ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies

Molecular Neurodegeneration, Journal Year: 2022, Volume and Issue: 17(1)

Published: Nov. 8, 2022

Alzheimer's disease (AD) is the most common cause of dementia worldwide, and its prevalence rapidly increasing due to extended lifespans. Among number genetic risk factors identified, apolipoprotein E (APOE) gene remains strongest prevalent, impacting more than half all AD cases. While ε4 allele APOE significantly increases risk, ε2 protective relative ε3 allele. These alleles encode three apoE protein isoforms that differ at two amino acid positions. The primary physiological function mediate lipid transport in brain periphery; however, additional functions diverse biological have been recognized. Pathogenically, seeds amyloid-β (Aβ) plaques with apoE4 driving earlier abundant amyloids. ApoE also differential effects on multiple Aβ-related or Aβ-independent pathways. complexity biology pathobiology presents challenges designing effective apoE-targeted therapeutic strategies. This review examines key pathobiological pathways related targeting strategies a specific focus latest technological advances tools.

Language: Английский

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Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Feb. 16, 2024

Abstract The human gastrointestinal tract is populated with a diverse microbial community. vast genetic and metabolic potential of the gut microbiome underpins its ubiquity in nearly every aspect biology, including health maintenance, development, aging, disease. advent new sequencing technologies culture-independent methods has allowed researchers to move beyond correlative studies toward mechanistic explorations shed light on microbiome–host interactions. Evidence unveiled bidirectional communication between central nervous system, referred as “microbiota–gut–brain axis”. microbiota–gut–brain axis represents an important regulator glial functions, making it actionable target ameliorate development progression neurodegenerative diseases. In this review, we discuss mechanisms As provides essential cues microglia, astrocytes, oligodendrocytes, examine communications microbiota these cells during healthy states Subsequently, diseases using metabolite-centric approach, while also examining role microbiota-related neurotransmitters hormones. Next, targeting intestinal barrier, blood–brain meninges, peripheral immune system counteract dysfunction neurodegeneration. Finally, conclude by assessing pre-clinical clinical evidence probiotics, prebiotics, fecal transplantation A thorough comprehension will foster effective therapeutic interventions for management

Language: Английский

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Emerging roles of innate and adaptive immunity in Alzheimer’s disease

Immunity, Journal Year: 2022, Volume and Issue: 55(12), P. 2236 - 2254

Published: Nov. 8, 2022

Language: Английский

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The gut microbiome in Alzheimer’s disease: what we know and what remains to be explored

Molecular Neurodegeneration, Journal Year: 2023, Volume and Issue: 18(1)

Published: Feb. 1, 2023

Alzheimer's disease (AD), the most common cause of dementia, results in a sustained decline cognition. There are currently few effective modifying therapies for AD, but insights into mechanisms that mediate onset and progression may lead to new, therapeutic strategies. Amyloid beta oligomers plaques, tau aggregates, neuroinflammation play critical role neurodegeneration impact clinical AD progression. The upstream modulators these pathological features have not been fully clarified, recent evidence indicates gut microbiome (GMB) an influence on therefore human patients. In this review, we summarize studies identified alterations GMB correlate with pathophysiology patients mouse models. Additionally, discuss findings manipulations models potential GMB-targeted therapeutics AD. Lastly, diet, sleep, exercise as modifiers relationship between conclude future directions recommendations further topic.

Language: Английский

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Astrocytes in human central nervous system diseases: a frontier for new therapies

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Oct. 13, 2023

Astroglia are a broad class of neural parenchymal cells primarily dedicated to homoeostasis and defence the central nervous system (CNS). contribute pathophysiology all neurological neuropsychiatric disorders in ways that can be either beneficial or detrimental disorder outcome. Pathophysiological changes astroglia primary secondary result gain loss functions. respond external, non-cell autonomous signals associated with any form CNS pathology by undergoing complex variable their structure, molecular expression, function. In addition, internally driven, cell astroglial innate properties lead pathologies. Astroglial is complex, different pathophysiological states phenotypes context-specific vary disorder, disorder-stage, comorbidities, age, sex. Here, we classify into (i) reactive astrogliosis, (ii) atrophy function, (iii) degeneration death, (iv) astrocytopathies characterised aberrant forms drive disease. We review across spectrum human diseases disorders, including neurotrauma, stroke, neuroinfection, autoimmune attack epilepsy, as well neurodevelopmental, neurodegenerative, metabolic disorders. Characterising cellular mechanisms represents new frontier identify novel therapeutic strategies.

Language: Английский

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APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints

Nature Immunology, Journal Year: 2023, Volume and Issue: 24(11), P. 1839 - 1853

Published: Sept. 25, 2023

Language: Английский

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Cell type-specific roles of APOE4 in Alzheimer disease

Nature reviews. Neuroscience, Journal Year: 2024, Volume and Issue: 25(2), P. 91 - 110

Published: Jan. 8, 2024

Language: Английский

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Multifaceted roles of APOE in Alzheimer disease

Nature Reviews Neurology, Journal Year: 2024, Volume and Issue: 20(8), P. 457 - 474

Published: June 21, 2024

Language: Английский

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Report of the APOE4 National Institute on Aging/Alzheimer Disease Sequencing Project Consortium Working Group: Reducing APOE4 in Carriers is a Therapeutic Goal for Alzheimer's Disease

Annals of Neurology, Journal Year: 2024, Volume and Issue: 95(4), P. 625 - 634

Published: Jan. 5, 2024

Alzheimer's disease (AD) is the most common neurodegenerative disorder and one of leading causes disability worldwide. The apolipoprotein E4 gene (APOE4) strongest genetic risk factor for AD. In 2023, APOE4 National Institute on Aging/Alzheimer's Disease Sequencing Project working group came together to gather data discuss question whether reduce or increase as a therapeutic intervention It was unanimous consensus that cumulative from multiple studies in humans animal models support lowering should be target approaches carriers. ANN NEUROL 2024;95:625-634.

Language: Английский

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Reactive Astrocytes and Emerging Roles in Central Nervous System (CNS) Disorders

Cold Spring Harbor Perspectives in Biology, Journal Year: 2024, Volume and Issue: 16(7), P. a041356 - a041356

Published: Feb. 5, 2024

In addition to their many functions in the healthy central nervous system (CNS), astrocytes respond CNS damage and disease through a process called "reactivity." Recent evidence reveals that astrocyte reactivity is heterogeneous spectrum of potential changes occur context-specific manner. These are determined by diverse signaling events vary not only with nature severity different insults but also location CNS, genetic predispositions, age, potentially "molecular memory" previous events. Astrocyte can be associated both essential beneficial as well harmful effects. The available information rapidly expanding much has been learned about molecular diversity reactivity. Emerging functional associations point toward roles for determining outcome disorders.

Language: Английский

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