Cell type-specific roles of APOE4 in Alzheimer disease

Nature reviews. Neuroscience, Год журнала: 2024, Номер 25(2), С. 91 - 110

Опубликована: Янв. 8, 2024

Язык: Английский

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Multifaceted roles of APOE in Alzheimer disease

Nature Reviews Neurology, Год журнала: 2024, Номер 20(8), С. 457 - 474

Опубликована: Июнь 21, 2024

Язык: Английский

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Mitochondria in Alzheimer’s Disease Pathogenesis

Life, Год журнала: 2024, Номер 14(2), С. 196 - 196

Опубликована: Янв. 30, 2024

Alzheimer’s disease (AD) is a progressive and incurable neurodegenerative disorder that primarily affects persons aged 65 years above. It causes dementia with memory loss deterioration in thinking language skills. AD characterized by specific pathology resulting from the accumulation brain of extracellular plaques amyloid-β intracellular tangles phosphorylated tau. The importance mitochondrial dysfunction pathogenesis, while previously underrecognized, now more appreciated. Mitochondria are an essential organelle involved cellular bioenergetics signaling pathways. Mitochondrial processes crucial for synaptic activity such as mitophagy, trafficking, fission, fusion dysregulated brain. Excess fission fragmentation yield mitochondria low energy production. Reduced glucose metabolism also observed hypometabolic state, particularly temporo-parietal regions. This review addresses multiple ways which abnormal structure function contribute to AD. Disruption electron transport chain ATP production neurotoxic because cells have disproportionately high demands. In addition, oxidative stress, extremely damaging nerve cells, rises dramatically dyshomeostasis. Restoring health may be viable approach treatment.

Язык: Английский

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Upregulated astrocyte HDAC7 induces Alzheimer-like tau pathologies via deacetylating transcription factor-EB and inhibiting lysosome biogenesis

Molecular Neurodegeneration, Год журнала: 2025, Номер 20(1)

Опубликована: Янв. 13, 2025

Astrocytes, the most abundant glial cell type in brain, will convert into reactive state response to proteotoxic stress such as tau accumulation, a characteristic feature of Alzheimer's disease (AD) and other tauopathies. The formation astrocytes is partially attributed disruption autophagy lysosomal signaling, inhibiting some histone deacetylases (HDACs) has been demonstrated reduce molecular functional characteristics astrocytes. However, precise role signaling that regulates pathology remains unclear. We investigated expression class IIa HDAC7 from AD patients PS19 mice. mice were treated with AAVs expressing shRNA for astrocyte-specific promoter selective HDAC inhibitor, TMP195, effects on pathology, gliosis, synaptic plasticity cognition-related behavioral performance measured. Tau uptake degradation assays cultured utilized investigate astrocyte-mediated clearance. Immunoprecipitation, immunofluorescence, western blotting, RT-qPCR, mass spectrometric, luciferase reporter assay used identify substrates, modification site related pathways astrocyte-tau generated new antibody clarify HDAC7-mediated Here, we found level deacetylase 7 (HDAC7) was remarkably increased P301S transgenic (PS19) Genetic or pharmacological inhibition effectively enhanced astrocytic clearance improved cognitive functions could modulate proteins through transcriptional factor EB (TFEB) acetylation-dependent manner. Specifically, deacetylation TFEB at K310 by prevented nuclear translocation reduced biogenesis astrocytes, whereas restored acetylation Our findings suggest upregulation induces AD-like pathologies via deacetylating downregulating HDAC7-TFEB promising arresting

Язык: Английский

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The Glutamate/GABA‐Glutamine Cycle: Insights, Updates, and Advances

Journal of Neurochemistry, Год журнала: 2025, Номер 169(3)

Опубликована: Март 1, 2025

ABSTRACT Synaptic homeostasis of the principal neurotransmitters glutamate and GABA is tightly regulated by an intricate metabolic coupling between neurons astrocytes known as glutamate/GABA‐glutamine cycle. In this cycle, take up from synapse convert these into glutamine. Astrocytic glutamine subsequently transferred to neurons, serving precursor for neuronal synthesis. The cycle integrates multiple cellular processes, including neurotransmitter release, uptake, synthesis, metabolism. All processes are deeply interdependent closely coupled energy Astrocytes display highly active mitochondrial oxidative metabolism several unique features, glycogen storage pyruvate carboxylation, which essential sustain continuous release. However, new roles oligodendrocytes microglia in recycling emerging. Malfunction can lead severe synaptic disruptions may be implicated brain diseases. Here, I review central aspects recent advances highlight how functionally connected critical functions First, overview glutamate, GABA, transport provided relation recycling. Then, reviewed, with a special emphasis on glial cells. Finally, discuss aberrant linked neurodegeneration disease, focusing astrocyte dysfunction lipid emerging pathological mechanisms. Instead viewing individual biochemical more holistic integrative approach needed advance our understanding modulates function both health disease. image

Язык: Английский

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The circular RNA circbabo(5,6,7,8S) regulates lipid metabolism and neuronal integrity via TGF-β/ROS/JNK/SREBP signaling axis in Drosophila

BMC Biology, Год журнала: 2025, Номер 23(1)

Опубликована: Март 5, 2025

Lipid droplets (LDs) are dynamic cytoplasmic lipid-storing organelles that play a pivotal role in maintaining cellular energy balance, lipid homeostasis, and metabolic signaling. Dysregulation of metabolism, particularly excessive lipogenesis, contributes to the abnormal accumulation LDs nervous system, which is associated with several neurodegenerative diseases. Circular RNAs (circRNAs) new class non-coding regulatory widely expressed eukaryotes. However, only subset has been functionally characterized. Here, we identified characterized circular RNA circbabo(5,6,7,8S) regulates lipogenesis neuronal integrity Drosophila melanogaster. derived from babo locus encodes type I receptor for transforming growth factor β (TGF-β). Depletion flies causes elevated droplet accumulation, progressive photoreceptor cell loss shortened lifespan, phenotypes rescued by restoring expression. In addition, RNA-seq epistasis analyses reveal these abnormalities caused aberrant activation SREBP signaling pathway. Furthermore, circbabo(5,6,7,8S)-depleted tissues display enhanced TGF-β pathway compromised mitochondrial function, resulting upregulation reactive oxygen species (ROS). Moreover, provide evidence protein circbabo(5,6,7,8S)-p, inhibits interfering assembly babo/put heterodimer complex. Lastly, show dysregulation ROS/JNK/SREBP cascade responsible LD neurodegeneration, lifespan elicited depletion. Our study demonstrates physiological protein-coding circRNA regulating metabolism integrity.

Язык: Английский

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Lysosomal acidification impairment in astrocyte-mediated neuroinflammation

Journal of Neuroinflammation, Год журнала: 2025, Номер 22(1)

Опубликована: Март 10, 2025

Abstract Astrocytes are a major cell type in the central nervous system (CNS) that play key role regulating homeostatic functions, responding to injuries, and maintaining blood-brain barrier. also regulate neuronal functions survival by modulating myelination degradation of pathological toxic protein aggregates. have recently been proposed possess both autophagic activity active phagocytic capability which largely depend on sufficiently acidified lysosomes for complete cellular cargos. Defective lysosomal acidification astrocytes impairs their resulting accumulation debris, excessive myelin lipids, aggregates, ultimately contributes propagation neuroinflammation neurodegenerative pathology. Restoration impaired represent new neuroprotective strategy therapeutic direction. In this review, we summarize pathogenic factors, including neuroinflammatory signaling, metabolic stressors, lipid mediated toxicity, contribute impairment associated dysfunction astrocytes. We discuss astrocyte-mediated primarily context diseases along with other brain injuries. then highlight re-acidification as restore well degradative capacity conclude providing future perspectives phagocytes crosstalk CNS cells impart or effects.

Язык: Английский

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Recognizing Alzheimer's disease from perspective of oligodendrocytes: Phenomena or pathogenesis?

CNS Neuroscience & Therapeutics, Год журнала: 2024, Номер 30(3)

Опубликована: Март 1, 2024

Abstract Background Accumulation of amyloid beta, tau hyperphosphorylation, and microglia activation are the three highly acknowledged pathological factors Alzheimer's disease (AD). However, oligodendrocytes (OLs) were also widely investigated in pathogenesis treatment for AD. Aims We aimed to update regulatory targets differentiation maturation OLs, emphasized key role OLs occurrence Methods This review first concluded OL with AD pathogenesis, then advanced based on both clinic basic experiments. Later, we extensively discussed possible application current progress diagnosis this complex disease. Results Molecules involving OLs’ or maturation, including various transcriptional factors, cholesterol homeostasis regulators, microRNAs could participate Clinical data point towards impairment patients. Basic research further supports central regulation pathologies. Additionally, classic drugs, donepezil, edaravone, fluoxetine, clemastine demonstrate their potential remedying models, new therapeutics from perspective is constantly being developed. Conclusions believe that dysfunction one important Factors regulating might be biomarkers early agents stimulating warrant development anti‐AD drugs.

Язык: Английский

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New insights into innate immunity in Alzheimer’s disease: from APOE protective variants to therapies

Trends in Immunology, Год журнала: 2024, Номер unknown

Опубликована: Сен. 1, 2024

Язык: Английский

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TRPV1 alleviates APOE4-dependent microglial antigen presentation and T cell infiltration in Alzheimer's disease

Translational Neurodegeneration, Год журнала: 2024, Номер 13(1)

Опубликована: Окт. 29, 2024

Abstract Background Persistent innate and adaptive immune responses in the brain contribute to progression of Alzheimer’s disease (AD). APOE4 , most important genetic risk factor for sporadic AD, encodes apolipoprotein E4, which by itself is a potent modulator response. However, little known about hub that governs crosstalk between nervous systems. Transient receptor potential vanilloid type 1 (TRPV1) channel ligand-gated, nonselective cation with Ca 2+ permeability, has been proposed as neuroprotective target AD. Methods Using -sensitive dyes, dynamic changes microglia were measured, including exogenous uptake endoplasmic reticulum release. The mRFP-GFP-tagged LC3 plasmid was expressed characterize role TRPV1 autophagic flux. Transcriptomic analyses flow cytometry performed investigate effects on T cells from APOE -targeted replacement mice microglia-specific gene deficiency. Results Both derived induced pluripotent stem AD patients -related tauopathy mouse model showed significantly increased cholesterol biosynthesis accumulation compared their APOE3 counterparts. Further, dysregulation associated persistent activation elevation major histocompatibility complex II-dependent antigen presentation microglia, subsequently accompanied cell infiltration. In addition, TRPV1-mediated transient influx mitigated suppressing transcriptional sterol regulatory element-binding protein 2, promoted activity reduced lysosomal accumulation, sufficient resolve excessive response neurodegeneration model. Moreover, deficiency accelerated glial inflammation, an Conclusions findings provide new perspectives treatment -dependent

Язык: Английский

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