bims-brabim Biomed News
on Brain bioenergetics and metabolism
Issue of 2021–11–14
39 papers selected by
João Victor Cabral-Costa, University of São Paulo
  1. The role of pathological tau in synaptic dysfunction in Alzheimer's diseases.
  2. Age-associated changes in microglia and astrocytes ameliorate blood-brain barrier dysfunction.
  3. Mitochondrial iron metabolism and neurodegenerative diseases.
  4. Disentangling Mitochondria in Alzheimer's Disease.
  5. Cholesterol in Brain Development and Perinatal Brain Injury: more than a Building Block.
  6. Multifaced role of protein deacetylase sirtuins in neurodegenerative disease.
  7. Alteration of mitochondrial homeostasis is an early event in a C. elegans model of human tauopathy.
  8. Amyloid beta increases ABCA1 and HMGCR protein expression, and cholesterol synthesis and accumulation in mice neurons and astrocytes.
  9. Mitochondrial dysfunction, oxidative stress, neuroinflammation, and metabolic alterations in the progression of Alzheimer's disease: A meta-analysis of in vivo magnetic resonance spectroscopy studies.
  10. Nitric Oxide Pathways in Neurovascular Coupling Under Normal and Stress Conditions in the Brain: Strategies to Rescue Aberrant Coupling and Improve Cerebral Blood Flow.
  11. Isoform-Specific Effects of Apolipoprotein E on Hydrogen Peroxide-Induced Apoptosis in Human Induced Pluripotent Stem Cell (iPSC)-Derived Cortical Neurons.
  12. Honokiol improves cognitive impairment in APP/PS1 mice through activating mitophagy and mitochondrial unfolded protein response.
  13. Characterization of mitochondrial DNA quantity and quality in the human aged and Alzheimer's disease brain.
  14. Conditional disruption of AMP kinase in dopaminergic neurons promotes Parkinson's disease-associated phenotypes in vivo.
  15. NLRP3 Inflammasome Blocking as a Potential Treatment of Central Insulin Resistance in Early-Stage Alzheimer's Disease.
  16. Astrocyte Circadian Timekeeping in Brain Health and Neurodegeneration.
  17. Revealing the Molecular Mechanisms of Alzheimer's Disease Based on Network Analysis.
  18. Lactate is an energy substrate for rodent cortical neurons and enhances their firing activity.
  19. Mitochondria as the target for disease related hormonal dysregulation.
  20. Pioglitazone transiently stimulates paraoxonase-2 expression in male nonhuman primate brain: Implications for sex-specific therapeutics in neurodegenerative disorders.
  21. Advances in PPARs Molecular Dynamics and Glitazones as a Repurposing Therapeutic Strategy through Mitochondrial Redox Dynamics against Neurodegeneration.
  22. Increased protein expression of ABCA1, HMG-CoA reductase, and CYP46A1 induced by garlic and allicin in the brain mouse and astrocytes-isolated from C57BL/6J.
  23. Omega-3 Polyunsaturated Fatty Acid Attenuates Uremia-Induced Brain Damage in Mice.
  24. Circadian Clocks, Sleep, and Metabolism.
  25. Ghrelin signaling in dCA1 suppresses neuronal excitability and impairs memory acquisition via PI3K/Akt/GSK-3β cascades.
  26. Mitophagy enhancers against phosphorylated Tau-induced mitochondrial and synaptic toxicities in Alzheimer disease.
  27. Genetic mutations of APOEε4 carriers in cardiovascular patients lead to the development of insulin resistance and risk of Alzheimer's disease.
  28. A noncanonical autophagy is involved in the transfer of Plasmodium-microvesicles to astrocytes.
  29. Targetable Pathways for Alleviating Mitochondrial Dysfunction in Neurodegeneration of Metabolic and Non-Metabolic Diseases.
  30. A fiber-deprived diet causes cognitive impairment and hippocampal microglia-mediated synaptic loss through the gut microbiota and metabolites.
  31. Role of Glia-Derived Extracellular Vesicles in Neurodegenerative Diseases.
  32. Brain transcriptome analysis of a CLN2 mouse model as a function of disease progression.
  33. Regulation of NAD+ metabolism in aging and disease.
  34. Hyperexcitability and brain morphological differences in mice lacking the cystine/glutamate antiporter, system xc.
  35. Molecular and Biochemical Pathways Encompassing Diabetes Mellitus and Dementia.
  36. Iron homeostasis and organismal aging.
  37. The role of microglia in prion diseases and possible therapeutic targets: a literature review.
  38. Astrocytic transcription factor REST upregulates glutamate transporter EAAT2, protecting dopaminergic neurons from manganese-induced excitotoxicity.
  39. The role of the host microbiome in autism and neurodegenerative disorders and effect of epigenetic procedures in the brain functions.
  1. Transl Neurodegener. 2021 Nov 10. 10(1): 45
    The role of pathological tau in synaptic dysfunction in Alzheimer's diseases.
    Moxin Wu, Manqing Zhang, Xiaoping Yin, Kai Chen, Zhijian Hu, Qin Zhou, Xianming Cao, Zhiying Chen, Dan Liu.
      Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, accompanied by amyloid-β (Aβ) overload and hyperphosphorylated tau accumulation in the brain. Synaptic dysfunction, an important pathological hallmark in AD, is recognized as the main cause of the cognitive impairments. Accumulating evidence suggests that synaptic dysfunction could be an early pathological event in AD. Pathological tau, which is detached from axonal microtubules and mislocalized into pre- and postsynaptic neuronal compartments, is suggested to induce synaptic dysfunction in several ways, including reducing mobility and release of presynaptic vesicles, decreasing glutamatergic receptors, impairing the maturation of dendritic spines at postsynaptic terminals, disrupting mitochondrial transport and function in synapses, and promoting the phagocytosis of synapses by microglia. Here, we review the current understanding of how pathological tau mediates synaptic dysfunction and contributes to cognitive decline in AD. We propose that elucidating the mechanism by which pathological tau impairs synaptic function is essential for exploring novel therapeutic strategies for AD.
    Keywords:  Alzheimer’s disease; Pathological tau; Synaptic dysfunction; Synaptic plasticity
    DOI:  https://doi.org/10.1186/s40035-021-00270-1
  2. Mol Ther Nucleic Acids. 2021 Dec 03. 26 970-986
    Age-associated changes in microglia and astrocytes ameliorate blood-brain barrier dysfunction.
    Jie Pan, Nana Ma, Jie Zhong, Bo Yu, Jun Wan, Wei Zhang.
      Blood-brain barrier (BBB) dysfunction is associated with an accumulation of neurotoxic molecules and increased infiltration of peripheral cells within the brain parenchyma. Accruing evidence suggests that microglia and astrocytes play a crucial role in the recovery of BBB integrity and the corralling of infiltrating cells into clusters after brain damage, but the mechanisms involved remain unclear. Intriguingly, the results of flow cytometry and immunofluorescence analyses have shown that BBB permeability to peripheral cells is substantially enhanced during normal aging at 12 months in mice. Thus, we used the SMART-seq2 method to perform RNA sequencing of microglia and astrocytes at five time points before and immediately after the BBB permeability change. Our comprehensive analyses revealed that microglia are characterized by marked alterations in the negative regulation of protein phosphorylation and phagocytic vesicles, whereas astrocytes show elevated enzyme or peptidase-inhibitor activity in the recovery of BBB function. Moreover, we identified a cassette of key genes that might ameliorate the insults of pathophysiological events in aging and neurodegenerative disease.
    Keywords:  RNA-seq; astrocyte; blood-brain barrier; dysfunction; microglia
    DOI:  https://doi.org/10.1016/j.omtn.2021.08.030
  3. Neurotoxicology. 2021 Nov 05. pii: S0161-813X(21)00153-4. [Epub ahead of print]
    Mitochondrial iron metabolism and neurodegenerative diseases.
    Ruiying Cheng, Varun Dhorajia, Jonghan Kim, Yuho Kim.
      Iron is a key element for mitochondrial function and homeostasis, which is also crucial for maintaining the neuronal system, but too much iron promotes oxidative stress. A large body of evidence has indicated that abnormal iron accumulation in the brain is associated with various neurogenerative diseases such as Huntington's disease, Alzheimer's disease, Parkinson's disease, and Friedreich's ataxia. However, it is still unclear how irregular iron status contributes to the development of neuronal disorders. Hence, the current review provides an update on the causal effects of iron overload in the development and progression of neurodegenerative diseases and discusses important roles of mitochondrial iron homeostasis in these disease conditions. Furthermore, this review discusses potential therapeutic targets for the treatments of iron overload-linked neurodegenerative diseases.
    Keywords:  Brain iron; Iron overload; Iron transport; Mitochondria; Neuron
    DOI:  https://doi.org/10.1016/j.neuro.2021.11.003
  4. Int J Mol Sci. 2021 Oct 26. pii: 11520. [Epub ahead of print]22(21):
    Disentangling Mitochondria in Alzheimer's Disease.
    Ashu Johri.
      Alzheimer's disease (AD) is a major cause of dementia in older adults and is fast becoming a major societal and economic burden due to an increase in life expectancy. Age seems to be the major factor driving AD, and currently, only symptomatic treatments are available. AD has a complex etiology, although mitochondrial dysfunction, oxidative stress, inflammation, and metabolic abnormalities have been widely and deeply investigated as plausible mechanisms for its neuropathology. Aβ plaques and hyperphosphorylated tau aggregates, along with cognitive deficits and behavioral problems, are the hallmarks of the disease. Restoration of mitochondrial bioenergetics, prevention of oxidative stress, and diet and exercise seem to be effective in reducing Aβ and in ameliorating learning and memory problems. Many mitochondria-targeted antioxidants have been tested in AD and are currently in development. However, larger streamlined clinical studies are needed to provide hard evidence of benefits in AD. This review discusses the causative factors, as well as potential therapeutics employed in the treatment of AD.
    Keywords:  Alzheimer’s disease; PGC-1α; antioxidants; mitochondria; neurodegeneration; sirtuins
    DOI:  https://doi.org/10.3390/ijms222111520
  5. Curr Neuropharmacol. 2021 Nov 11.
    Cholesterol in Brain Development and Perinatal Brain Injury: more than a Building Block.
    Fuxin Lu, Donna M Ferriero, Xiangning Jiang.
      The central nervous system (CNS) is enriched with important classes of lipids, in which cholesterol is known to make up a major portion of myelin sheaths, besides being a structural and functional unit of CNS cell membranes. Unlike in the adult brain where the cholesterol pool is relatively stable, cholesterol is synthesized and accumulated at the highest rate in the developing brain to meet the needs of rapid brain growth at this stage, which is also a critical period for neuroplasticity. In addition to its biophysical role in membrane organization, cholesterol is crucial for brain development due to its involvement in brain patterning, myelination, neuronal differentiation and synaptogenesis. Thus any injuries to the immature brain that affect cholesterol homeostasis may have long-term adverse neurological consequences. In this review, we describe the unique features of brain cholesterol biosynthesis and metabolism, cholesterol trafficking between different cell types, and highlight cholesterol-dependent biological processes during brain maturation. We also discuss the association of impaired cholesterol homeostasis with several forms of perinatal brain disorders in term and preterm newborns, including hypoxic-ischemic encephalopathy. Strategies targeting the cholesterol pathways may open new avenues for diagnosis and treatment of developmental brain injury.
    Keywords:  brain development; brain injury; cholesterol
    DOI:  https://doi.org/10.2174/1570159X19666211111122311
  6. Neurosci Biobehav Rev. 2021 Nov 03. pii: S0149-7634(21)00489-9. [Epub ahead of print]
    Multifaced role of protein deacetylase sirtuins in neurodegenerative disease.
    Rohan Gupta, Rashmi K Ambasta, Pravir Kumar.
      Sirtuins, a class III histone/protein deacetylase, is a central regulator of metabolic function and cellular stress response. This plays a pivotal role in the pathogenesis and progression of diseases such as cancer, neurodegeneration, metabolic syndromes, and cardiovascular disease. Sirtuins regulate biological and cellular processes, for instance, mitochondrial biogenesis, lipid and fatty acid oxidation, oxidative stress, gene transcriptional activity, apoptosis, inflammatory response, DNA repair mechanism, and autophagic cell degradation, which are known components for the progression of the neurodegenerative diseases (NDDs). Emerging evidence suggests that sirtuins are the useful molecular targets against NDDs like, Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD), and Amyotrophic Lateral Sclerosis (ALS). However, the exact mechanism of neuroprotection mediated through sirtuins remains unsettled. The manipulation of sirtuins activity with its modulators, calorie restriction (CR), and micro RNAs (miR) is a novel therapeutic approach for the treatment of NDDs. Herein, we reviewed the current putative therapeutic role of sirtuins in regulating synaptic plasticity and cognitive functions, which are mediated through the different molecular phenomenon to prevent neurodegeneration. We also explained the implications of sirtuin modulators, and miR based therapies for the treatment of life-threatening NDDs.
    Keywords:  Mitochondrial Biogenesis; Neurodegenerative Disease; Sirtuins; Sirtuins Modulators; Synaptic Plasticity
    DOI:  https://doi.org/10.1016/j.neubiorev.2021.10.047
  7. Aging (Albany NY). 2021 Nov 09. 13(undefined):
    Alteration of mitochondrial homeostasis is an early event in a C. elegans model of human tauopathy.
    Konstantinos Palikaras, Kavya Achanta, Seoyun Choi, Mansour Akbari, Vilhelm A Bohr.
      Tauopathies are a group of progressive neurodegenerative disorders characterized by the presence of insoluble intracellular tau filaments in the brain. Evidence suggests that there is a tight connection between mitochondrial dysfunction and tauopathies, including Alzheimer's disease. However, whether mitochondrial dysfunction occurs prior to the detection of tau aggregates in tauopathies remains elusive. Here, we utilized transgenic nematodes expressing the full length of wild type tau in neuronal cells and monitored mitochondrial morphology alterations over time. Although tau-expressing nematodes did not accumulate detectable levels of tau aggregates during larval stages, they displayed increased mitochondrial damage and locomotion defects compared to the control worms. Chelating calcium restored mitochondrial activity and improved motility in the tau-expressing larvae suggesting a link between mitochondrial damage, calcium homeostasis and neuronal impairment in these animals. Our findings suggest that defective mitochondrial function is an early pathogenic event of tauopathies, taking place before tau aggregation and undermining neuronal homeostasis and organismal fitness. Understanding the molecular mechanisms causing mitochondrial dysfunction early in tauopathy will be of significant clinical and therapeutic value and merits further investigation.
    Keywords:  Alzheimer’s disease; C. elegans; aging; energy metabolism; mitochondria; tau; tauopathy
    DOI:  https://doi.org/10.18632/aging.203683
  8. Biochim Biophys Acta Mol Cell Biol Lipids. 2021 Oct 28. pii: S1388-1981(21)00197-9. [Epub ahead of print]1867(1): 159069
    Amyloid beta increases ABCA1 and HMGCR protein expression, and cholesterol synthesis and accumulation in mice neurons and astrocytes.
    Shirin Azizidoost, Hossein Babaahmadi-Rezaei, Zahra Nazeri, Maryam Cheraghzadeh, Alireza Kheirollah.
       INTRODUCTION: Imbalanced cholesterol metabolism in the brain is one of the main pathophysiological mechanisms involved in Alzheimer's disease. We investigated the effect of amyloid-beta (Aβ) on the main proteins involved in regulation of cholesterol metabolism along with cholesterol content in astrocytes and neurons.
    METHODS: Astrocytes and neurons were cultured and treated with Aβ. Apolipoprotein E (apoE) level in the cells and conditioned media, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), ATP-binding cassette transporter A1 (ABCA1), and cytochrome P450 46A1 (CYP46A1) in cell lysates were determined using immunoblotting. Astrocyte media was added to the Aβ-pretreated neurons then, HMGCR was assessed. Cholesterol was measured in both cells and media.
    RESULTS: Aβ caused a significant increase in HMGCR and ABCA1 protein levels and cholesterol content in both cells without increasing cholesterol efflux. A similar increase was seen for cellular apoE level in astrocytes with no changes in media with a significant reduction of cholesterol efflux. HMGCR level was restored to near control level when Aβ-pretreated neurons were exposed to media from culture astrocytes.
    CONCLUSION: Almost all events related to cholesterol homeostasis in neurons and astrocytes, are somehow affected by Aβ. However, because ABCA1 has the most important role(s) in brain cholesterol homeostasis, all subsequent events associated with astrocytes-cholesterol synthesis and its shuttling to neurons are influenced by the effects of Aβ on ABCA1 which could likely be responsible for altered brain cholesterol metabolism in Alzheimer's disease.
    Keywords:  Alzheimer's disease; Amyloid-beta; Astrocytes; Brain apoE; Cholesterol; Neuron
    DOI:  https://doi.org/10.1016/j.bbalip.2021.159069
  9. Ageing Res Rev. 2021 Oct 29. pii: S1568-1637(21)00250-6. [Epub ahead of print]72 101503
    Mitochondrial dysfunction, oxidative stress, neuroinflammation, and metabolic alterations in the progression of Alzheimer's disease: A meta-analysis of in vivo magnetic resonance spectroscopy studies.
    Tao Song, Xiaopeng Song, Chenyawen Zhu, Regan Patrick, Miranda Skurla, Isabella Santangelo, Morgan Green, David Harper, Boyu Ren, Brent P Forester, Dost Öngür, Fei Du.
      Accumulating evidence demonstrates that metabolic changes in the brain associated with neuroinflammation, oxidative stress, and mitochondrial dysfunction play an important role in the pathophysiology of mild cognitive impairment (MCI) and Alzheimer's disease (AD). However, the neural signatures associated with these metabolic alterations and underlying molecular mechanisms are still elusive. Accordingly, we reviewed the literature on in vivo human brain 1H and 31P-MRS studies and use meta-analyses to identify patterns of brain metabolic alterations in MCI and AD. 40 and 39 studies on MCI and AD, respectively, were classified according to brain regions. Our results indicate decreased N-acetyl aspartate and creatine but increased myo-inositol levels in both MCI and AD, decreased glutathione level in MCI as well as disrupted energy metabolism in AD. In addition, the hippocampus shows the strongest alterations in most of these metabolites. This meta-analysis also illustrates progressive metabolite alterations from MCI to AD. Taken together, it suggests that 1) neuroinflammation and oxidative stress may occur in the early stages of AD, and likely precede neuron loss in its progression; 2) the hippocampus is a sensitive region of interest for early diagnosis and monitoring the response of interventions; 3) targeting bioenergetics associated with neuroinflammation/oxidative stress is a promising approach for treating AD.
    Keywords:  Alzheimer’s disease; Magnetic resonance spectroscopy; Mild cognitive impairment; Mitochondrial dysfunction; Neuroinflammation; Oxidative stress
    DOI:  https://doi.org/10.1016/j.arr.2021.101503
  10. Front Physiol. 2021 ;12 729201
    Nitric Oxide Pathways in Neurovascular Coupling Under Normal and Stress Conditions in the Brain: Strategies to Rescue Aberrant Coupling and Improve Cerebral Blood Flow.
    Cátia F Lourenço, João Laranjinha.
      The brain has impressive energy requirements and paradoxically, very limited energy reserves, implying its huge dependency on continuous blood supply. Aditionally, cerebral blood flow must be dynamically regulated to the areas of increased neuronal activity and thus, of increased metabolic demands. The coupling between neuronal activity and cerebral blood flow (CBF) is supported by a mechanism called neurovascular coupling (NVC). Among the several vasoactive molecules released by glutamatergic activation, nitric oxide (•NO) is recognized to be a key player in the process and essential for the development of the neurovascular response. Classically, •NO is produced in neurons upon the activation of the glutamatergic N-methyl-D-aspartate (NMDA) receptor by the neuronal isoform of nitric oxide synthase and promotes vasodilation by activating soluble guanylate cyclase in the smooth muscle cells of the adjacent arterioles. This pathway is part of a more complex network in which other molecular and cellular intervenients, as well as other sources of •NO, are involved. The elucidation of these interacting mechanisms is fundamental in understanding how the brain manages its energy requirements and how the failure of this process translates into neuronal dysfunction. Here, we aimed to provide an integrated and updated perspective of the role of •NO in the NVC, incorporating the most recent evidence that reinforces its central role in the process from both viewpoints, as a physiological mediator and a pathological stressor. First, we described the glutamate-NMDA receptor-nNOS axis as a central pathway in NVC, then we reviewed the link between the derailment of the NVC and neuronal dysfunction associated with neurodegeneration (with a focus on Alzheimer's disease). We further discussed the role of oxidative stress in the NVC dysfunction, specifically by decreasing the •NO bioavailability and diverting its bioactivity toward cytotoxicity. Finally, we highlighted some strategies targeting the rescue or maintenance of •NO bioavailability that could be explored to mitigate the NVC dysfunction associated with neurodegenerative conditions. In line with this, the potential modulatory effects of dietary nitrate and polyphenols on •NO-dependent NVC, in association with physical exercise, may be used as effective non-pharmacological strategies to promote the •NO bioavailability and to manage NVC dysfunction in neuropathological conditions.
    Keywords:  cerebral blood flow (CBF); diet; exercise; neurodegeneration; neurovascular coupling (NVC); nitric oxide; oxidative stress
    DOI:  https://doi.org/10.3389/fphys.2021.729201
  11. Int J Mol Sci. 2021 Oct 27. pii: 11582. [Epub ahead of print]22(21):
    Isoform-Specific Effects of Apolipoprotein E on Hydrogen Peroxide-Induced Apoptosis in Human Induced Pluripotent Stem Cell (iPSC)-Derived Cortical Neurons.
    Huiling Gao, Wei Zheng, Cheng Li, He Xu.
      Hydrogen peroxide (H2O2)-induced neuronal apoptosis is critical to the pathology of Alzheimer's disease (AD) as well as other neurodegenerative diseases. The neuroprotective effects of apolipoprotein (ApoE) isoforms against apoptosis and the underlying mechanism remains controversial. Here, we have generated human cortical neurons from iPSCs and induced apoptosis with H2O2. We show that ApoE2 and ApoE3 pretreatments significantly attenuate neuronal apoptosis, whereas ApoE4 has no neuroprotective effect and higher concentrations of ApoE4 even display toxic effect. We further identify that ApoE2 and ApoE3 regulate Akt/FoxO3a/Bim signaling pathway in the presence of H2O2. We propose that ApoE alleviates H2O2-induced apoptosis in human iPSC-derived neuronal culture in an isoform specific manner. Our results provide an alternative mechanistic explanation on how ApoE isoforms influence the risk of AD onset as well as a promising therapeutic target for diseases involving neuronal apoptosis in the central nervous system.
    Keywords:  Alzheimer’s disease; apolipoprotein E; apoptosis; iPSC-derived cortical neurons; neurodegeneration
    DOI:  https://doi.org/10.3390/ijms222111582
  12. Chem Biol Interact. 2021 Nov 06. pii: S0009-2797(21)00379-3. [Epub ahead of print] 109741
    Honokiol improves cognitive impairment in APP/PS1 mice through activating mitophagy and mitochondrial unfolded protein response.
    Mingyue Hou, Wenfang Bao, Yuanyuan Gao, Jiayue Chen, Guijun Song.
      Activated mitophagy and mitochondrial unfolded protein response (UPRmt) has been reported to protect against mitochondrial dysfunction, which is closely related to the onset of Alzheimer's disease (AD). Honokiol (HKL, C18H18O2) is a kind of natural extraction from bark of Magnolia officinalis with anti-AD effect, and our study aims to explore the effect of HKL on mitophagy and UPRmt in AD. Briefly, male APP/PS1 mice and Aβ oligmer (AβO)-treated primary hippocampal neurons were respectively used to mimic AD in vivo and in vitro. It was determined that HKL significantly ameliorated cognitive impairment and synaptic damages in APP/PS1 mice. Besides, the activated mitophagy and UPRmt together with inhibited oxidative stress and improved mitochondrial dynamic disorder were further validated in hippocampus of HKL-treated APP/PS1 mice. Meanwhile, HKL-treated mice displayed much higher hippocampal expression and activity of mitochondrial sirtuin 3 (SIRT3). Therefore, SIRT3 knockdown was further achieved in primary hippocampal neurons by effective shRNA, and we determined that HKL improved synaptic damage, mitochondrial dysfunction, mitophagy and UPRmt in AβO-treated primary hippocampal neurons in a SIRT3-dependent manner. In summary, our study validates the protective effect of HKL on AD, and highlights that HKL exerts anti-AD effect by activating mitophagy and UPRmt.
    Keywords:  Alzheimer's disease; Honokiol; Mitophagy; SIRT3; UPR(mt)
    DOI:  https://doi.org/10.1016/j.cbi.2021.109741
  13. Mol Neurodegener. 2021 Nov 06. 16(1): 75
    Characterization of mitochondrial DNA quantity and quality in the human aged and Alzheimer's disease brain.
    Hans-Ulrich Klein, Caroline Trumpff, Hyun-Sik Yang, Annie J Lee, Martin Picard, David A Bennett, Philip L De Jager.
       BACKGROUND: Mitochondrial dysfunction is a feature of neurodegenerative diseases, including Alzheimer's disease (AD). Changes in the mitochondrial DNA copy number (mtDNAcn) and increased mitochondrial DNA mutation burden have both been associated with neurodegenerative diseases and cognitive decline. This study aims to systematically identify which common brain pathologies in the aged human brain are associated with mitochondrial recalibrations and to disentangle the relationship between these pathologies, mtDNAcn, mtDNA heteroplasmy, aging, neuronal loss, and cognitive function.
    METHODS: Whole-genome sequencing data from n = 1361 human brain samples from 5 different regions were used to quantify mtDNAcn as well as heteroplasmic mtDNA point mutations and small indels. Brain samples were assessed for 10 common pathologies. Annual cognitive test results were used to assess cognitive function proximal to death. For a subset of samples, neuronal proportions were estimated from RNA-seq profiles, and mass spectrometry was used to quantify the mitochondrial protein content of the tissue.
    RESULTS: mtDNAcn was 7-14% lower in AD relative to control participants. When accounting for all 10 common neuropathologies, only tau was significantly associated with lower mtDNAcn in the dorsolateral prefrontal cortex. In the posterior cingulate cortex, TDP-43 pathology demonstrated a distinct association with mtDNAcn. No changes were observed in the cerebellum, which is affected late by pathologies. Neither age nor gender was associated with mtDNAcn in the studied brain regions when adjusting for pathologies. Mitochondrial content and mtDNAcn independently explained variance in cognitive function unaccounted by pathologies, implicating complex mitochondrial recalibrations in cognitive decline. In contrast, mtDNA heteroplasmy levels increased by 1.5% per year of life in the cortical regions, but displayed no association with any of the pathologies or cognitive function.
    CONCLUSIONS: We studied mtDNA quantity and quality in relation to mixed pathologies of aging and showed that tau and not amyloid-β is primarily associated with reduced mtDNAcn. In the posterior cingulate cortex, the association of TDP-43 with low mtDNAcn points to a vulnerability of this region in limbic-predominant age-related TDP-43 encephalopathy. While we found low mtDNAcn in brain regions affected by pathologies, the absence of associations with mtDNA heteroplasmy burden indicates that mtDNA point mutations and small indels are unlikely to be involved in the pathogenesis of late-onset neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; Amyloid; Mitochondria; Mitochondrial DNA copy number; Mitochondrial heteroplasmy; Neurodegeneration; TDP-43; Tau
    DOI:  https://doi.org/10.1186/s13024-021-00495-8
  14. Neurobiol Dis. 2021 Nov 09. pii: S0969-9961(21)00309-0. [Epub ahead of print] 105560
    Conditional disruption of AMP kinase in dopaminergic neurons promotes Parkinson's disease-associated phenotypes in vivo.
    Liting Hang, Ziyin Wang, Aaron S C Foo, Geraldine W Y Goh, Huey Ching Choong, John Thundyil, Shengli Xu, Lam Kong Peng, Kah-Leong Lim.
      Emerging studies implicate energy dysregulation as an underlying trigger for Parkinson's disease (PD), suggesting that a better understanding of the molecular pathways governing energy homeostasis could help elucidate therapeutic targets for the disease. A critical cellular energy regulator is AMP kinase (AMPK), which we have previously shown to be protective in PD models. However, precisely how AMPK function impacts on dopaminergic neuronal survival and disease pathogenesis remains elusive. Here, we showed that Drosophila deficient in AMPK function exhibits PD-like features, including dopaminergic neuronal loss and climbing impairment that progress with age. We also created a tissue-specific AMPK-knockout mouse model where the catalytic subunits of AMPK are ablated in nigral dopaminergic neurons. Using this model, we demonstrated that loss of AMPK function promotes dopaminergic neurodegeneration and associated locomotor aberrations. Accompanying this is an apparent reduction in the number of mitochondria in the surviving AMPK-deficient nigral dopaminergic neurons, suggesting that an impairment in mitochondrial biogenesis may underlie the observed PD-associated phenotypes. Importantly, the loss of AMPK function enhances the susceptibility of nigral dopaminergic neurons in these mice to 6-hydroxydopamine-induced toxicity. Notably, we also found that AMPK activation is reduced in post-mortem PD brain samples. Taken together, these findings highlight the importance of neuronal energy homeostasis by AMPK in PD and position AMPK pathway as an attractive target for future therapeutic exploitation.
    Keywords:  AMPK; Mitochondria; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.nbd.2021.105560
  15. Int J Mol Sci. 2021 Oct 27. pii: 11588. [Epub ahead of print]22(21):
    NLRP3 Inflammasome Blocking as a Potential Treatment of Central Insulin Resistance in Early-Stage Alzheimer's Disease.
    Yulia K Komleva, Ilia V Potapenko, Olga L Lopatina, Yana V Gorina, Anatoly Chernykh, Elena D Khilazheva, Alla B Salmina, Anton N Shuvaev.
       BACKGROUND: Alzheimer's disease (AD) is a devastating neurodegenerative disorder. In recent years, attention of researchers has increasingly been focused on studying the role of brain insulin resistance (BIR) in the AD pathogenesis. Neuroinflammation makes a significant contribution to the BIR due to the activation of NLRP3 inflammasome. This study was devoted to the understanding of the potential therapeutic roles of the NLRP3 inflammasome in neurodegeneration occurring concomitant with BIR and its contribution to the progression of emotional disorders.
    METHODS: To test the impact of innate immune signaling on the changes induced by Aβ1-42 injection, we analyzed animals carrying a genetic deletion of the Nlrp3 gene. Thus, we studied the role of NLRP3 inflammasomes in health and neurodegeneration in maintaining brain insulin signaling using behavioral, electrophysiological approaches, immunohistochemistry, ELISA and real-time PCR.
    RESULTS: We revealed that NLRP3 inflammasomes are required for insulin-dependent glucose transport in the brain and memory consolidation. Conclusions NLRP3 knockout protects mice against the development of BIR: Taken together, our data reveal the protective role of Nlrp3 deletion in the regulation of fear memory and the development of Aβ-induced insulin resistance, providing a novel target for the clinical treatment of this disorder.
    Keywords:  Alzheimer’s disease; NLRP3 inflammasome; brain insulin resistance; cognitive disorders; neuroinflammation
    DOI:  https://doi.org/10.3390/ijms222111588
  16. Adv Exp Med Biol. 2021 ;1344 87-110
    Astrocyte Circadian Timekeeping in Brain Health and Neurodegeneration.
    Marco Brancaccio, Anne C Wolfes, Natalie Ness.
      Almost three decades ago, astrocytes neighbouring clock neurons of the suprachiasmatic nucleus, the hypothalamic tissue responsible for synchronising circadian timekeeping in mammals, were found to undergo morphological and protein expression changes in a cyclic 24-h pattern, suggesting that glia could harbour circadian timekeeping mechanisms and that neuron-glia interactions could play a part in the daily organisation of rhythms of physiology and behaviour. Recently, it has become clear that astrocytes are circadian timekeepers, capable of initiating daily patterns of behaviour and imposing their intrinsic circadian tempo in mammals. In this chapter, we will describe properties of intracellular timekeeping of astrocytes and the mechanisms by which astrocytes functionally integrate in brain circuits underlying circadian, sleep, and cognitive behaviours in mammals. We will then discuss how altered astrocyte timekeeping may be involved in early brain vulnerability underpinning neurodegeneration. We will focus on Alzheimer's disease as a template of how altered astrocyte timekeeping may be involved in neurodegeneration, both directly via unbalancing of inflammatory and oxidative stress cellular pathways, and indirectly, by altering sleep and cognitive functions.
    Keywords:  Alzheimer’s disease; Astrocyte timekeeping; Circadian clocks; Neurodegeneration; Sleep
    DOI:  https://doi.org/10.1007/978-3-030-81147-1_6
  17. Int J Mol Sci. 2021 Oct 26. pii: 11556. [Epub ahead of print]22(21):
    Revealing the Molecular Mechanisms of Alzheimer's Disease Based on Network Analysis.
    Abdulahad Bayraktar, Simon Lam, Ozlem Altay, Xiangyu Li, Meng Yuan, Cheng Zhang, Muhammad Arif, Hasan Turkez, Mathias Uhlén, Saeed Shoaie, Adil Mardinoglu.
      The complex pathology of Alzheimer's disease (AD) emphasises the need for comprehensive modelling of the disease, which may lead to the development of efficient treatment strategies. To address this challenge, we analysed transcriptome data of post-mortem human brain samples of healthy elders and individuals with late-onset AD from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) and Mayo Clinic (MayoRNAseq) studies in the AMP-AD consortium. In this context, we conducted several bioinformatics and systems medicine analyses including the construction of AD-specific co-expression networks and genome-scale metabolic modelling of the brain in AD patients to identify key genes, metabolites and pathways involved in the progression of AD. We identified AMIGO1 and GRPRASP2 as examples of commonly altered marker genes in AD patients. Moreover, we found alterations in energy metabolism, represented by reduced oxidative phosphorylation and ATPase activity, as well as the depletion of hexanoyl-CoA, pentanoyl-CoA, (2E)-hexenoyl-CoA and numerous other unsaturated fatty acids in the brain. We also observed that neuroprotective metabolites (e.g., vitamins, retinoids and unsaturated fatty acids) tend to be depleted in the AD brain, while neurotoxic metabolites (e.g., β-alanine, bilirubin) were more abundant. In summary, we systematically revealed the key genes and pathways related to the progression of AD, gained insight into the crucial mechanisms of AD and identified some possible targets that could be used in the treatment of AD.
    Keywords:  Alzheimer’s disease; energy metabolism; gene co-expression network; genome-scale metabolic model; reporter metabolite analysis
    DOI:  https://doi.org/10.3390/ijms222111556
  18. Elife. 2021 Nov 12. pii: e71424. [Epub ahead of print]10
    Lactate is an energy substrate for rodent cortical neurons and enhances their firing activity.
    Anastassios Karagiannis, Thierry Gallopin, Alexandre Lacroix, Fabrice Plaisier, Juliette Piquet, Hélène Geoffroy, Régine Hepp, Jérémie Naudé, Benjamin Le Gac, Richard Egger, Bertrand Lambolez, Dongdong Li, Jean Rossier, Jochen F Staiger, Hiromi Imamura, Susumu Seino, Jochen Roeper, Bruno Cauli.
      Glucose is the mandatory fuel for the brain, yet the relative contribution of glucose and lactate for neuronal energy metabolism is unclear. We found that increased lactate, but not glucose concentration, enhances the spiking activity of neurons of the cerebral cortex. Enhanced spiking was dependent on ATP-sensitive potassium (KATP) channels formed with KCNJ11 and ABCC8 subunits, which we show are functionally expressed in most neocortical neuronal types. We also demonstrate the ability of cortical neurons to take-up and metabolize lactate. We further reveal that ATP is produced by cortical neurons largely via oxidative phosphorylation and only modestly by glycolysis. Our data demonstrate that in active neurons, lactate is preferred to glucose as an energy substrate, and that lactate metabolism shapes neuronal activity in the neocortex through KATP channels. Our results highlight the importance of metabolic crosstalk between neurons and astrocytes for brain function.
    Keywords:  mouse; neuroscience; rat
    DOI:  https://doi.org/10.7554/eLife.71424
  19. Brain Behav Immun Health. 2021 Dec;18 100350
    Mitochondria as the target for disease related hormonal dysregulation.
    Gladys A Shaw.
      Mitochondria play an important role in the synthesis of steroid hormones, including the sex hormone estrogen. Sex-specific regulation of these hormones is important for phenotypic development and downstream, sex-specific activational effects in both brain and behavior. First, mitochondrial contribution to the synthesis of estrogen, followed by a discussion of the signaling interactions between estrogen and the mitochondria will be reviewed. Next, disorders with an established sex difference related to aging, mood, and cognition will be examined. Finally, review of mitochondria as a biomarker of disease and data supporting efforts in targeting mitochondria as a therapeutic target for the amelioration of these disorders will be discussed. Taken together, this review aims to assess the influence of E2 on mitochondrial function within the brain via exploration of E2-ER interactions within neural mitochondria and how they may act to influence the development and presentation of neurodegenerative and neurocognitive diseases with known sex differences.
    Keywords:  Aging; Estrogen; Inflammation; Mitochondria; Neurodegeneration; Stress
    DOI:  https://doi.org/10.1016/j.bbih.2021.100350
  20. Neurochem Int. 2021 Nov 09. pii: S0197-0186(21)00268-0. [Epub ahead of print] 105222
    Pioglitazone transiently stimulates paraoxonase-2 expression in male nonhuman primate brain: Implications for sex-specific therapeutics in neurodegenerative disorders.
    Jennifer K Blackburn, Sumit Jamwal, Weiwei Wang, John D Elsworth.
      Paraoxonase-2 (PON2) enhances mitochondria function and protects against oxidative stress. Stimulating its expression has therapeutic potential for diseases where oxidative stress plays a significant role in the pathology, such as Parkinson's disease. Clinical and preclinical evidence suggest that the anti-diabetic drug pioglitazone may provide neuroprotection in Parkinson's disease, Alzheimer's disease, and stroke, but the biochemical pathway(s) responsible has not been fully elucidated. To determine the effect of pioglitazone on PON2 expression we treated male African green monkeys with oral pioglitazone (5 mg/kg/day) for 1 and 3 weeks. We found that pioglitazone increased PON2 mRNA and protein expression in brain following 1 week of treatment, however, by 3 weeks of treatment PON2 expression had returned to baseline. This transient increase was detected in substantia nigra, striatum, hippocampus, and dorsolateral prefrontal cortex The short-term impact of pioglitazone on PON2 expression in striatum may contribute to the discrepancy in the potency of the drug between short-term animal models and clinical trials for Parkinson's disease. Both PON2 and pioglitazone's receptor, peroxisome proliferator-activated receptor gamma (PPARγ), possess sex- and brain region-dependent expression, which may play a role in the short-term effect of pioglitazone and provide clues to extending the beneficial effects of PON2 activation.
    Keywords:  Paraoxonase-2; Parkinson's disease; Peroxisome proliferator-activated receptor gamma; Pioglitazone; Striatum; Substantia nigra
    DOI:  https://doi.org/10.1016/j.neuint.2021.105222
  21. Curr Neuropharmacol. 2021 Nov 09.
    Advances in PPARs Molecular Dynamics and Glitazones as a Repurposing Therapeutic Strategy through Mitochondrial Redox Dynamics against Neurodegeneration.
    Priya Durai, Narasimha M Beeraka, Hemanth Vikram, Prakash Krishnan, Pranesh Gudur, Nalgumnalli Manjunathaiah Raghavendra, Prashantha Kumar.
      Peroxisome proliferator activated receptors (PPARs) activity exhibit significant implications for the development of novel therapeutic modalities against neurodegenerative diseases. PPAR-α, PPAR-β/δ, and PPAR-γ nuclear receptors expression are significantly reported in the brain, their implications in brain physiology and other neurodegenerative diseases still require extensive studies. PPAR signaling can modulate various cell signaling mechanisms involved inside the cells contributing to on- and -off target actions selectively to promote therapeutic effects as well as the adverse effects of PPAR ligands. Both natural and synthetic ligands for the PPARα, PPARγ, and PPARβ/δ have been reported. PPARα (WY 14.643) and PPARγ agonists can confer neuroprotection by modulating mitochondrial dynamics through the redox system. The pharmacological effect of these agonists may deliver effective clinical responses by protecting vulnerable neurons to Aβ toxicity in Alzheimer's disease (AD) patients. Therefore, the current review delineated the ligands interaction with 3D- PPARs to modulate neuroprotection and also deciphered the efficacy of numerous drugs viz., Aβ aggregation inhibitors, vaccines, and γ-secretase inhibitors against AD; this review elucidated the role of PPAR and their receptor isoforms in neural systems, and neurodegeneration in human beings. Further, we have substantially discussed the efficacy of PPREs as potent transcription factors in the brain, and the role of PPAR agonists in neurotransmission, PPAR gamma coactivator-1α (PGC-1α), and mitochondrial dynamics in neuroprotection during AD conditions. This review concludes with the statement; development of novel PPARs agonists may benefit patients with neurodegeneration mainly in AD patients to mitigate the pathophysiology & dementia subsequently to improve overall patient's quality of life.
    Keywords:  Alzheimer's disease; PPARs; glitazones; mitochondrial dynamics; neurodegeneration; neuroinflammation
    DOI:  https://doi.org/10.2174/1570159X19666211109141330
  22. Avicenna J Phytomed. 2021 Sep-Oct;11(5):11(5): 473-483
    Increased protein expression of ABCA1, HMG-CoA reductase, and CYP46A1 induced by garlic and allicin in the brain mouse and astrocytes-isolated from C57BL/6J.
    Zahra Nazeri, Shirin Azizidoost, Maryam Cheraghzadeh, Asma Mohammadi, Alireza Kheirollah.
       Objective: Regulation of cholesterol level is essential for the brain optimal function. The beneficial effect of garlic consumption on cholesterol homeostasis is well known; however, the molecular mechanism to support its properties is unclear. Here, we investigated the beneficial effect of aqueous extract of garlic and allicin on lipid profile and the main players involved in brain cholesterol homeostasis including ABCA1, HMG-CoA reductase, and CYP46A1 in both C57BL/6J mice brain and astrocytes.
    Materials and Methods: Thirty mice were divided into control and garlic groups. Garlic group was fed with the aqueous extract of garlic. Serum lipids were measured and brain protein levels of ABCA1, HMGCR, and CYP46A1 were determined by western blotting. Changes in these proteins expression were also studied in the presence of allicin in cultured astrocytes.
    Results: A moderate decrease in serum total cholesterol and a significant increase in plasma HDL-C levels (p<0.05) were detected. A significant increase in ABCA1, HMGCR, and CYP46A1 protein levels was observed in the garlic group and in the cultured astrocytes treated with allicin by western blotting (p<0.05).
    Conclusion: Our findings indicated that the main players involved in cholesterol turnover including HMGCR that is involved in cholesterol synthesis, ABCA1 that is important in cholesterol efflux, and CYP46A1 that is necessary in cholesterol degradation, were up regulated by garlic/allicin in both animal and cell culture model. We concluded that increasing cholesterol turnover is a possible mechanism for the beneficial effects of garlic in cholesterol homeostasis.
    Keywords:  ATP binding cassette transporter 1; Allicin; CYP46A1; Garlic; HMG-CoA reductases
    DOI:  https://doi.org/10.22038/AJP.2021.17834
  23. Int J Mol Sci. 2021 Oct 30. pii: 11802. [Epub ahead of print]22(21):
    Omega-3 Polyunsaturated Fatty Acid Attenuates Uremia-Induced Brain Damage in Mice.
    Eun-Ji Kim, Young Rok Ham, Jin Ah Shin, Jin Young Jeong, Ki Ryang Na, Kang Wook Lee, Jwa-Jin Kim, Dae Eun Choi.
      Although the cause of neurological disease in patients with chronic kidney disease (CKD) has not been completely identified yet, recent papers have identified accumulated uremic toxin as its main cause. Additionally, omega-3 polyunsaturated fatty acid (ω-3 PUFA) plays an important role in maintaining normal nerve function, but its protective effects against uremic toxin is unclear. The objective of this study was to identify brain damage caused by uremic toxicity and determine the protective effects of ω-3 PUFA against uremic toxin. We divided mice into the following groups: wild-type (wt) sham (n = 8), ω-3 PUFA sham (n = 8), Fat-1 sham (n = 8), ischemia-reperfusion (IR) (n = 20), and ω-3 PUFA+IR (n = 20) Fat-1+IR (n = 20). Brain tissue, kidney tissue, and blood were collected three days after the operation of mice (sham and IR operation). This study showed that Ki67 and neuronal nuclei (NeuN) decreased in the brain of uremic mice as compared to wt mice brain, but increased in the ω-3 PUFA-treated uremic mice and the brain of uremic Fat-1 mice as compared to the brain of uremic mice. The pro-apoptotic protein expressions were increased, whereas anti-apoptotic protein expression decreased in the brain of uremic mice as compared to wt mice brain. However, apoptotic protein expression decreased in the ω-3 PUFA-treated uremic mice and the brain of uremic Fat-1 mice as compared to the brain of uremic mice. Furthermore, the brain of ω-3 PUFA-treated uremic mice and uremic Fat-1 mice showed increased expression of p-PI3K, p-PDK1, and p-Akt as compared to the brain of uremic mice. We confirm that uremic toxin damages the brain and causes cell death. In these injuries, ω-3 PUFA plays an important role in neuroprotection through PI(3)K-Akt signaling.
    Keywords:  PI(3)K-Akt signaling; apoptosis; brain injury; indoxyl sulfate; ischemia-reperfusion; uremic toxin; ω3-PUFA
    DOI:  https://doi.org/10.3390/ijms222111802
  24. Adv Exp Med Biol. 2021 ;1344 21-42
    Circadian Clocks, Sleep, and Metabolism.
    Nora Nowak, Audrey Rawleigh, Steven A Brown.
      A molecular circadian clock exists not only in the brain, but also in most cells of the body. Research over the past two decades has demonstrated that it directs daily rhythmicity of nearly every aspect of metabolism. It also consolidates sleep-wake behavior each day into an activity/feeding period and a sleep/fasting period. Otherwise, sleep-wake states are mostly controlled by hypothalamic and thalamic regulatory circuits in the brain that direct overall brain state. Recent evidence suggests that hypothalamic control of appetite and metabolism may be concomitant with sleep-wake regulation, and even share the same control centers. Thus, circadian control of metabolic pathways might be overlaid by sleep-wake control of the same pathways, providing a flexible and redundant system to modify metabolism according to both activity and environment.
    Keywords:  Circadian; Homeostasis; Hypothalamus; Metabolism; Sleep; Sleep disorder
    DOI:  https://doi.org/10.1007/978-3-030-81147-1_2
  25. Neuropharmacology. 2021 Nov 04. pii: S0028-3908(21)00426-3. [Epub ahead of print] 108871
    Ghrelin signaling in dCA1 suppresses neuronal excitability and impairs memory acquisition via PI3K/Akt/GSK-3β cascades.
    Nan Li, Kewei Xiao, Xue Mi, Na Li, Li Guo, Xiaorong Wang, Yuxiang Sun, Guo-Dong Li, Yu Zhou.
      Ghrelin is a circulating peptide hormone that promotes feeding and regulates metabolism in humans and rodents. The action of ghrelin is mediated by the growth hormone secretagogue receptor type 1a (GHSR-1a) that is widely distributed in the brain, including the hippocampus. Studies have demonstrated the critical role of hippocampal ghrelin/GHS-R1a signaling in synaptic physiology and memory. However, those findings are controversial, and the mechanism underlying ghrelin modulation of learning and memory is uncertain. Here, we report that micro-infusion of ghrelin in the CA1 region of the dorsal hippocampus during training specifically impairs memory acquisition. The activation of GHS-R1a and the subsequent PI3K/Akt/GSK3β signaling cascades are involved in this process. Moreover, we report that bath application of ghrelin suppresses the intrinsic excitability of dCA1 pyramidal neurons through activating GHS-R1a, and PI3K inhibitor LY294002 blocks ghrelin's effect. However, LY294002 fails to rescue ghrelin-induced LTP impairment. Our findings support an adverse effect of ghrelin-dependent activation of GHS-R1a on memory acquisition, and suggest that PI3K/Akt/GSK3β signaling-dependent repression of neuronal intrinsic excitability is an important novel mechanism underlying memory inhibition of ghrelin in the hippocampus.
    Keywords:  GHS-R1a; Ghrelin; Hippocampus; Memory acquisition; Neuronal excitability; Synaptic plasticity
    DOI:  https://doi.org/10.1016/j.neuropharm.2021.108871
  26. Pharmacol Res. 2021 Nov 08. pii: S1043-6618(21)00557-0. [Epub ahead of print] 105973
    Mitophagy enhancers against phosphorylated Tau-induced mitochondrial and synaptic toxicities in Alzheimer disease.
    Sudhir Kshirsagar, Neha Sawant, Hallie Morton, Arubala P Reddy, P Hemachandra Reddy.
      The purpose of our study is to determine the protective effects of mitophagy enhancers against phosphorylated tau (P-tau)-induced mitochondrial and synaptic toxicities in Alzheimer's disease (AD). Mitochondrial abnormalities, including defective mitochondrial dynamics, biogenesis, axonal transport and impaired clearance of dead mitochondria are linked to P-tau in AD. Mitophagy enhancers are potential therapeutic candidates to clear dead mitochondria and improve synaptic and cognitive functions in AD. We recently optimized the doses of mitophagy enhancers urolithin A, actinonin, tomatidine, nicotinamide riboside in immortalized mouse primary hippocampal (HT22) neurons. In the current study, we treated mutant Tau expressed in HT22 (mTau-HT22) cells with mitophagy enhancers and assessed mRNA and protein levels of mitochondrial/synaptic genes, cell survival and mitochondrial respiration. We also assessed mitochondrial morphology in mTau-HT22 cells treated and untreated with mitophagy enhancers. Mutant Tau-HT22 cells showed increased fission, decreased fusion, synaptic & mitophagy genes, reduced cell survival and defective mitochondrial respiration. However, these events were reversed in mitophagy enhancers treated mTau-HT22 cells. Cell survival was increased, mRNA and protein levels of mitochondrial fusion, synaptic and mitophagy genes were increased, and mitochondrial fragmentation is reduced in mitophagy enhancers treated mTau-HT22 cells. Further, urolithin A showed strongest protective effects among all enhancers tested in AD. Our combination treatments of urolithin A + EGCG, addition to urolithin A and EGCG individual treatment revealed that combination treatments approach is even stronger than urolithin A treatment. Based on these findings, we cautiously propose that mitophagy enhancers are promising therapeutic drugs to treat mitophagy in patients with AD.
    Keywords:  Mitochondria: Synaptic activity; Mitochondrial fragmentation; Mitophagy enhancers; Urolithin A
    DOI:  https://doi.org/10.1016/j.phrs.2021.105973
  27. J Biochem Mol Toxicol. 2021 Nov 10. e22953
    Genetic mutations of APOEε4 carriers in cardiovascular patients lead to the development of insulin resistance and risk of Alzheimer's disease.
    Komal Jabeen, Kanwal Rehman, Muhammad Sajid Hamid Akash.
      Type 2 diabetes mellitus and Alzheimer's disease (AD), both are chronic and progressive diseases. Many cardiovascular and genetic risk factors are considered responsible for the development of AD and diabetes mellitus (DM). Genetic risk factor such as apolipoprotein E (APOE) plays a critical role in the progression of AD. Specifically, APOEε4 is genetically the strongest isoform associated with neuronal insulin deficiency, altered lipid homeostasis, and metabolism, decreased glucose uptake, impaired gray matter volume, and cerebrovascular functions. In this article, we have summarized the mechanisms of cardiovascular disturbances associated with AD and DM, impact of amyloid-β aggregation, and neurofibrillary tangles formation in AD. Moreover, cardiovascular risk factors leading to insulin resistance (IR) and amyloid-β aggregation are highlighted along with the effects of APOE risk alleles on cerebral, lipid, and cholesterol metabolism leading to CVD-mediated IR. Correspondingly, the contribution of IR, genetic and cardiovascular risk factors in amyloid-β aggregation, which may lead to the late onset of AD and DM, has been also discussed. In short, IR is related to significantly lower cerebral glucose metabolism, which sequentially forecasts poorer memory performance. Hence, there will be more chances for neural glucose intolerance and impairment of cognitive function in cardiac patients, particularly APOEε4 carriers having IR. Hence, this review provides a better understanding of the corresponding crosstalk among different pathways. This will help to investigate the rational application of preventive measures against IR and cognitive dysfunction, specifically in APOEε4 carriers' cardio-metabolic patients.
    Keywords:  Alzheimer disease; Apolipoprotein E; amyloid aggregation; cardiovascular diseases; diabetes mellitus; insulin resistance
    DOI:  https://doi.org/10.1002/jbt.22953
  28. Autophagy. 2021 Nov 06. 1-16
    A noncanonical autophagy is involved in the transfer of Plasmodium-microvesicles to astrocytes.
    Inès Leleu, Delphine Genete, Sophie Salomé Desnoulez, Nasreddine Saidi, Priscille Brodin, Frank Lafont, Stanislas Tomavo, Sylviane Pied.
      Cerebral malaria is a neuroinflammatory disease induced by P. falciparum infection. In animal models, the neuro-pathophysiology of cerebral malaria results from the sequestration of infected red blood cells (iRBCs) in microvessels that promotes the activation of glial cells in the brain. This activation provokes an exacerbated inflammatory response characterized by the secretion of proinflammatory cytokines and chemokines, leading to brain infiltration by pathogenic CD8+ T lymphocytes. Astrocytes are a major subtype of brain glial cells that play an important role in maintaining the homeostasis of the central nervous system, the integrity of the brain-blood barrier and in mounting local innate immune responses. We have previously shown that parasitic microvesicles (PbA-MVs) are transferred from iRBCs to astrocytes. The present study shows that an unconventional LC3-mediated autophagy pathway independent of ULK1 is involved in the transfer and degradation of PbA-MVs inside the astrocytes. We further demonstrate that inhibition of the autophagy process by treatment with 3-methyladenine blocks the transfer of PbA-MVs, which remain localized in the astrocytic cell membrane and are not internalized. Moreover, bafilomycin A1, another drug against autophagy promotes the accumulation of PbA-MVs inside the astrocytes by inhibiting the fusion with lysosomes, and prevents ECM in mice infected with PbA. Finally, we establish that RUBCN/rubicon or ATG5 silencing impede astrocyte production in CCL2 and CXCL10 chemokines induced by PbA stimulation. Altogether, our data suggest that a non-canonical autophagy-lysosomal pathway may play a key role in cerebral malaria through regulation of brain neuro-inflammation by astrocytes.
    Keywords:  Astrocyte; autophagy; cerebral malaria; inflammation; parasite microvesicles
    DOI:  https://doi.org/10.1080/15548627.2021.1993704
  29. Int J Mol Sci. 2021 Oct 23. pii: 11444. [Epub ahead of print]22(21):
    Targetable Pathways for Alleviating Mitochondrial Dysfunction in Neurodegeneration of Metabolic and Non-Metabolic Diseases.
    Lauren Elizabeth Millichap, Elisabetta Damiani, Luca Tiano, Iain P Hargreaves.
      Many neurodegenerative and inherited metabolic diseases frequently compromise nervous system function, and mitochondrial dysfunction and oxidative stress have been implicated as key events leading to neurodegeneration. Mitochondria are essential for neuronal function; however, these organelles are major sources of endogenous reactive oxygen species and are vulnerable targets for oxidative stress-induced damage. The brain is very susceptible to oxidative damage due to its high metabolic demand and low antioxidant defence systems, therefore minimal imbalances in the redox state can result in an oxidative environment that favours tissue damage and activates neuroinflammatory processes. Mitochondrial-associated molecular pathways are often compromised in the pathophysiology of neurodegeneration, including the parkin/PINK1, Nrf2, PGC1α, and PPARγ pathways. Impairments to these signalling pathways consequently effect the removal of dysfunctional mitochondria, which has been suggested as contributing to the development of neurodegeneration. Mitochondrial dysfunction prevention has become an attractive therapeutic target, and there are several molecular pathways that can be pharmacologically targeted to remove damaged mitochondria by inducing mitochondrial biogenesis or mitophagy, as well as increasing the antioxidant capacity of the brain, in order to alleviate mitochondrial dysfunction and prevent the development and progression of neurodegeneration in these disorders. Compounds such as natural polyphenolic compounds, bioactive quinones, and Nrf2 activators have been reported in the literature as novel therapeutic candidates capable of targeting defective mitochondrial pathways in order to improve mitochondrial function and reduce the severity of neurodegeneration in these disorders.
    Keywords:  Parkinson’s disease; antioxidant defenses; lysosomal storage disorders; methylmalonic acidaemia; mitochondrial biogenesis; mitochondrial dysfunction; mitophagy; neurodegeneration; oxidative stress; therapeutics
    DOI:  https://doi.org/10.3390/ijms222111444
  30. Microbiome. 2021 Nov 11. 9(1): 223
    A fiber-deprived diet causes cognitive impairment and hippocampal microglia-mediated synaptic loss through the gut microbiota and metabolites.
    Hongli Shi, Xing Ge, Xi Ma, Mingxuan Zheng, Xiaoying Cui, Wei Pan, Peng Zheng, Xiaoying Yang, Peng Zhang, Minmin Hu, Tao Hu, Renxian Tang, Kuiyang Zheng, Xu-Feng Huang, Yinghua Yu.
       BACKGROUND: Cognitive impairment, an increasing mental health issue, is a core feature of the aging brain and neurodegenerative diseases. Industrialized nations especially, have experienced a marked decrease in dietary fiber intake, but the potential mechanism linking low fiber intake and cognitive impairment is poorly understood. Emerging research reported that the diversity of gut microbiota in Western populations is significantly reduced. However, it is unknown whether a fiber-deficient diet (which alters gut microbiota) could impair cognition and brain functional elements through the gut-brain axis.
    RESULTS: In this study, a mouse model of long-term (15 weeks) dietary fiber deficiency (FD) was used to mimic a sustained low fiber intake in humans. We found that FD mice showed impaired cognition, including deficits in object location memory, temporal order memory, and the ability to perform daily living activities. The hippocampal synaptic ultrastructure was damaged in FD mice, characterized by widened synaptic clefts and thinned postsynaptic densities. A hippocampal proteomic analysis further identified a deficit of CaMKIId and its associated synaptic proteins (including GAP43 and SV2C) in the FD mice, along with neuroinflammation and microglial engulfment of synapses. The FD mice also exhibited gut microbiota dysbiosis (decreased Bacteroidetes and increased Proteobacteria), which was significantly associated with the cognitive deficits. Of note, a rapid differentiating microbiota change was observed in the mice with a short-term FD diet (7 days) before cognitive impairment, highlighting a possible causal impact of the gut microbiota profile on cognitive outcomes. Moreover, the FD diet compromised the intestinal barrier and reduced short-chain fatty acid (SCFA) production. We exploit these findings for SCFA receptor knockout mice and oral SCFA supplementation that verified SCFA playing a critical role linking the altered gut microbiota and cognitive impairment.
    CONCLUSIONS: This study, for the first time, reports that a fiber-deprived diet leads to cognitive impairment through altering the gut microbiota-hippocampal axis, which is pathologically distinct from normal brain aging. These findings alert the adverse impact of dietary fiber deficiency on brain function, and highlight an increase in fiber intake as a nutritional strategy to reduce the risk of developing diet-associated cognitive decline and neurodegenerative diseases. Video Abstract.
    Keywords:  Cognition; Dietary fiber deficiency; Gut microbiota; Gut-brain axis; Short-chain fatty acids
    DOI:  https://doi.org/10.1186/s40168-021-01172-0
  31. Front Aging Neurosci. 2021 ;13 765395
    Role of Glia-Derived Extracellular Vesicles in Neurodegenerative Diseases.
    Tianbai Li, Xiang Tan, Song Li, Murad Al-Nusaif, Weidong Le.
      Extracellular vesicles (EVs), as nano-sized vesicles secreted by almost all cells, have been recognized as the essential transmitter for cell-to-cell communication and participating in multiple biological processes. Neurodegenerative diseases (ND), such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, share common mechanisms of the aggregation and propagation of distinct pathologic proteins among cells in the nervous systems and neuroinflammatory reactions mediated by glia during the pathogenic process. This feature indicates the vital role of crosstalk between neurons and glia in the pathogenesis of ND. In recent years, glia-derived EVs have been investigated as potential mediators of signals between neurons and glia, which provides a new direction and strategy for understanding ND. By a comprehensive summary, it can be concluded that glia-derived EVs have both a beneficial and/or a detrimental effect in the process of ND. Therefore, this review article conveys the role of glia-derived EVs in the pathogenesis of ND and raises current limitations of their potential application in the diagnosis and treatment of ND.
    Keywords:  astrocyte; extracellular vesicles; glia; microglia; neurodegenerative diseases
    DOI:  https://doi.org/10.3389/fnagi.2021.765395
  32. J Neuroinflammation. 2021 Nov 08. 18(1): 262
    Brain transcriptome analysis of a CLN2 mouse model as a function of disease progression.
    Miriam S Domowicz, Wen-Ching Chan, Patricia Claudio-Vázquez, Tatiana Gonzalez, Nancy B Schwartz.
       BACKGROUND: Neuronal ceroid lipofuscinoses, (NCLs or Batten disease) are a group of inherited, early onset, fatal neurodegenerative diseases associated with mutations in 13 genes. All forms of the disease are characterized by lysosomal accumulation of fluorescent storage material, as well as profound neurodegeneration, but the relationship of the various genes' function to a single biological process is not obvious. In this study, we used a well-characterized mouse model of classical late infantile NCL (cLINCL) in which the tripeptidyl peptidase 1 (Tpp1) gene is disrupted by gene targeting, resulting in loss of detectable TPP1 activity and leading to progressive neurological phenotypes including ataxia, increased motor deficiency, and early death.
    METHODS: In order to identify genes and pathways that may contribute to progression of the neurodegenerative process, we analyzed forebrain/midbrain and cerebellar transcriptional differences at 1, 2, 3 and 4 months of age in control and TPP1-deficient mice by global RNA-sequencing.
    RESULTS: Progressive neurodegenerative inflammatory responses involving microglia, astrocytes and endothelial cells were observed, accompanied by activation of leukocyte extravasation signals and upregulation of nitric oxide production and reactive oxygen species. Several astrocytic (i.e., Gfap, C4b, Osmr, Serpina3n) and microglial (i.e., Ctss, Itgb2, Itgax, Lyz2) genes were identified as strong markers for assessing disease progression as they showed increased levels of expression in vivo over time. Furthermore, transient increased expression of choroid plexus genes was observed at 2 months in the lateral and fourth ventricle, highlighting an early role for the choroid plexus and cerebrospinal fluid in the disease pathology. Based on these gene expression changes, we concluded that neuroinflammation starts, for the most part, after 2 months in the Tpp1-/- brain and that activation of microglia and astrocytes occur more rapidly in cerebellum than in the rest of the brain; confirming increased severity of inflammation in this region.
    CONCLUSIONS: These findings have led to a better understanding of cLINCL pathological onset and progression, which may aid in development of future therapeutic treatments for this disease.
    Keywords:  Choroid plexus; Lysosomal tripeptidyl peptidase 1; Neuroinflammation; Neuronal ceroid lipofuscinoses; Pediatric neurodegeneration; Transcriptome
    DOI:  https://doi.org/10.1186/s12974-021-02302-z
  33. Metabolism. 2021 Oct 28. pii: S0026-0495(21)00223-7. [Epub ahead of print]126 154923
    Regulation of NAD+ metabolism in aging and disease.
    Xiaogang Chu, Raghavan Pillai Raju.
      More than a century after discovering NAD+, information is still evolving on the role of this molecule in health and diseases. The biological functions of NAD+ and NAD+ precursors encompass pathways in cellular energetics, inflammation, metabolism, and cell survival. Several metabolic and neurological diseases exhibit reduced tissue NAD+ levels. Significantly reduced levels of NAD+ are also associated with aging, and enhancing NAD+ levels improved healthspan and lifespan in animal models. Recent studies suggest a causal link between senescence, age-associated reduction in tissue NAD+ and enzymatic degradation of NAD+. Furthermore, the discovery of transporters and receptors involved in NAD+ precursor (nicotinic acid, or niacin, nicotinamide, and nicotinamide riboside) metabolism allowed for a better understanding of their role in cellular homeostasis including signaling functions that are independent of their functions in redox reactions. We also review studies that demonstrate that the functional effect of niacin is partially due to the activation of its cell surface receptor, GPR109a. Based on the recent progress in understanding the mechanism and function of NAD+ and NAD+ precursors in cell metabolism, new strategies are evolving to exploit these molecules' pharmacological potential in the maintenance of metabolic balance.
    Keywords:  NAD; Niacin; Niacin receptor; Nicotinamide adenine mononucleotide; Nicotinamide riboside
    DOI:  https://doi.org/10.1016/j.metabol.2021.154923
  34. J Neurosci Res. 2021 Nov 08.
    Hyperexcitability and brain morphological differences in mice lacking the cystine/glutamate antiporter, system xc.
    Sheila M S Sears, Sarah H Roberts, Sandra J Hewett.
      System xc - (Sxc - ) is a heteromeric antiporter (L-cystine/L-glutamate exchanger) expressed predominately on astrocytes in the central nervous system. Its activity contributes importantly to the maintenance of the ambient extracellular glutamate levels, as well as, to cellular redox homeostasis. Since alterations in glutamate levels and redox modifications could cause structural changes, we analyzed gross regional morphology of thionin-stained brain sections and cellular and subcellular morphology of Golgi-Cox stained layer V pyramidal neurons in the primary motor cortex (PM1) of mice naturally null for SLC7A11 (SLC7A11sut/sut )-the gene that encodes the substrate specific light chain (xCT) for Sxc - . Intriguingly, in comparison to age- and sex-matched wild-type (SLC7A11+/+ ) littermate controls, we found morphologic changes-including increased dendritic complexity and mushroom spine area in males and reduced corpus callosum and soma size in females-that have previously been described, in each case, as morphological correlates of excitability. Consistent with this, we found that both male and female SLC7A11sut/sut mice had lower convulsive seizure thresholds and greater seizure severity than their sex-matched wild-type (SLC7A11+/+ ) littermates after acute challenge with two pharmacologically distinct chemoconvulsants: the Glu receptor agonist, kainic acid (KA), or the GABAA receptor antagonist, pentylenetetrazole (PTZ). These results suggest that the loss of Sxc - signaling in males and females perturbs excitatory/inhibitory (E/I) balance in vivo, potentially through its regulation of cellular and subcellular morphology.
    Keywords:  RRID: SCR_003070; SLC7A11; excitatory/inhibitory balance; xCT
    DOI:  https://doi.org/10.1002/jnr.24971
  35. CNS Neurol Disord Drug Targets. 2021 Nov 09.
    Molecular and Biochemical Pathways Encompassing Diabetes Mellitus and Dementia.
    Tapan Behl, Arpita Arora, Aayush Sehgal, Sukhbir Singh, Neelam Sharma, Saurabh Bhatia, Ahmed Al-Harrasi, Simona Bungau, Ebrahim Mostafavi.
      Diabetes mellitus is a major metabolic disorder that has now emerged as an epidemic, and it affects the brain through an array of pathways. Diabetes mellitus patients can develop pathological changes in the brain, which eventually take the shape of mild cognitive impairment progressing to Alzheimer's Disease. A number of preclinical and clinical studies demonstrate this fact, and it comes out to be those molecular pathways such as amyloidogenesis, oxidative stress, inflammation, and impaired insulin signaling are identical in diabetes mellitus and dementia. However, the critical player involved in the vicious cycle of diabetes mellitus and dementia is insulin, whose signaling, when impaired in diabetes mellitus (both type 1 and 2), leads to a decline in cognition, although other pathways are also essential contributors. Moreover, it is not only that diabetes mellitus patients indicate cognitive decline at a later stage; many Alzheimer's Disease patients also reflect symptoms of diabetes mellitus, thus creating a vicious cycle inculcating a web of complex molecular mechanisms and hence categorizing Alzheimer's Disease as 'brain diabetes'. Thus, it is practical to suggest that anti-diabetic drugs are beneficial in Alzheimer's Disease; but only smaller trials, not the larger ones, have showcased positive outcomes mainly because of the late onset of therapy. Therefore, it is extremely important to develop more of such molecules that target insulin in dementia patients along with such methods that diagnose impaired insulin signaling and the associated cognitive decline so that early therapy may be initiated and the progression of the disease be prevented.
    Keywords:  Alzheimer's disease; Forkhead box O (FOXO); diabetes mellitus; glycogen synthase kinase 3 beta (GSK3β); insulin resistance; metabolic disorder
    DOI:  https://doi.org/10.2174/1871527320666211110115257
  36. Ageing Res Rev. 2021 Nov 09. pii: S1568-1637(21)00257-9. [Epub ahead of print] 101510
    Iron homeostasis and organismal aging.
    Rola S Zeidan, Sung Min Han, Christiaan Leeuwenburgh, Rui Xiao.
      Iron is indispensable for normal body functions across species because of its critical roles in red blood cell function and many essential proteins and enzymes required for numerous physiological processes. Regulation of iron homeostasis is an intricate process involving multiple modulators at the systemic, cellular, and molecular levels. Interestingly, emerging evidence has demonstrated that many modulators of iron homeostasis contribute to organismal aging and longevity. On the other hand, the age-related dysregulation of iron homeostasis is often associated with multiple age-related pathologies including bone resorption and neurodegenerative diseases such as Alzheimer's disease. Thus, a thorough understanding on the interconnections between systemic and cellular iron balance and organismal aging may help decipher the etiologies of multiple age-related diseases, which could ultimately lead to developing therapeutic strategies to delay aging and treat various age-related diseases. Here we present the current understanding on the mechanisms of iron homeostasis. We also discuss the impacts of aging on iron homeostatic processes and how dysregulated iron metabolism may affect aging and organismal longevity.
    Keywords:  C. elegans; Drosophila; Iron; aging; homeostasis; human diseases; longevity
    DOI:  https://doi.org/10.1016/j.arr.2021.101510
  37. Prion. 2021 Dec;15(1): 191-206
    The role of microglia in prion diseases and possible therapeutic targets: a literature review.
    Ananda Sampaio Lamenha Falcão de Melo, Juliana Louise Dias Lima, Maria Carolina Silva Malta, Natália França Marroquim, Álvaro Rivelli Moreira, Isabelle de Almeida Ladeia, Fabrizio Dos Santos Cardoso, Daniel Buzaglo Gonçalves, Bruna Guimarães Dutra, Júlio César Claudino Dos Santos.
      Creutzfeldt-Jakob disease (CJD) is a rare and fatal condition that leads to progressive neurodegeneration due to gliosis, vacuolation of central nervous system tissue, and loss of neurons. Microglia play a crucial role in maintaining Central Nervous System (CNS) homoeostasis, both in health and disease, through phagocytosis and cytokine production. In the context of CJD, the immunomodulatory function of microglia turns it into a cell of particular interest. Microglia would be activated by infectious prion proteins, initially acquiring a phagocytic and anti-inflammatory profile (M2), and producing cytokines such as IL-4, IL-10, and TGF-β. Therefore, microglia are seen as a key target for the development of new treatment approaches, with many emerging strategies to guide it towards a beneficial role upon neuroinflammation, by manipulating its metabolic pathways. In such a setting, many cellular targets in microglia that can be involved in phenotype modulation, such as membrane receptors, have been identified and pointed out as possible targets for further experiments and therapeutic approaches. In this article, we review the major findings about the role of microglia in CJD, including its relationship to some risk factors associated with the development of the disease. Furthermore, considering its central role in neural immunity, we explore microglial connection with other elements of the immune system and cell signalling, such as inflammasomes, the complement and purinergic systems, and the latest finding strategies to guide these cells from harmful to beneficial roles.
    Keywords:  Creutzfeldt-Jakob disease; microglia; neuroinflammation pathways
    DOI:  https://doi.org/10.1080/19336896.2021.1991771
  38. J Biol Chem. 2021 Oct 28. pii: S0021-9258(21)01178-9. [Epub ahead of print] 101372
    Astrocytic transcription factor REST upregulates glutamate transporter EAAT2, protecting dopaminergic neurons from manganese-induced excitotoxicity.
    Edward Pajarillo, Alexis Digman, Ivan Nyarko-Danquah, Deok-Soo Son, Karam F A Soliman, Michael Aschner, Eunsook Lee.
      Chronic exposure to high levels of manganese (Mn) leads to manganism, a neurological disorder with similar symptoms to those inherent to Parkinson's disease. However, the underlying mechanisms of this pathological condition have yet to be established. Since the human excitatory amino acid transporter 2 (EAAT2) (glutamate transporter 1 (GLT-1) in rodents) is predominantly expressed in astrocytes and its dysregulation is involved in Mn-induced excitotoxic neuronal injury, characterization of the mechanisms that mediate the Mn-induced impairment in EAAT2 function is crucial for the development of novel therapeutics against Mn neurotoxicity. Repressor element 1-silencing transcription factor (REST) exerts protective effects in many neurodegenerative diseases. But REST's effects on EAAT2 expression and ensuing neuroprotection are unknown. Given that the EAAT2 promoter contains REST binding sites, the present study investigated the role of REST in EAAT2 expression at the transcriptional level in astrocytes and Mn-induced neurotoxicity in an astrocyte-neuron co-culture system. The results reveal that astrocytic REST positively regulates EAAT2 expression with the recruitment of an epigenetic modifier, CREB-binding protein (CBP)/p300, to its consensus binding sites in the EAAT2 promoter. Moreover, astrocytic overexpression of REST attenuates Mn-induced reduction in EAAT2 expression, leading to attenuation of glutamate-induced neurotoxicity in the astrocyte-neuron co-culture system. Our findings demonstrate that astrocytic REST plays a critical role in protection against Mn-induced neurotoxicity by attenuating Mn-induced EAAT2 repression and the ensuing excitotoxic dopaminergic neuronal injury. This indicates that astrocytic REST could be a potential molecular target for the treatment of Mn toxicity and other neurological disorders associated with EAAT2 dysregulation.
    Keywords:  EAAT2; GLT-1; Parkinson’s disease; RE1-silencing transcription factor (REST); astrocyte-neuron co-culture; dopaminergic neurons; excitotoxicity; manganese; neuron-restrictive silencing factor (NRSF); neurotoxicity
    DOI:  https://doi.org/10.1016/j.jbc.2021.101372
  39. Neurosci Biobehav Rev. 2021 Nov 03. pii: S0149-7634(21)00488-7. [Epub ahead of print]
    The role of the host microbiome in autism and neurodegenerative disorders and effect of epigenetic procedures in the brain functions.
    Bahman Yousefi, Parviz Kokhaei, Fatemeh Mehranfar, Aisa Bahar, Anna Abdolshahi, Alireza Emadi, Majid Eslami.
      Autism Spectrum Disorder (ASD) is a severe neurological/neurodegenerative syndrome that results in cognitive and communication disorders. The degree of dysbiosis is related to the severity of ASD signs. The gut is conferred with a variety of sensory receptors that cooperate with effector systems including the endocrine, nervous and gut immune systems of the intestine. Gut dysbiosis causes amplified inflammation, the launch of the HPA axis, changed levels of neurotransmitters and bacterial metabolites; these may donate to abnormal signaling throughout the Vagus nerve in ASD. Decreased integrity of the gastrointestinal barrier led to extreme leakage of substances as of the intestine in early life and inflammation followed by disruption of BBB integrity maybe increase the risk of ASD. Microbiota, by controlling the barrier permeability, regulate the quantity and types of bioactive materials that are transferred from the intestine to the brain. Exposure to metabolites and microbial products regulate significant procedures in the CNS, including glial cell role, myelination, synaptic pruning, and play a role in neurobehavioral, neurodegenerative, psychiatric, and metabolic syndrome.
    Keywords:  Autism; Immune responses; Microbiota; Neurodegenerative; Neurological disorder
    DOI:  https://doi.org/10.1016/j.neubiorev.2021.10.046
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