The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease

Nature, Год журнала: 2016, Номер 537(7618), С. 50 - 56

Опубликована: Авг. 30, 2016

Язык: Английский

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Microglia in Alzheimer’s disease

The Journal of Cell Biology, Год журнала: 2017, Номер 217(2), С. 459 - 472

Опубликована: Дек. 1, 2017

Proliferation and activation of microglia in the brain, concentrated around amyloid plaques, is a prominent feature Alzheimer’s disease (AD). Human genetics data point to key role for pathogenesis AD. The majority risk genes AD are highly expressed (and many selectively expressed) by brain. There mounting evidence that protect against incidence AD, as impaired microglial activities altered responses β-amyloid associated with increased risk. On other hand, there also abundant activated can be harmful neurons. Microglia mediate synapse loss engulfment synapses, likely via complement-dependent mechanism; they exacerbate tau pathology secrete inflammatory factors injure neurons directly or neurotoxic astrocytes. Gene expression profiles indicate multiple states neurodegenerative settings, which might explain disparate roles development progression pathology.

Язык: Английский

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Microglia in neurodegeneration

Nature Neuroscience, Год журнала: 2018, Номер 21(10), С. 1359 - 1369

Опубликована: Сен. 19, 2018

Язык: Английский

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The Amyloid-β Pathway in Alzheimer’s Disease

Molecular Psychiatry, Год журнала: 2021, Номер 26(10), С. 5481 - 5503

Опубликована: Авг. 30, 2021

Abstract Breakthroughs in molecular medicine have positioned the amyloid-β (Aβ) pathway at center of Alzheimer’s disease (AD) pathophysiology. While detailed mechanisms and spatial-temporal dynamics leading to synaptic failure, neurodegeneration, clinical onset are still under intense investigation, established biochemical alterations Aβ cycle remain core biological hallmark AD promising targets for development disease-modifying therapies. Here, we systematically review update vast state-of-the-art literature science with evidence from basic research studies human genetic multi-modal biomarker investigations, which supports a crucial role dyshomeostasis pathophysiological dynamics. We discuss highlighting differentiated interaction distinct species other AD-related mechanisms, such as tau-mediated, neuroimmune inflammatory changes, well neurochemical imbalance. Through lens latest multimodal vivo biomarkers AD, this cross-disciplinary examines compelling hypothesis- data-driven rationale Aβ-targeting therapeutic strategies early treatment AD.

Язык: Английский

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Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model

Nature Neuroscience, Год журнала: 2019, Номер 22(5), С. 719 - 728

Опубликована: Апрель 1, 2019

Язык: Английский

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TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques

The Journal of Experimental Medicine, Год журнала: 2016, Номер 213(5), С. 667 - 675

Опубликована: Апрель 18, 2016

Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial that recognizes changes in the lipid microenvironment, which may occur during amyloid β (Aβ) accumulation and neuronal degeneration Alzheimer's disease (AD). Rare TREM2 variants affect function lead to an increased risk of developing AD. In murine models AD, deficiency prevents clustering around Aβ deposits. However, origin surrounding impact are matter debate. Using parabiosis, we found amyloid-associated derive from brain-resident microglia rather than recruitment peripheral blood monocytes. To determine accumulation, examined plaques 5XFAD model AD at onset Aβ-related pathology. At this early time point, was similar TREM2-deficient -sufficient mice. absence TREM2, were not fully enclosed by microglia; they more diffuse, less dense, associated with significantly greater neuritic damage. Thus, protects enabling surround alter plaque structure, thereby limiting

Язык: Английский

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TREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy

Neuron, Год журнала: 2016, Номер 90(4), С. 724 - 739

Опубликована: Май 1, 2016

Язык: Английский

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Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model

Nature Communications, Год журнала: 2019, Номер 10(1)

Опубликована: Авг. 21, 2019

Abstract Many risk genes for the development of Alzheimer’s disease (AD) are exclusively or highly expressed in myeloid cells. Microglia dependent on colony-stimulating factor 1 receptor (CSF1R) signaling their survival. We designed and synthesized a selective brain-penetrant CSF1R inhibitor (PLX5622) allowing extended specific microglial elimination, preceding during pathology development. find that 5xFAD mouse model AD, plaques fail to form parenchymal space following depletion, except areas containing surviving microglia. Instead, Aβ deposits cortical blood vessels reminiscent cerebral amyloid angiopathy. Altered gene expression hippocampus is also reversed by absence Transcriptional analyses residual plaque-forming microglia show they exhibit disease-associated profile. Collectively, we describe structure, formulation, efficacy PLX5622, which allows sustained depletion identify roles initiating plaque pathogenesis.

Язык: Английский

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Eliminating microglia in Alzheimer’s mice prevents neuronal loss without modulating amyloid-β pathology

Brain, Год журнала: 2016, Номер 139(4), С. 1265 - 1281

Опубликована: Фев. 26, 2016

In addition to amyloid-β plaque and tau neurofibrillary tangle deposition, neuroinflammation is considered a key feature of Alzheimer's disease pathology. Inflammation in characterized by the presence reactive astrocytes activated microglia surrounding amyloid plaques, implicating their role pathogenesis. Microglia healthy adult mouse depend on colony-stimulating factor 1 receptor (CSF1R) signalling for survival, pharmacological inhibition this results rapid elimination nearly all central nervous system. study, we set out determine if chronically brain are also dependent CSF1R signalling, so, how these cells contribute Ten-month-old 5xfAD mice were treated with selective inhibitor month, resulting ∼80% microglia. Chronic microglial does not alter levels or load; however, it rescue dendritic spine loss prevent neuronal mice, as well reduce overall neuroinflammation. Importantly, behavioural testing revealed improvements contextual memory. Collectively, demonstrate that loss, memory impairments but do mediate protect from Microglia-mediated inflammation driving force Spangenberg et al . show improves cognitive function ameliorates synaptic/neuronal without altering load. Thus, act downstream plaques damage brain.

Язык: Английский

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A Breakdown in Metabolic Reprogramming Causes Microglia Dysfunction in Alzheimer's Disease

Cell Metabolism, Год журнала: 2019, Номер 30(3), С. 493 - 507.e6

Опубликована: Июнь 27, 2019

Язык: Английский

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