Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Сен. 22, 2023

Abstract Microglia activation is observed in various neurodegenerative diseases. Recent advances single-cell technologies have revealed that these reactive microglia were with high spatial and temporal heterogeneity. Some identified specific states correlate pathological hallmarks are associated functions. both exert protective function by phagocytosing clearing protein aggregates play detrimental roles due to excessive uptake of aggregates, which would lead microglial phagocytic ability impairment, neuroinflammation, eventually neurodegeneration. In addition, peripheral immune cells infiltration shapes into a pro-inflammatory phenotype accelerates disease progression. also act as mobile vehicle propagate aggregates. Extracellular vesicles released from autophagy impairment all contribute progression Thus, enhancing phagocytosis, reducing microglial-mediated inhibiting exosome synthesis secretion, promoting conversion considered be promising strategies for the therapy Here we comprehensively review biology diseases, including Alzheimer’s disease, Parkinson’s multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, dementia Lewy bodies Huntington’s disease. We summarize possible microglia-targeted interventions treatments against diseases preclinical clinical evidence cell experiments, animal studies, trials.

Язык: Английский

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

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Фев. 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

Язык: Английский

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

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Окт. 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.

Язык: Английский

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The effects of microglia-associated neuroinflammation on Alzheimer’s disease

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Фев. 22, 2023

Alzheimer’s disease (AD) is defined as a severe chronic degenerative neurological in human. The pathogenic mechanism of AD has been convincingly elucidated by the “amyloid cascade hypothesis” with main focus pathological accretion β-amyloid (Aβ) peptides outside cell. However, increasing evidence suggests that this hypothesis weak explaining pathogenesis AD. Neuroinflammation crucial development AD, which proven elevated levels inflammatory markers and identification risk genes relevant to innate immune function. Here, we summarize effects microglia-mediated neuroinflammation on focusing temporal spatial changes microglial phenotype, interactions among microglia, Aβ, tau, neurons, prospects recent advances diagnostic therapeutic target

Язык: Английский

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Advancing cell therapy for neurodegenerative diseases

Cell stem cell, Год журнала: 2023, Номер 30(5), С. 512 - 529

Опубликована: Апрель 20, 2023

Язык: Английский

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Adult hippocampal neurogenesis in Alzheimer’s disease: A roadmap to clinical relevance

Cell stem cell, Год журнала: 2023, Номер 30(2), С. 120 - 136

Опубликована: Фев. 1, 2023

Adult hippocampal neurogenesis (AHN) drops sharply during early stages of Alzheimer's disease (AD), via unknown mechanisms, and correlates with cognitive status in AD patients. Understanding AHN regulation could provide a framework for innovative pharmacological interventions. We here combine molecular, behavioral, clinical data critically discuss the multicellular complexity niche relation to pathophysiology. further present roadmap toward better understanding role by probing promises caveats latest technological advancements field addressing conceptual methodological challenges ahead.

Язык: Английский

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Iron, ferroptosis, and ischemic stroke

Journal of Neurochemistry, Год журнала: 2023, Номер 165(4), С. 487 - 520

Опубликована: Март 13, 2023

Abstract Over 30 million people suffer from the consequences of ischemic stroke. The precise molecular mechanism neuronal damage during stroke remains unclear; therefore, effective treatment post‐ischemic a critical challenge. Recently, iron has emerged as crucial factor in post‐reperfusion injuries, participating cell peroxidation, excitotoxicity, and distinctive death pathway, namely, ferroptosis. Since is tightly regulated brain important for functions, imbalance its metabolism, including overload deficiency, been shown to impact outcomes. This review summarizes current understanding pathological events associated with discusses relevant drug development. image

Язык: Английский

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Mitochondrial complex I activity in microglia sustains neuroinflammation

Nature, Год журнала: 2024, Номер 628(8006), С. 195 - 203

Опубликована: Март 13, 2024

Abstract Sustained smouldering, or low-grade activation, of myeloid cells is a common hallmark several chronic neurological diseases, including multiple sclerosis 1 . Distinct metabolic and mitochondrial features guide the activation diverse functional states 2 However, how these act to perpetuate inflammation central nervous system unclear. Here, using multiomics approach, we identify molecular signature that sustains microglia through complex I activity driving reverse electron transport production reactive oxygen species. Mechanistically, blocking in pro-inflammatory protects against neurotoxic damage improves outcomes an animal disease model vivo. Complex potential therapeutic target foster neuroprotection inflammatory disorders 3

Язык: Английский

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Exposure of iPSC-derived human microglia to brain substrates enables the generation and manipulation of diverse transcriptional states in vitro

Nature Immunology, Год журнала: 2023, Номер 24(8), С. 1382 - 1390

Опубликована: Июль 27, 2023

Abstract Microglia, the macrophages of brain parenchyma, are key players in neurodegenerative diseases such as Alzheimer’s disease. These cells adopt distinct transcriptional subtypes known states. Understanding state function, especially human microglia, has been elusive owing to a lack tools model and manipulate these cells. Here, we developed platform for modeling microglia states vitro. We found that exposure stem-cell-differentiated synaptosomes, myelin debris, apoptotic neurons or synthetic amyloid-beta fibrils generated diversity mapped gene signatures identified including disease-associated enriched diseases. Using new lentiviral approach, demonstrated transcription factor MITF drives signature highly phagocytic state. Together, enable manipulation functional interrogation microglial both homeostatic disease-relevant contexts.

Язык: Английский

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Border-associated macrophages mediate the neuroinflammatory response in an alpha-synuclein model of Parkinson disease

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Июнь 26, 2023

Abstract Dopaminergic cell loss due to the accumulation of α-syn is a core feature pathogenesis Parkinson disease. Neuroinflammation specifically induced by α-synuclein has been shown exacerbate neurodegeneration, yet role central nervous system (CNS) resident macrophages in this process remains unclear. We found that specific subset CNS macrophages, border-associated (BAMs), play an essential mediating related neuroinflammation their unique as antigen presenting cells necessary initiate CD4 T response whereas MHCII presentation on microglia had no effect neuroinflammation. Furthermore, expression led expansion macrophage numbers and damage-associated activation state. Through combinatorial approach single-cell RNA sequencing depletion experiments, we played immune recruitment, infiltration, presentation. were identified post-mortem PD brain close proximity cells. These results point for disease through orchestration α-synuclein-mediated neuroinflammatory response.

Язык: Английский

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