Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation

Journal of Neuroinflammation, Journal Year: 2023, Volume and Issue: 20(1)

Published: July 14, 2023

Abstract Alzheimer’s Disease (AD) contributes to most cases of dementia. Its prominent neuropathological features are the extracellular neuritic plaques and intercellular neurofibrillary tangles composed aggregated β-amyloid (Aβ) hyperphosphorylated tau protein, respectively. In past few decades, disease-modifying therapy targeting Aβ has been focus AD drug development. Even though it is encouraging that two these drugs have recently received accelerated US Food Drug Administration approval for treatment, their efficacy or long-term safety controversial. Tau increasing attention as a potential therapeutic target, since evidence indicates pathology more associated with cognitive dysfunction. Moreover, inflammation, especially neuroinflammation, accompanies pathological processes also linked deficits. Accumulating inflammation complex tight interplay pathology. Here, we review recent on interaction between pathology, focusing post-translational modification dissemination, neuroinflammatory responses, including glial cell activation inflammatory signaling pathways. Then, summarize latest clinical trials neuroinflammation. Sustained increased responses in cells neurons pivotal cellular drivers regulators exacerbation which further its worsening by aggravating responses. Unraveling precise mechanisms underlying relationship neuroinflammation will provide new insights into discovery translation targets other tau-related diseases (tauopathies). Targeting multiple pathologies precision strategies be crucial direction developing tauopathies.

Language: Английский

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Intersection of pathological tau and microglia at the synapse

Acta Neuropathologica Communications, Journal Year: 2019, Volume and Issue: 7(1)

Published: July 5, 2019

Tauopathies are a heterogenous class of diseases characterized by cellular accumulation aggregated tau and include such as Alzheimer's disease (AD), progressive supranuclear palsy chronic traumatic encephalopathy. Tau pathology is strongly linked to neurodegeneration clinical symptoms in tauopathy patients. Furthermore, synapse loss an early pathological event tauopathies the strongest correlate cognitive decline. additionally associated with neuroinflammatory processes, reactive microglia, astrocytes, increased levels pro-inflammatory molecules (e.g. complement proteins, cytokines). Recent studies show that principal immune cells brain, microglia play particularly important role initiation progression neurodegeneration. AD risk genes Triggering receptor expressed on myeloid 2 (TREM2) Apolipoprotein E (APOE) enriched innate system modulate response pathology. Microglia can active synaptic dysfunction abnormally phagocytosing compartments neurons involved spreading - process which thought underlie nature propagation through brain. Spreading also predominant target for tau-based immunotherapy. Active vaccines, therapeutic antibodies other approaches targeting actively explored treatment options tauopathies. This review describes pathobiology mechanism action potential therapeutics

Language: Английский

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Astrocytes: a double-edged sword in neurodegenerative diseases

Neural Regeneration Research, Journal Year: 2021, Volume and Issue: 16(9), P. 1702 - 1702

Published: Jan. 1, 2021

Astrocytes play multifaceted and vital roles in maintaining neurophysiological function of the central nervous system by regulating homeostasis, increasing synaptic plasticity, sustaining neuroprotective effects. become activated as a result inflammatory responses during progression pathological changes associated with neurodegenerative disorders. Reactive astrocytes (neurotoxic A1 A2) are triggered disease pathogenesis due to neuroinflammation ischemia. However, only limited body literature describes morphological functional diseases. The present review investigated detrimental beneficial diseases reported recent studies, these cells have promising therapeutic potential offer new approaches for treatment

Language: Английский

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Synapse pathology in Alzheimer’s disease

Seminars in Cell and Developmental Biology, Journal Year: 2022, Volume and Issue: 139, P. 13 - 23

Published: June 9, 2022

Synapse loss and damage are central features of Alzheimer's disease (AD) contribute to the onset progression its behavioural physiological features. Here we review literature describing synapse pathology in AD, from what have learned microscopy terms impacts on architecture, mechanistic role Aβ, tau glial cells, mitochondrial dysfunction, link with AD risk genes. We consider emerging view that may operate at a further level, diversity, discuss prospects for leveraging new synaptome mapping methods comprehensively understand molecular properties vulnerable resilient synapses. Uncovering brain diversity should inform therapeutic approaches targeted preserving or replenishing lost damaged synapses aid interpretation clinical imaging aim measure damage.

Language: Английский

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Astrocytes in Alzheimer’s Disease: Pathological Significance and Molecular Pathways

Cells, Journal Year: 2021, Volume and Issue: 10(3), P. 540 - 540

Published: March 4, 2021

Astrocytes perform a wide variety of essential functions defining normal operation the nervous system and are active contributors to pathogenesis neurodegenerative disorders such as Alzheimer’s among others. Recent data provide compelling evidence that distinct astrocyte states associated with specific stages Alzheimer´s disease. The advent transcriptomics technologies enables rapid progress in characterisation pathological states. In this review, we an overview origin, main functions, molecular morphological features astrocytes physiological well conditions related We will also explore roles disease summarize transcriptional changes altered pathways observed during course

Language: Английский

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Microglia and Astrocyte Function and Communication: What Do We Know in Humans?

Frontiers in Neuroscience, Journal Year: 2022, Volume and Issue: 16

Published: Feb. 16, 2022

Microglia and astrocytes play essential roles in the central nervous system contributing to many functions including homeostasis, immune response, blood-brain barrier maintenance synaptic support. Evidence has emerged from experimental models of glial communication that microglia influence coordinate each other their effects on brain environment. However, due difference cells between humans rodents, it is confirm relevance these findings human brains. Here, we aim review current knowledge microglia-astrocyte crosstalk humans, exploring novel methodological techniques used health disease conditions. This will include an in-depth look at cell culture iPSCs,

Language: Английский

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Transgenic Mouse Models of Alzheimer’s Disease: An Integrative Analysis

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(10), P. 5404 - 5404

Published: May 12, 2022

Alzheimer's disease (AD) constitutes the most prominent form of dementia among elderly individuals worldwide. Disease modeling using murine transgenic mice was first initiated thanks to discovery heritable mutations in amyloid precursor protein (APP) and presenilins (PS) genes. However, due repeated failure translational applications from animal models human patients, along with recent advances genetic susceptibility our current understanding on biology, these have evolved over time an attempt better reproduce complexity this devastating improve their applicability. In review, we provide a comprehensive overview about major pathological elements AD (plaques, tauopathy, synaptic damage, neuronal death, neuroinflammation glial dysfunction), discussing knowledge that available mouse provided mechanisms underlying disease. Moreover, highlight pros cons models, revolution offered by concomitant use omics technologies may lead more rapid improvement present battery.

Language: Английский

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The role of astrocyte structural plasticity in regulating neural circuit function and behavior

Glia, Journal Year: 2022, Volume and Issue: 70(8), P. 1467 - 1483

Published: May 10, 2022

Abstract Brain circuits undergo substantial structural changes during development, driven by the formation, stabilization, and elimination of synapses. Synaptic connections continue to experience‐dependent rearrangements throughout life, which are postulated underlie learning memory. Astrocytes, a major glial cell type in brain, physically contact with synaptic through their ensheathment Astrocytes strongly contribute remodeling structures healthy diseased central nervous systems regulating connectivity behaviors. However, whether plasticity astrocytes is involved critical functions at synapse unknown. This review will discuss emerging evidence linking astrocytic circuit regulation Moreover, we survey possible molecular cellular mechanisms non‐cell‐autonomous effects on neuronal plasticity. Finally, how astrocyte morphological different physiological states disease conditions function dysfunction.

Language: Английский

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Interactions of glial cells with neuronal synapses, from astrocytes to microglia and oligodendrocyte lineage cells

Glia, Journal Year: 2023, Volume and Issue: 71(6), P. 1383 - 1401

Published: Feb. 17, 2023

Abstract The mammalian brain is a complex organ comprising neurons, glia, and more than 1 × 10 14 synapses. Neurons are heterogeneous group of electrically active cells, which form the framework circuitry brain. However, glial primarily divided into astrocytes, microglia, oligodendrocytes (OLs), oligodendrocyte precursor cells (OPCs), constitute approximately half all neural in central nervous system (CNS) mainly provide nutrition tropic support to neurons In last two decades, concept “tripartite synapses” has drawn great attention, emphasizes that astrocytes an integral part synapse regulate neuronal activity feedback manner after receiving signals. Since then, synaptic modulation by been extensively studied substantially revised. this review, we summarize latest significant findings on how particular, microglia OL lineage impact remodel structure function synapses Our review highlights cellular molecular aspects neuron‐glia crosstalk provides additional information aberrant communication between glia may contribute pathologies.

Language: Английский

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Microglial debris is cleared by astrocytes via C4b-facilitated phagocytosis and degraded via RUBICON-dependent noncanonical autophagy in mice

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Oct. 24, 2022

Abstract Microglia are important immune cells in the central nervous system (CNS) that undergo turnover throughout lifespan. If microglial debris is not removed a timely manner, accumulated may influence CNS function. Clearance of crucial for homeostasis. However, underlying mechanisms remain obscure. We here investigate how dead microglia removed. find although can phagocytose vitro, territory-dependent competition hinders microglia-to-microglial engulfment vivo. In contrast, mainly phagocytosed by astrocytes brain, facilitated C4b opsonization. The engulfed fragments then degraded via RUBICON-dependent LC3-associated phagocytosis (LAP), form noncanonical autophagy. Interference with C4b-mediated and subsequent LAP disrupt removal degradation debris, respectively. Together, we elucidate cellular molecular mice, extending knowledge on maintenance

Language: Английский

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