Alzheimer disease

Nature Reviews Disease Primers, Journal Year: 2021, Volume and Issue: 7(1)

Published: May 13, 2021

Language: Английский

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Astrocytic and microglial cells as the modulators of neuroinflammation in Alzheimer’s disease

Journal of Neuroinflammation, Journal Year: 2022, Volume and Issue: 19(1)

Published: Aug. 17, 2022

Abstract Neuroinflammation is instigated by the misfiring of immune cells in central nervous system (CNS) involving microglia and astrocytes as key cell-types. a consequence CNS injury, infection, toxicity, or autoimmunity. It favorable well detrimental process for neurodevelopment associated processes. Transient activation inflammatory response release cytokines growth factors positively affects development post-injury tissue. However, chronic uncontrolled responses may lead to various neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's (PD), amyotrophic lateral sclerosis, multiple sclerosis. These diseases have variable clinical pathological features, but are underlaid aggregation misfolded proteins with cytotoxic effect. Notably, abnormal glial could mediate neuroinflammation, leading condition. Microglia, type cell, resident form forefront defense system. Dysfunctional astrocyte, different kind cell homeostatic function, impairs protein aggregate (amyloid-beta plaque) clearance AD. Studies shown that undergo alterations their genetic profile, cellular molecular responses, thus promote dysfunctional cross-talk Hence, targeting astrocytes-driven pathways resolve particular layers neuroinflammation set reliable therapeutic intervention AD progression.

Language: Английский

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Microbiota-derived short chain fatty acids modulate microglia and promote Aβ plaque deposition

eLife, Journal Year: 2021, Volume and Issue: 10

Published: April 13, 2021

Previous studies have identified a crucial role of the gut microbiome in modifying Alzheimer’s disease (AD) progression. However, mechanisms microbiome–brain interaction AD were so far unknown. Here, we identify microbiota-derived short chain fatty acids (SCFA) as microbial metabolites which promote Aβ deposition. Germ-free (GF) mice exhibit substantially reduced plaque load and markedly SCFA plasma concentrations; conversely, supplementation to GF increased levels conventionally colonized (specific pathogen-free [SPF]) animals SPF even further exacerbated load. This was accompanied by pronounced alterations microglial transcriptomic profile, including upregulation ApoE. Despite recruitment plaques upon supplementation, microglia contained less intracellular Aβ. Taken together, our results demonstrate that are critical mediators along gut-brain axis deposition likely via modulation phenotype.

Language: Английский

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Solving neurodegeneration: common mechanisms and strategies for new treatments

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

Published: March 21, 2022

Across neurodegenerative diseases, common mechanisms may reveal novel therapeutic targets based on neuronal protection, repair, or regeneration, independent of etiology site disease pathology. To address these and discuss emerging treatments, in April, 2021, Glaucoma Research Foundation, BrightFocus the Melza M. Frank Theodore Barr Foundation collaborated to bring together key opinion leaders experts field for a virtual meeting titled "Solving Neurodegeneration". This "think-tank" style focused uncovering mechanistic roots promising new catalyzed by goal finding treatments glaucoma, world's leading cause irreversible blindness interest three hosting foundations. Glaucoma, which causes vision loss through degeneration optic nerve, likely shares early cellular molecular events with other diseases central nervous system. Here we major areas overlap between system: neuroinflammation, bioenergetics metabolism, genetic contributions, neurovascular interactions. We summarize important discussion points emphasis research that are most innovative treatment neurodegeneration yet require further development. The is highlighted provides unique opportunities collaboration will lead efforts preventing ultimately loss.

Language: Английский

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Immunotherapy for Alzheimer’s disease: targeting β-amyloid and beyond

Translational Neurodegeneration, Journal Year: 2022, Volume and Issue: 11(1)

Published: March 18, 2022

Alzheimer's disease (AD) is the most common neurodegenerative in elderly worldwide. However, complexity of AD pathogenesis leads to discrepancies understanding this disease, and may be main reason for failure drug development. Fortunately, many ongoing preclinical clinical studies will continually open up avenues unravel mechanisms guide strategies diagnosis For example, immunotherapeutic targeting amyloid-β (Aβ) tau proteins were once deemed almost certainly effective treatment due excellent results. repeated failures trials on vaccines humanized anti-Aβ anti-tau monoclonal antibodies have resulted doubts strategy. Recently, a new antibody (Aducanumab) has been approved by US Food Drug Administration, which brings us back realization that immunotherapy Aβ still promising. Meanwhile, immunotherapies based other targets such as tau, microglia gut-brain axis are also under Further research needed clarify forms epitopes targeted improve accuracy effectiveness drugs. In review, we focus Aβ, their action AD. addition, present up-to-date advances future perspectives

Language: Английский

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Amyloid-type Protein Aggregation and Prion-like Properties of Amyloids

Chemical Reviews, Journal Year: 2021, Volume and Issue: 121(13), P. 8285 - 8307

Published: June 17, 2021

This review will focus on the process of amyloid-type protein aggregation. Amyloid fibrils are an important hallmark misfolding diseases and therefore have been investigated for decades. Only recently, however, atomic or near-atomic resolution structures elucidated from various in vitro ex vivo obtained fibrils. In parallel, fibril formation has studied under highly artificial but comparatively reproducible conditions. The starts with a summary what is known speculated aggregation experiments. A partially hypothetic selection model be described that may suitable to explain why amyloid look way they do, particular, at least all so far reported high cryo-electron microscopy register, cross-β-sheet mostly consist two protofilaments twisted around each other. An intrinsic feature prion-like nature assemblies. Transferring point view situation not straightforward, hypothetic, leaves many open questions need addressed future.

Language: Английский

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Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic

Cell, Journal Year: 2021, Volume and Issue: 184(18), P. 4651 - 4668.e25

Published: Aug. 26, 2021

Language: Английский

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The role of innate immune genes in Alzheimer's disease

Current Opinion in Neurology, Journal Year: 2021, Volume and Issue: 34(2), P. 228 - 236

Published: Feb. 3, 2021

Purpose of review The aim this study was to provide an update on the role innate immune system and neuroinflammation in pathogenesis Alzheimer's disease, with emphasis microglial receptors CD33 TREM2. Recent findings Genome-wide association studies (GWAS) have identified many disease risk genes related response microglia including phagocytic TREM2 . GWAS pathway analyses emphasize crucial disease. Disease-associated been characterized by TREM2-dependent upregulation lipid metabolism genes. Impaired phagocytosis results amyloid beta (Aβ) accumulation leading that is primary cause neurodegeneration. modulate emerged as therapeutic targets Progress has made inhibit gene therapy, small molecules or immunotherapy, increase activity immunotherapy. Finally, mAbs against entered clinical trials may reduce brain. Summary Targeting via inhibition and/or activation important implications for neurodegeneration be addition monoclonal anti-Aβ antibody treatments remove plaques without reducing neuroinflammation.

Language: Английский

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A TREM2-activating antibody with a blood–brain barrier transport vehicle enhances microglial metabolism in Alzheimer’s disease models

Nature Neuroscience, Journal Year: 2023, Volume and Issue: unknown

Published: Jan. 12, 2023

Abstract Loss-of-function variants of TREM2 are associated with increased risk Alzheimer’s disease (AD), suggesting that activation this innate immune receptor may be a useful therapeutic strategy. Here we describe high-affinity human TREM2-activating antibody engineered monovalent transferrin (TfR) binding site, termed transport vehicle (ATV), to facilitate blood–brain barrier transcytosis. Upon peripheral delivery in mice, ATV:TREM2 showed improved brain biodistribution and enhanced signaling compared standard anti-TREM2 antibody. In induced pluripotent stem cell (iPSC)-derived microglia, proliferation mitochondrial metabolism. Single-cell RNA sequencing morphometry revealed shifted microglia metabolically responsive states, which were distinct from those by amyloid pathology. an AD mouse model, boosted microglial activity glucose Thus, represents promising approach improve function treat hypometabolism found patients AD.

Language: Английский

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Impaired insulin signalling and allostatic load in Alzheimer disease

Nature reviews. Neuroscience, Journal Year: 2022, Volume and Issue: 23(4), P. 215 - 230

Published: Feb. 28, 2022

Language: Английский

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