SLC transporter

DOI:  https://doi.org/10.1007/s00018-021-04074-4
J Nutr. 2021 Dec 27. pii: nxab429. [Epub ahead of print]

Choline Supplementation Partially Restores Dendrite Structural Complexity in Developing Iron-Deficient Mouse Hippocampal Neurons.

Thomas W Bastian, William C von Hohenberg, Olivia R Kaus, Lorene M Lanier, Michael K Georgieff.

   BACKGROUND: Fetal-neonatal iron deficiency causes learning/memory deficits that persist after iron repletion. Simplified hippocampal neuron dendrite structure is a key mechanism underlying these long-term impairments. Early-life choline supplementation, with postnatal iron repletion, improves learning/memory performance in formerly iron-deficient (ID) rats.
OBJECTIVE: To understand how choline improves iron deficiency-induced hippocampal dysfunction, we hypothesized that direct choline supplementation of ID hippocampal neurons may restore cellular energy production and dendrite structure.
METHODS: Embryonic mouse hippocampal neuron cultures were made ID with 9µM deferoxamine beginning at 3 days in vitro (DIV). At 11DIV, iron repletion (i.e., deferoxamine removal) was performed on a subset of ID cultures. These neuron cultures, and iron-sufficient (IS) control cultures, were treated with 30µM choline (or vehicle) between 11 and 18DIV. At 18DIV, the independent and combined effects of iron and choline treatments (two-factor ANOVA) on neuronal dendrite numbers, lengths and overall complexity and mitochondrial respiration and glycolysis were analyzed.
RESULTS: Choline treatment of ID neurons (ID+Cho) significantly increased overall dendrite complexity (150, 160, 180 and 210µm from the soma) compared to untreated ID neurons to a level that was no longer significantly different from IS neurons. The average and total length of primary dendrites in ID+Cho neurons were significantly increased by ∼15% compared to ID neurons, indicating choline stimulation of dendrite growth. Measures of mitochondrial respiration, glycolysis and ATP production rates were not significantly altered in ID+Cho neurons compared to ID neurons, remaining significantly reduced compared to IS neurons. Iron repletion significantly improved mitochondrial respiration, ATP production rates, overall dendrite complexity (100-180µm from the soma) and dendrite and branch lengths compared to untreated ID neurons.
CONCLUSIONS: Since choline partially restores dendrite structure in ID neurons without iron repletion, it may have therapeutic potential when iron treatment is not possible or advisable. Choline's mechanism in ID neurons requires further investigation.

Keywords:  ATP; Iron; brain development; choline; dendrites; energy metabolism; glycolysis; iron deficiency; mitochondria; neuron development; oxidative phosphorylation

DOI:  https://doi.org/10.1093/jn/nxab429
Nutrients. 2021 Dec 10. pii: 4433. [Epub ahead of print]13(12):

Nutrients to Improve Mitochondrial Function to Reduce Brain Energy Deficit and Oxidative Stress in Migraine.

Michal Fila, Cezary Chojnacki, Jan Chojnacki, Janusz Blasiak.

  The mechanisms of migraine pathogenesis are not completely clear, but 31P-nuclear magnetic resonance studies revealed brain energy deficit in migraineurs. As glycolysis is the main process of energy production in the brain, mitochondria may play an important role in migraine pathogenesis. Nutrition is an important aspect of migraine pathogenesis, as many migraineurs report food-related products as migraine triggers. Apart from approved anti-migraine drugs, many vitamins and supplements are considered in migraine prevention and therapy, but without strong supportive evidence. In this review, we summarize and update information about nutrients that may be important for mitochondrial functions, energy production, oxidative stress, and that are related to migraine. Additionally, we present a brief overview of caffeine and alcohol, as they are often reported to have ambiguous effects in migraineurs. The nutrients that can be considered to supplement the diet to prevent and/or ameliorate migraine are riboflavin, thiamine, magnesium ions, niacin, carnitine, coenzyme Q10, melatonin, lipoic acid, pyridoxine, folate, and cobalamin. They can supplement a normal, healthy diet, which should be adjusted to individual needs determined mainly by the physiological constitution of an organism. The intake of caffeine and alcohol should be fine-tuned to the history of their use, as withdrawal of these agents in regular users may become a migraine trigger.

Keywords:  dietary intervention in migraine; energy production; glycolysis; migraine; mitochondria; oxidative stress

DOI:  https://doi.org/10.3390/nu13124433
Nutrients. 2021 Nov 26. pii: 4242. [Epub ahead of print]13(12):

Effects of Simultaneous Exposure to a Western Diet and Wheel-Running Training on Brain Energy Metabolism in Female Rats.

Marta Maria Nowacka-Chmielewska, Daniela Liśkiewicz, Konstancja Grabowska, Arkadiusz Liśkiewicz, Łukasz Marczak, Anna Wojakowska, Natalia Pondel, Mateusz Grabowski, Jarosław Jerzy Barski, Andrzej Małecki.

   BACKGROUND: In the pathogenesis of central nervous system disorders (e.g., neurodegenerative), an important role is attributed to an unhealthy lifestyle affecting brain energy metabolism. Physical activity in the prevention and treatment of lifestyle-related diseases is getting increasing attention.
METHODS: We performed a series of assessments in adult female Long Evans rats subjected to 6 weeks of Western diet feeding and wheel-running training. A control group of lean rats was fed with a standard diet. In all experimental groups, we measured physiological parameters (animal weights, body composition, serum metabolic parameters). We assessed the impact of simultaneous exposure to a Western diet and wheel-running on the cerebrocortical protein expression (global proteomic profiling), and in the second part of the experiment, we measured the cortical levels of protein related to brain metabolism (Western blot).
RESULTS: Western diet led to an obese phenotype and induced changes in the serum metabolic parameters. Wheel-running did not reduce animal weights or fat mass but significantly decreased serum glucose level. The global proteome analysis revealed that the altered proteins were functionally annotated as they were involved mostly in metabolic pathways. Western blot analysis showed the downregulation of the mitochondrial protein-Acyl-CoA dehydrogenase family member 9, hexokinase 1 (HK1)-enzyme involved in principal glucose metabolism pathways and monocarboxylate transporter 2 (MCT2). Wheel-running reversed this decline in the cortical levels of HK1 and MCT2.
CONCLUSION: The cerebrocortical proteome is affected by a combination of physical activity and Western diet in female rats. An analysis of the cortical proteins involved in brain energy metabolism provides a valuable basis for the deeper investigation of changes in the brain structure and function induced by simultaneous exposure to a Western diet and physical activity.

Keywords:  brain energy metabolism; female rats; global brain proteome; western diet; wheel-running training

DOI:  https://doi.org/10.3390/nu13124242
Mol Genet Metab. 2021 Dec 17. pii: S1096-7192(21)01190-2. [Epub ahead of print]

Current and potential new treatment strategies for creatine deficiency syndromes.

Gabriella Fernandes-Pires, Olivier Braissant.

  Creatine deficiency syndromes (CDS) are inherited metabolic disorders caused by mutations in GATM, GAMT and SLC6A8 and mainly affect central nervous system (CNS). AGAT- and GAMT-deficient patients lack the functional brain endogenous creatine (Cr) synthesis pathway but express the Cr transporter SLC6A8 at blood-brain barrier (BBB), and can thus be treated by oral supplementation of high doses of Cr. For Cr transporter deficiency (SLC6A8 deficiency or CTD), current treatment strategies benefit one-third of patients. However, as their phenotype is not completely reversed, and for the other two-thirds of CTD patients, the development of novel more effective therapies is needed. This article aims to review the current knowledge on Cr metabolism and CDS clinical aspects, highlighting their current treatment possibilities and the most recent research perspectives on CDS potential therapeutics designed, in particular, to bring new options for the treatment of CTD.

Keywords:  Creatine deficiency syndromes; Creatine treatment; GAMT, AGAT; Gene therapy.; SLC6A8

DOI:  https://doi.org/10.1016/j.ymgme.2021.12.005
Alzheimers Dement. 2021 Dec;17 Suppl 2 e058620

Decreased O-GlcNAcylation and mitochondrial dysfunction are involving in low glucose induced Alzheimer's disease-like phenotype in induced pluripotent stem cell-derived neurons.

Chia-Wei Huang, Gerald W Hart.

BACKGROUND: Evidence supporting that glucose metabolic abnormalities occur prior to Alzheimer's disease (AD) symptoms. Reduced O-GlcNAc (OGN) levels likely arise from impaired glucose metabolism or availability and correlates with AD pathogenesis. So far, the mechanism of sAD and the role of OGN in AD pathology remained largely unknown due to a lack of human sAD model.
METHOD: We generated human cortical neurons from human-induced pluripotent stem cells and treated neurons with glucose reduction media. FluoroJADE staining and cell viability assays were used to study the effects of low glucose on the degenerative status and cell viability of neurons. Abnormal protein production, phosphorylation, and accumulation were detected by western blotting and immunofluorescence staining using antibody against p-tau and beta-amyloid. Neurite and synaptic structure were observed by immunofluorescence staining, while neuronal network activity was detected by multi-electrode array electrophysiological analyses. Mitochondrial abnormalities, including increased oxidative stress, reduced membrane potential, and mitochondrial dysfunction, were evaluated using CM-H2 DCFDA, JC-1 and Seahorse, respectively.
RESULT: We show that lowering glucose level to 2mM leads to dramatic increases of neuron degeneration on day 3 and 5 of treatment and decreased cell viability on day 7. Interestingly, long-term low glucose treatment induces AD features in neurons, including abnormal hyperphosphorylated tau accumulation and increasing beta-amyloid production. Besides, glucose deficiency also causes decreased neurite coverage, synapse density, and neuron network activity. Furthermore, we find that O-GlcNAc levels are significantly reduced soon after low glucose treatment and remain low until the end of experiment. Raising O-GlcNAc levels by thiamet-G, inhibitor of O-GlcNAcase, even in low glucose treated neurons, rescues low glucose-induced AD phenotypes. Moreover, our data shows that O-GlcNAc dysregulation causes mitochondrial abnormalities, which occur before any other degenerative phenotype appeared, and may be one of the underlying mechanisms of sAD onset and pathogenesis.
CONCLUSION: We established a human neuron model in which the pathological features are reproduced by glucose deficiency. This platform can serve as a tool for better understanding molecular processes involved in neurodegeneration in sAD. Our results also suggest that dysregulated O-GlcNAc levels and mitochondrial dysfunction by glucose deficiency are involved in the onset and progression of sAD.

DOI: https://doi.org/10.1002/alz.058620
Nutr Rev. 2021 Dec 27. pii: nuab118. [Epub ahead of print]

Role of ketone bodies in diabetes-induced dementia: sirtuins, insulin resistance, synaptic plasticity, mitochondrial dysfunction, and neurotransmitter.

Ji Yeon Chung, Oh Yoen Kim, Juhyun Song.

  Patients with type 2 diabetes can have several neuropathologies, such as memory deficits. Recent studies have focused on the association between metabolic imbalance and neuropathological problems, and the associated molecular pathology. Diabetes triggers neuroinflammation, impaired synaptic plasticity, mitochondrial dysfunction, and insulin resistance in the brain. Glucose is a main energy substrate for neurons, but under certain conditions, such as fasting and starvation, ketone bodies can be used as an energy fuel for these cells. Recent evidence has shed new light on the role of ketone bodies in regulating several anti-inflammation cellular pathways and improving glucose metabolism, insulin action, and synaptic plasticity, thereby being neuroprotective. However, very high amount of ketone bodies can be toxic for the brain, such as in ketoacidosis, a dangerous complication that may occur in type 1 diabetes mellitus or alcoholism. Recent findings regarding the relationship between ketone bodies and neuropathogenesis in dementia are reviewed in this article. They suggest that the adequately low amount of ketone bodies can be a potential energy source for the treatment of diabetes-induced dementia neuropathology, considering the multifaceted effects of the ketone bodies in the central nervous system. This review can provide useful information for establishing the therapeutic guidelines of a ketogenic diet for diabetes-induced dementia.

Keywords:  diabetes-induced dementia; insulin resistance; ketone bodies; mitochondrial dysfunction; neuroinflammation; sirtuins

DOI:  https://doi.org/10.1093/nutrit/nuab118
Nutrients. 2021 Nov 24. pii: 4222. [Epub ahead of print]13(12):

Sexually Dimorphic Effects of a Western Diet on Brain Mitochondrial Bioenergetics and Neurocognitive Function.

Magen N Lord, Jun-Won Heo, Albino G Schifino, Jessica R Hoffman, Kristen N Donohue, Jarrod A Call, Emily E Noble.

  A Western diet (WD), high in sugars and saturated fats, impairs learning and memory function and contributes to weight gain. Mitochondria in the brain provide energy for neurocognitive function and may play a role in body weight regulation. We sought to determine whether a WD alters behavior and metabolic outcomes in male and female rodents through impacting hippocampal and hypothalamic mitochondrial bioenergetics. Results revealed a sexually dimorphic macronutrient preference, where males on the WD consumed a greater percentage of calories from fat/protein and females consumed a greater percentage of calories from a sugar-sweetened beverage. Both males and females on a WD gained body fat and showed impaired glucose tolerance when compared to same-sex controls. Males on a WD demonstrated impaired hippocampal functioning and an elevated tendency toward a high membrane potential in hippocampal mitochondria. Comprehensive bioenergetics analysis of WD effects in the hypothalamus revealed a tissue-specific adaption, where males on the WD oxidized more fat, and females oxidized more fat and carbohydrates at peak energy demand compared to same-sex controls. These results suggest that adult male rats show a susceptibility toward hippocampal dysfunction on a WD, and that hypothalamic mitochondrial bioenergetics are altered by WD in a sex-specific manner.

Keywords:  hippocampus; learning and memory; metabolic flexibility; mitochondrial respiration; obesity

DOI:  https://doi.org/10.3390/nu13124222
Alzheimers Dement. 2021 Dec;17 Suppl 2 e058627

Exercise-induced metabolic changes in astrocytes in the 5xFAD mouse model of Alzheimer's Disease.

Sarah Alyssa Rosolen.

BACKGROUND: Alzheimer's Disease (AD), a progressive neurodegenerative disease and the second most common cause of death in Australia (ABS 2019), is an increasingly prominent societal issue, exacerbated by an ageing population and the absence of effective disease modifying treatments. Focus has shifted to targeting modifiable risk factors to slow or prevent AD onset and progression, such as exercise, diet and other lifestyle factors. Adiponectin, an anti-inflammatory adipokine, regulates energy metabolism and is associated with metabolic pathways potentiated following exercise. Animal and human studies involving both healthy individuals and those with metabolic dysfunction, have consistently demonstrated increased serum adiponectin levels following various exercise regimes. The ability of adiponectin to cross the blood brain barrier and thus mediate neuronal metabolism is contentious. However, the expression of adiponectin receptors within neuronal cells implies adiponectin holds an important function within the brain.
METHODS: We investigated the cortical expression of adiponectin receptors, AdipoR1 and AdipoR2, in the aged 5XFAD mouse model of AD following an exercise intervention. Immunohistochemical techniques were applied to double stain brain tissue for adiponectin receptor and astrocyte expression.
RESULTS: We observed neuronal AdipoR1 and AdipoR2 expression throughout the cortex of both exercised and sedentary control mice, as well as extensive expression of activated astrocytes.
CONCLUSIONS: Colocalisation analysis suggests astrocytes may utilise adiponectin receptors to fuel their metabolic activity in degrading toxic amyloid plaques within the AD brain.

DOI: https://doi.org/10.1002/alz.058627
Neurosci Lett. 2021 Dec 23. pii: S0304-3940(21)00795-3. [Epub ahead of print]771 136416

Spinal cord injury chronically depresses glucose uptake in the rodent model.

Shalini Jaiswal, Fiona Brabazon, Ramona von Leden, Deanna Acs, Sean Collier, Nathanael Allison, Bernard Dardzinski, Kimberly R Byrnes.

  The pathophysiology following spinal cord injury (SCI) progresses from its lesion epicenter resulting in cellular and systemic changes acutely, sub-acutely and chronically. The symptoms of the SCI depend upon the severity of the injury and its location in the spinal cord. However, there is lack of studies that have longitudinally assessed acute through chronic in vivo changes following SCI. In this combinatorial study we fill this gap by evaluating acute to chronic effects of moderate SCI in rats. We have used fluorodeoxyglucose (FDG) imaging with positron emission tomography (PET) as a marker to assess glucose metabolism, motor function, and immunohistochemistry to examine changes following moderate SCI. Our results demonstrate decreased FDG uptake at the injury site chronically at days 28 and 90 post injury compared to baseline. This alteration in glucose uptake was not restricted to the lesion site, showing depressed FDG uptake in non-injured areas (cervical spinal cord and cerebellum). The alteration in glucose uptake was correlated with reductions in neuronal cell viability and increases in glial cell activation at 90 days at the lesion site, as well as chronic impairments in motor function. These data demonstrate the chronic effects of SCI on glucose metabolism both within the lesion and distally within the spinal cord and brain.

Keywords:  Fluorodeoxyglucose; PET/CT; Spinal Cord Injury

DOI:  https://doi.org/10.1016/j.neulet.2021.136416
Nutrients. 2021 Nov 23. pii: 4191. [Epub ahead of print]13(12):

Exposure to 3'Sialyllactose-Poor Milk during Lactation Impairs Cognitive Capabilities in Adulthood.

Edoardo Pisa, Alberto Martire, Valentina Chiodi, Alice Traversa, Viviana Caputo, Jonas Hauser, Simone Macrì.

  Breast milk exerts pivotal regulatory functions early in development whereby it contributes to the maturation of brain and associated cognitive functions. However, the specific components of maternal milk mediating this process have remained elusive. Sialylated human milk oligosaccharides (HMOs) represent likely candidates since they constitute the principal neonatal dietary source of sialic acid, which is crucial for brain development and neuronal patterning. We hypothesize that the selective neonatal lactational deprivation of a specific sialylated HMOs, sialyl(alpha2,3)lactose (3'SL), may impair cognitive capabilities (attention, cognitive flexibility, and memory) in adulthood in a preclinical model. To operationalize this hypothesis, we cross-fostered wild-type (WT) mouse pups to B6.129-St3gal4tm1.1Jxm/J dams, knock-out (KO) for the gene synthesizing 3'SL, thereby providing milk with approximately 80% 3'SL content reduction. We thus exposed lactating WT pups to a selective reduction of 3'SL and investigated multiple cognitive domains (including memory and attention) in adulthood. Furthermore, to account for the underlying electrophysiological correlates, we investigated hippocampal long-term potentiation (LTP). Neonatal access to 3'SL-poor milk resulted in decreased attention, spatial and working memory, and altered LTP compared to the control group. These results support the hypothesis that early-life dietary sialylated HMOs exert a long-lasting role in the development of cognitive functions.

Keywords:  3′-sialyllactose; brain; breast milk; executive function; human milk oligosaccharides; lactation; memory; sialic acid

DOI:  https://doi.org/10.3390/nu13124191
Alzheimers Dement. 2021 Dec;17 Suppl 2 e058576

Modeling AD-related metabolic impairments in the TgF344-AD rat model.

Abbi Lynn R Hernandez, Sarah L Ding, Alexis L Simley, Lori L McMahon, Christy S Carter.

BACKGROUND: Alzheimer's disease (AD) not only affects cognition and neuropathology, but has several other facets capable of negatively impacting quality of life, including impaired metabolic function, which is present in ∼80% of cases. However, the influence of metabolism is seldom considered when utilizing rodent models of AD, particularly in conjunction with cognitive impairment and neuropathology. Therefore, we characterized metabolic and cognitive status of the TgF344-AD rat model first presented in Cohen et al. in 2013.
METHOD: Aged (20-26 mo) female rats were utilized. Metabolic health was characterized through body composition analysis, food consumption quantification, insulin and glucose tolerance tests and hypothalamic p-AKT/AKT response to insulin. Cognition was assessed through object discrimination tasks, including novel object discrimination, working memory/object discrimination and working memory/biconditional association tasks. This series of increasingly complex behavioral tasks requires proper function of individual brain regions, as well as integration of information across these regions, in which AD-related pathology is commonly observed.
RESULT: AD rats required significantly more trials before reaching criterion performance across several tasks, including a working memory/object recognition task and a working memory/biconditional association task. However, there were no group differences in ability to perform a simple object discrimination, demonstrating all rats were able to participate procedurally, therefore differences in performance can be attributed to cognitive impairment. AD rats had significantly more body fat than WT, and lost significantly less weight than their wild type (WT) counterparts while relocating to our colony, despite consistent food consumption across groups. Moreover, glucose appears to be rapidly degraded in AD rats relative to WT controls, indicating significant differences in metabolic function across genotypes.
CONCLUSION: Together, these data indicate that not only do we observe genotype-specific deficits in cognitive function, but also that the transgenic rats metabolize their energy sources in different ways than WT littermates. The long range projection neurons required to support task acquisition are more metabolically costly than locally projecting neurons, and thus most likely affected by the impaired metabolic function in this rats. Therefore, treatments targeting these metabolic deficits may help prevent or ameliorate AD-related cognitive decline.

DOI: https://doi.org/10.1002/alz.058576
J Cell Mol Med. 2021 Dec 28.

Interfering with mitochondrial dynamics sensitizes glioblastoma multiforme to temozolomide chemotherapy.

Nan Wang, Renxuan Huang, Kunmeng Yang, Yichun He, Yufei Gao, Delu Dong.

  Glioblastoma multiforme (GBM) is a primary tumour of the central nervous system (CNS) that exhibits the highest degree of malignancy. Radiotherapy and chemotherapy are essential to prolong the survival time of patients. However, clinical work has demonstrated that sensitivity of GBM to chemotherapy decreases with time. The phenomenon of multi-drug resistance (MDR) reminds us that there may exist some fundamental mechanisms in the process of chemo-resistance. We tried to explore the mechanism of GBM chemo-resistance from the perspective of energy metabolism. First, we found that the oxidative phosphorylation (OXPHOS) level of SHG44 and U87 cells increased under TMZ treatment. In further studies, it was found that the expression of PINK1 and mitophagy flux downstream was downregulated in GBM cells, which were secondary to the upregulation of TP53 in tumour cells under TMZ treatment. At the same time, we examined the mitochondrial morphology in tumour cells and found that the size of mitochondria in tumour cells increased under the treatment of TMZ, which originated from the regulation of AMPK on the subcellular localization of Drp1 under the condition of unbalanced energy supply and demand in tumour cells. The accumulation of mitochondrial mass and the optimization of mitochondrial quality accounted for the increased oxidative phosphorylation, and interruption of the mitochondrial fusion process downregulated the efficiency of oxidative phosphorylation and sensitized GBM cells to TMZ, which was also confirmed in the in vivo experiment. What is more, interfering with this process is an innovative strategy to overcome the chemo-resistance of GBM cells.

Keywords:  AMPK; TP53; glioblastoma multiforme; mitochondrial dynamics; temozolomide

DOI:  https://doi.org/10.1111/jcmm.17147
Neuroimage. 2021 Dec 22. pii: S1053-8119(21)01118-6. [Epub ahead of print]247 118847

Neurometabolite correlates with personality and stress in healthy emerging adults: A focus on sex differences.

Noora Tuovinen, Nursen Yalcin-Siedentopf, Anna-Sophia Welte, Christian M Siedentopf, Ruth Steiger, Elke R Gizewski, Alex Hofer.

  Personality traits have been linked with both brain structure and function. However, the exact relationship between personality traits and other behavioural measures with neurometabolites, measured with proton magnetic resonance spectroscopy, is not clear. Here we investigated the association between behavioural measures (i.e., personality traits, resilience, perceived stress, self-esteem, hopelessness, psychological distress) and metabolite ratios (i.e., of choline-containing compounds [Cho], creatine and phosphocreatine [Cr], and N-acetyl-aspartate [NAA]) in the posterior cingulate cortex (pCC) and the dorsal anterior cingulate cortex (dACC) and surrounding white matter (WM) regions in healthy emerging adults (N = 57, 26 women, mean age=23.40 years, SD=2.50). The pCC and the dACC were selected for their known involvement as important brain network hubs and their association to five factor personality dimensions and other psychological measures. Spectral analysis as well as statistics for demographic, clinical, and imaging data were performed. Correlation and multiple regression analyses were used to test the relationship between metabolite ratios and behavioural scores in the entire sample as well as in female and male participants separately. The entire sample showed significant (p<0.05) negative correlates of stress with the NAA/Cr ratio in the pCC, and of extraversion with WM metabolite ratios. In regards of sex differences, a significantly higher NAA/Cho ratio in the pCC (p<0.05), the dACC (p<0.01), and in the left and right posterior WM matter (p<0.05), and a lower Cho/Cr ratio in the dACC (p<0.01) was detected in women. Moreover, the two sexes differed in regards of metabolite correlates of openness, conscientiousness, extraversion, agreeableness, neuroticism, stress, hopelessness, and self-esteem, and in multiple regression model predictions. Our results point to a role of the ACC in conscientiousness through its involvement in higher-order cognitive control as part of the salience network and internally directed thoughts as part of the default mode network (DMN). Furthermore, the two sexes differ in terms of metabolite correlates of openness and conscientiousness in the pCC, suggesting mental process involvement through the DMN, and of agreeableness in the dACC, possibly through involvement in social cognitive processes, particularly in women. Additionally, our results suggest that the ACC is linked to the so-called Alpha-factor of personality. Our findings on stress correlates contribute to the existing literature of the involvement of the ACC as part of the limbic system. In addition, our results suggest a possible role of the pCC in stress-regulatory processes through a possible co-involvement of stress, hopelessness, and self-esteem in the pCC in men, where higher self-esteem may help to cope with stress.

Keywords:  Dorsal anterior cingulate; Magnetic resonance spectroscopy; Personality traits; Posterior cingulate; Sex differences; Stress perception

DOI:  https://doi.org/10.1016/j.neuroimage.2021.118847
Alzheimers Dement. 2021 Dec;17 Suppl 12 e058399

Mitochondrial changes caused by LDL in hippocampal neurons.

Hemelin Resende Farias, Leo Martins, Lílian Corrêa Costa Beber, Matheus Scarpatto Rodrigues, Fátima Guma, Jade de Oliveira.

BACKGROUND: Familial hypercholesterolemia (FH) is characterized by high plasma accumulation of low-density lipoproteins (LDL) due to mutations in the LDL receptor gene (Hobbs et al., Hum. Mutat., 1: 445-466, 1992). Furthermore, FH patients present a high incidence of cognitive impairments (Zambón et al., Am J ed, 123:267-274, 2010; Ariza et al., Eur J Intern Med., 34:e29-e31, 2016). Experimental studies also demonstrated that FH leads to an increase in blood-brain-barrier permeability (De Oliveira et al., J Alzheimers Dis, 78:97-115, 2020), which could allow the LDL to pass from the peripheral system to the central nervous system. Importantly, the cellular mechanisms responsible for neurotoxicity induced by LDL are unclear. Herein, we aimed to investigate whether LDL causes mitochondrial alterations in neurons.
METHOD: We exposed HT-22 cells (Mouse Hippocampal Neuronal Cell) to human isolated LDL (50 and 300 ug/mL) for 24 hours. Furthermore, mass and potential mitochondrial were evaluated by Mitotracker green (MTG) and red (MTR), respectively, and the reactive species generation was evaluated by DCF.
RESULT: Notably, when HT-22 cells were incubated with LDL (50 ug/mL), MTR fluorescence was decreased compared with control cells. The ratio between MTG and MTR fluorescence showed increased mitochondria mass compared to their activity, suggesting an increase of swollen and non-functional mitochondria. We observed in HT-22 cells exposed to LDL (300 ug/mL) that both MTG, MTR, and ratio MTR/MTG were decreased, suggesting mitochondrial dysfunction. It is known that mitochondrial dysfunction leads to the excessive production of reactive species, and this may cause damage to essential cell components. In this regard, next, we evaluated the reactive species formation using DCF. The reactive species formation was significantly increased in cells exposed to both concentrations of LDL (50 and 300 ug/mL) in two times of exposure (1 and 24 hours) compared with the control cells.
CONCLUSION: These findings indicate that LDL causes mitochondrial dysfunction, which appears to be a relevant event in hypercholesterolemia-induced cerebral dysfunction.

DOI: https://doi.org/10.1002/alz.058399
Neurochem Int. 2021 Dec 22. pii: S0197-0186(21)00306-5. [Epub ahead of print]153 105260

Activation of vitamin D receptor inhibits Tau phosphorylation is associated with reduction of iron accumulation in APP/PS1 transgenic mice.

Ting-Yao Wu, Ling-Xiao Zhao, Yan-Hui Zhang, Yong-Gang Fan.

  Vitamin D deficiency and iron accumulation are prevalent in the brains of Alzheimer's disease (AD) patients, however, whether Vitamin D has a role in the regulations of iron metabolism in the condition of AD remains unknown. Our previous studies revealed that vitamin D deficiency promotes β-amyloid (Aβ) deposition in the APP/PS1 mouse brains, while supplemented with a specific agonist of vitamin D receptor (VDR), paricalcitol (PAL), significantly reduced Aβ production via promoting the lysosomal degradation of β-site APP cleavage enzyme 1 (BACE1). In this study, our data suggested that activation of VDR by PAL significantly reduced the iron accumulation in the cortex and hippocampus of APP/PS1 mice through downregulation of Transferrin receptor (TFR) by reducing iron-regulatory protein 2 (IRP2) expression. Furthermore, activation of VDR effectively reduced the phosphorylations of Tau at Ser396 and Thr181 sites via inhibiting the GSK3β phosphorylation (Tyr216). Taken together, our data suggest that activation of VDR could inhibit the phosphorylations of Tau possibly by repressing the iron accumulation-induced upregulation of GSK3β activity in the brains of APP/PS1 mice. Thus, activation of VDR may be an effective strategy for treating AD.

Keywords:  Alzheimer's disease; Iron accumulation; Tau phosphorylation; Vitamin D receptor

DOI:  https://doi.org/10.1016/j.neuint.2021.105260
Radiol Oncol. 2021 Dec 22.

Lack of association between cortical amyloid deposition and glucose metabolism in early stage Alzheimer´s disease patients.

Daniela Ehrlich, Andreas Dunzinger, Gertraud Malsiner-Walli, Bettina Grün, Raffi Topakian, Marina Hodolic, Elmar Kainz, Robert Pichler.

   BACKGROUND: Beta amyloid (Aβ) causes synaptic dysfunction leading to neuronal death. It is still controversial if the magnitude of Aβ deposition correlates with the degree of cognitive impairment. Diagnostic imaging may lead to a better understanding the role of Aβ in development of cognitive deficits. The aim of the present study was to investigate if Aβ deposition in the corresponding brain region of early stage Alzheimer´s disease (AD) patients, directly correlates to neuronal dysfunction and cognitive impairment indicated by reduced glucose metabolism.
PATIENTS AND METHODS: In 30 patients with a clinical phenotype of AD and amyloid positive brain imaging, 2-[18F] fluoro-2-deoxy-d-glucose (FDG) PET/CT was performed. We extracted the average [18F] flutemetamol (Vizamyl) uptake for each of the 16 regions of interest in both hemispheres and computed the standardized uptake value ratio (SUVR) by dividing the Vimazyl intensities by the mean signal of positive and negative control regions. Data were analysed using the R environment for statistical computing and graphics.
RESULTS: Any negative correlation between Aβ deposition and glucose metabolism in 32 dementia related and corresponding brain regions in AD patients was not found. None of the correlation coefficient values were statistically significant different from zero based on two-sided p- value.
CONCLUSIONS: Regional Aβ deposition did not correlate negatively with local glucose metabolism in early stage AD patients. Our findings support the role of Aβ as a valid biomarker, but does not permit to conclude that Aβ is a direct cause for an aberrant brain glucose metabolism and neuronal dysfunction.

Keywords:  Alzheimer disease; FDG; PET; tau

DOI:  https://doi.org/10.2478/raon-2021-0051
Am J Physiol Endocrinol Metab. 2021 Dec 27.

Long-term light and moderate exercise intervention similarly prevent both hippocampal and glycemic dysfunction in pre-symptomatic type 2 diabetic rats.

Subrina Jesmin, Takeru Shima, Mariko Soya, Kanako Takahashi, Koki Omura, Kasane Ogura, Hikaru Koizumi, Hideaki Soya.

  A pre-diabetic population has an increased risk of cognitive decline as well as type 2 diabetes mellitus (T2DM). The present study investigated whether the progression of memory dysfunction and dysregulated brain glycogen metabolism is prevented with four months of exercise intervention from the pre-symptomatic stage in T2DM rat model. Memory function and biochemical and molecular profiles were assessed in the pre-symptomatic stage of OLETF rats, a T2DM model, with LETO rats as genetic control. These rats were subjected to light- or moderate-intensity treadmill running for four months with repetition of the same experiments. Significant hippocampal-dependent memory dysfunction was observed in the pre-symptomatic stage of OLETF rats, accompanied by downregulated levels of hippocampal monocarboxylate transporter 2 (MCT2), a neuronal lactate-transporter, without alteration in hippocampal glycogen levels. Four months of light or moderate exercise from the pre-symptomatic stage of T2DM normalized glycemic parameters and also hippocampal molecular normalization through MCT2, glycogen, and brain-derived neurotrophic factor (BDNF) levels with the improvement of memory dysfunction in OLETF rats. A four-month exercise regimen from the pre-symptomatic stage of T2DM at light and moderate intensities contributed to the prevention of the development of T2DM and the progression of cognitive decline with hippocampal lactate-transport and BDNF improvement.

Keywords:  Brain-derived neurotrophic factor; Monocarboxylate transporter 2; Pre-diabetes; Spatial memory; Type 2 diabetes

DOI:  https://doi.org/10.1152/ajpendo.00326.2021
Front Mol Neurosci. 2021 ;14 797833

Mitochondrial Function and Parkinson's Disease: From the Perspective of the Electron Transport Chain.

Jeng-Lin Li, Tai-Yi Lin, Po-Lin Chen, Ting-Ni Guo, Shu-Yi Huang, Chun-Hong Chen, Chin-Hsien Lin, Chih-Chiang Chan.

  Parkinson's disease (PD) is known as a mitochondrial disease. Some even regarded it specifically as a disorder of the complex I of the electron transport chain (ETC). The ETC is fundamental for mitochondrial energy production which is essential for neuronal health. In the past two decades, more than 20 PD-associated genes have been identified. Some are directly involved in mitochondrial functions, such as PRKN, PINK1, and DJ-1. While other PD-associate genes, such as LRRK2, SNCA, and GBA1, regulate lysosomal functions, lipid metabolism, or protein aggregation, some have been shown to indirectly affect the electron transport chain. The recent identification of CHCHD2 and UQCRC1 that are critical for functions of complex IV and complex III, respectively, provide direct evidence that PD is more than just a complex I disorder. Like UQCRC1 in preventing cytochrome c from release, functions of ETC proteins beyond oxidative phosphorylation might also contribute to the pathogenesis of PD.

Keywords:  Parkinson’s disease; apoptosis; electron transport chain; mitochondria quality control; mitophagy

DOI:  https://doi.org/10.3389/fnmol.2021.797833
Alzheimers Dement. 2021 Dec;17 Suppl 2 e058533

Alzheimer's disease: A potential diabetes type 3.

Andrea González, Calfio Camila, Ricardo Benjamin Maccioni.

BACKGROUND: Alzheimer's disease (AD) is the most prevalent cause of dementia in the elderly. Neuronal death and synaptic dysfunctions are considered the main hallmarks of this disease. The latter could be directly associated to an impaired metabolism. In particular, glucose metabolism dysregulation has demonstrated to be a key regulatory element in the onset and progression of AD, which is why nowadays AD is considered the type 3 diabetes.
METHODS: Within this revised topic, we provide an analysis regarding the influence of glucose metabolism in AD from three different perspectives: i) As a regulator of the energy source, ii) through several metabolic alterations, such as insulin resistance, that modify peripheral signaling pathways that influence the activation of the immune system (e.g., insulin resistance, diabetes, etc.) and iii) as modulators of various key post-translational modifications for protein aggregation.
RESULTS: During our research, it was demonstrated the relationship between glucose metabolism dysregulation and the onset and Alzheimer's disease: The latter is mediated by several metabolic alterations. Among those, included in our research, are metabolic dysregulation events (e.g insulin resistance), which in turn alters the proper ATP generation, and finally, post-translational modifications, e.g., glycosylation and phosphorylation that mediates protein aggregation (i.e tau hyperphosphorylation that leads to misfolding and pathological self-assembly).
CONCLUSIONS: Alzheimer's disease onset and development is related to a glucose metabolism impairment that affects energy source (ATP) regulation, several metabolic alterations such as insulin resistance, and mediator of post-translational modifications in key proteins (i.e tau) that promotes its self-assembly and aggregation. Thus, considering all the above mentioned, is it seems plausible to consider Alzheimer as the diabetes type 3.

DOI: https://doi.org/10.1002/alz.058533
Alzheimers Dement. 2021 Dec;17 Suppl 2 e058489

Mitochondrial phenotypes in iPSC AD models.

Kaitlin Flannagan, Julia A Stopperan, Benjamin M Troutwine, Colton R Lysaker, Taylor Strope, Julia Draper, Cynthia Shaddy-Gouvion, Jay Vivian, Mohammad Haeri, Heather M Wilkins.

BACKGROUND: Mitochondrial dysfunction is observed in Alzheimer's disease (AD). Altered mitochondrial respiration, cytochrome oxidase (COX) Vmax, and mitophagy are observed in human subjects and animal models of AD. Models derived from induced pluripotent stem cells (iPSCs) may not recapitulate these phenotypes after reprogramming from differentiated adult cells. We examined mitochondrial function across iPSC derived models including cerebral organoids, forebrain neurons, and astrocytes. Postmortem brain tissue was used as a comparison.
METHOD: iPSCs were reprogrammed from fibroblasts either from the University of Kansas Alzheimer's Disease Research Center (KU ADRC) cohort or purchased from WiCell. Postmortem brain samples were from the KU ADRC cohort when available. A total of four non-demented and four sporadic AD iPSC lines were examined. Postmortem brain tissue was derived from 9 ND and 12 AD subjects. iPSCs were differentiated into neurons, astrocytes, or cerebral organoids using StemCell Technologies protocols and reagents. iPSC derived models and postmortem brain tissue were subjected to mitochondrial respiration analysis using Seahorse XF technology and spectrophotometric COX Vmax assays. iPSC derived neurons and astrocytes underwent fluorescent assays to determine mitochondrial mass, mitochondrial membrane potential, and mitophagy levels.
RESULT: iPSC derived neurons and cerebral organoids showed reduced COX Vmax in AD subjects. These results were not observed in astrocytes. Postmortem human brain samples showed reduced COX Vmax in AD subjects. iPSC derived neurons had reduced mitochondrial respiration parameters, mitochondrial mass, mitophagy, mitochondrial membrane potential, and mitochondrial superoxide production. iPSC derived astrocytes had reduced mitochondrial respiration parameters but increased mitochondrial membrane potential and no change in mitochondrial superoxide production.
CONCLUSION: iPSC derived models from AD subjects show mitochondrial dysfunction phenotypes like what is observed in postmortem brain. As iPSCs do not maintain their epigenetic signatures after reprogramming the observed phenotypes are likely due to other somatic factors.

DOI: https://doi.org/10.1002/alz.058489
Am J Transl Res. 2021 ;13(11): 12495-12508

1H NMR metabolomic profiling of human cerebrospinal fluid in aging process.

Huan-Tang Lin, Mei-Ling Cheng, Chi-Jen Lo, Wen-Chuin Hsu, Gigin Lin, Fu-Chao Liu.

The molecular process of biological aging might be accompanied by significant metabolic derangement, especially in the central nervous system (CNS), since the brain has an enormous energy demand. However, the metabolic signature of the aging process in cerebrospinal fluid (CSF) has not been thoroughly investigated, especially in the Asian population. In this prospective cohort study on CSF metabolomics using proton nuclear magnetic resonance (NMR) spectroscopy, fasting CSF samples from 75 cognitively unimpaired patients aged 20-92 years without diabetes or obesity, undergoing spinal anesthesia for elective surgery were analyzed. Several metabolites in CSF samples were identified as having a significant association with the aging process in cerebral circulation; among the metabolites, the levels of alanine, citrate, creatinine, lactate, leucine, tyrosine, and valine significantly increased in old patients compared to those in young patients. The combined CSF metabolite alterations in citrate, lactate, leucine, tyrosine, and valine had a superior correlation with the aging process in all age groups. In conclusion, our pilot study of aging CSF metabolomics in the Taiwanese population presents significantly altered CSF metabolites with potential relevance to the aging process. These metabolic alterations in CSF samples might imply increasing anaerobic glycolysis, mitochondrial dysfunction, and decreasing glucose utilization in cerebral circulation in aged patients.

Keywords: Aging process; cerebrospinal fluid; metabolomics; nuclear magnetic resonance
Yale J Biol Med. 2021 Dec;94(4): 645-655

Neuromonitoring in Rare Disorders of Metabolism.

Carlos Castillo-Pinto, Kuntal Sen, Andrea Gropman.

Inborn errors of metabolism (IEM) are a unique class of genetic diseases due to mutations in genes involved in key metabolic pathways. The combined incidence of IEM has been estimated to be as high as 1:1000. Urea Cycle disorders (UCD), one class of IEM, can present with cerebral edema and represent a possible target to explore the utility of different neuromonitoring techniques during an hyperammonemic crisis. The last two decades have brought advances in the early identification and comprehensive management of UCD, including further understanding of neuroimaging patterns associated with neurocognitive function. Nonetheless, very important questions remain about the potential acute neurotoxic effects of hyperammonemia to better understand how to treat and prevent secondary brain injury. In this review, we describe existing neuromonitoring techniques that have been used in rare metabolic disorders to assess and allow amelioration of ongoing brain injury. Directions of future research should be focused on identifying new diagnostic approaches in the management of metabolic crises to optimize care and reduce long term morbidity and mortality in patients with IEM.

Keywords: acute brain injury; inborn errors of metabolism; neuromonitoring; urea cycle disorders
J Gerontol A Biol Sci Med Sci. 2021 Nov 23. pii: glab353. [Epub ahead of print]

Late-Onset Calorie Restriction Worsens Cognitive Performances and Increases Frailty Level in Female Wistar Rats.

Milica R Prvulovic, Desanka J Milanovic, Predrag Z Vujovic, Milena S Jovic, Selma D Kanazir, Smilja T Todorovic, Aleksandra N Mladenovic.

  The current study aims to determine the potential benefits of calorie restriction (CR), one of the most promising paradigms for life span and healthspan extension, on cognitive performances in female Wistar rats during aging. As a measure of a healthspan, we evaluated the effects of different onset and duration of CR on frailty level. Female Wistar rats were exposed to either ad libitum (AL) or CR (60% of AL daily intake) food intake during aging. Two different CR protocols were used, life-long CR with an early-onset that started at the adult stage (6 months) and 3-month-long CR, started at the middle (15 months) and late-middle (21 months) age, thus defined as a late-onset CR. The effects of CR were evaluated using open-field, Y-maze, and novel object recognition tests. We broadened 2 tools for frailty assessment currently in use for experimental animals, and in alignment with our previous study, we created a physical-cognitive frailty tool that combines both physical and cognitive performances. Our results clearly showed that CR effects are highly dependent on CR duration and onset. While a life-long restriction with an early-onset has been proven as protective and beneficial, short-term restriction introduced at late age significantly worsens an animal's behavior and frailty. These results complement our previous study conducted in males and contribute to the understanding of sex differences in a response to CR during aging.

Keywords:  Aging; Healthspan; Memory; Nutrition; Sex

DOI:  https://doi.org/10.1093/gerona/glab353
FASEB J. 2022 Feb;36(2): e22123

Impact of GAD65 and/or GAD67 deficiency on perinatal development in rats.

Weiru Jiang, Toshikazu Kakizaki, Kazuyuki Fujihara, Shigeo Miyata, Yue Zhang, Takashi Suto, Daiki Kato, Shigeru Saito, Koji Shibasaki, Yasuki Ishizaki, Koji Isoda, Hideaki Yokoo, Hideru Obinata, Touko Hirano, Yoshiki Miyasaka, Tomoji Mashimo, Yuchio Yanagawa.

  GABA is a major neurotransmitter in the mammalian central nervous system. Glutamate decarboxylase (GAD) synthesizes GABA from glutamate, and two isoforms of GAD, GAD65, and GAD67, are separately encoded by the Gad2 and Gad1 genes, respectively. The phenotypes differ in severity between GAD single isoform-deficient mice and rats. For example, GAD67 deficiency causes cleft palate and/or omphalocele in mice but not in rats. In this study, to further investigate the functional roles of GAD65 and/or GAD67 and to determine the contribution of these isoforms to GABA synthesis during development, we generated various kinds of GAD isoform(s)-deficient rats and characterized their phenotypes. The age of death was different among Gad mutant rat genotypes. In particular, all Gad1-/- ; Gad2-/- rats died at postnatal day 0 and showed little alveolar space in their lungs, suggesting that the cause of their death was respiratory failure. All Gad1-/- ; Gad2-/- rats and 18% of Gad1-/- ; Gad2+/- rats showed cleft palate. In contrast, none of the Gad mutant rats including Gad1-/- ; Gad2-/- rats, showed omphalocele. These results suggest that both rat GAD65 and GAD67 are involved in palate formation, while neither isoform is critical for abdominal wall formation. The GABA content in Gad1-/- ; Gad2-/- rat forebrains and retinas at embryonic day 20 was extremely low, indicating that almost all GABA was synthesized from glutamate by GADs in the perinatal period. The present study shows that Gad mutant rats are a good model for further defining the role of GABA during development.

Keywords:  GABA; GAD65; GAD67; knockout rats; phenotypes

DOI:  https://doi.org/10.1096/fj.202101389R
Alzheimers Dement. 2021 Dec;17 Suppl 2 e058650

Astrocytic GLUT1 ablation improves systemic glucose metabolism and promotes cognition.

Carlos G Ardanaz, María Javier Ramírez Gil, Cristian Smerdou, Maite Solas.

BACKGROUND: Glucose supply from the blood to the brain is controlled by the glucose transporter GLUT1, highly expressed in astrocytes, which coordinate brain glucose supply, metabolization and storage. Ablating GLUT1 at the blood-brain barrier (BBB) endothelial cells leads to BBB breakdown, brain glucose hypometabolism and impaired cognition, but this approach cannot discriminate between insufficient glucose supply and BBB breakdown-derived effects. Such question is the focus of the present work, which aims to elucidate the relevance of astrocytic GLUT1 to cellular, brain and systemic glucose metabolism, and to cognition.
METHODS: To address these questions, GLUT1 was ablated from primary astrocytes. Cellular metabolism was examined using an extracellular flux analyzer (Seahorse). In vivo, astrocytic GLUT1 was ablated using a tamoxifen-inducible Cre/LoxP approach (GLUT1ΔGFAP mice). 18 F-FDG PET, glucose and insulin tolerance and insulin secretion and fasting-induced hyperphagia were characterized. BBB integrity was examined by vessel immunostaining and capillary-depleted brain analysis. Recognition and spatial memory were assessed using Novel Object Recognition and Morris Water Maze tasks. To address the implication of purinergic signaling in those effects, a purinergic receptor antagonist (PPADS) was intracerebroventricularly administered before each behavioral test.
RESULTS: GLUT1-ablated astrocytes showed reduced glucose uptake and glycolysis, although preserving total ATP production. Unexpectedly, postnatal astrocytic GLUT1 deletion increased CNS glucose utilization. GLUT1ΔGFAP mice showed an improved metabolic status from which obese animals especially benefited. Specifically, GLUT1ΔGFAP mice were more efficient at suppressing hyperphagia and readjusting systemic glucose levels after hyperglycemia, exhibiting marked increase in insulin secretion. These effects were coupled with enhanced BAT activity, and reduced BAT adiposity. In parallel with this improved systemic homeostasis, GLUT1ΔGFAP mice performed both recognition and spatial memory tasks properly, even outperforming control mice. Noteworthy, those effects could be due to higher astrocytic ATP release. Indeed, central administration of PPADS could reverse improvements in metabolic and cognitive behaviors in mice with astrocyte GLUT1 knockout.
CONCLUSION: Overall, this study demonstrates that astrocytic GLUT1 ablation impairs astrocytic glucose availability but enhances brain glucose utilization, reprograms systemic glucose metabolism towards a more efficient glucose-handling phenotype and promotes cognitive abilities, which could be a key factor in neurodegenerative diseases such as Alzheimer's disease.

DOI: https://doi.org/10.1002/alz.058650
J Inherit Metab Dis. 2021 Dec 28.

Neonatal GALT gene replacement offers metabolic and phenotypic correction through early adulthood in a rat model of classic galactosemia.

Jennifer M I Daenzer, Shauna A Rasmussen, Sneh Patel, James McKenna, Judith L Fridovich-Keil.



Keywords:  AAV9; GALT; galactosemia; gene therapy; metabolite; rat; scAAV9

DOI:  https://doi.org/10.1002/jimd.12471