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Updated: May 4, 2026
Cell-based Assay to Study Antibody-mediated Tau Clearance by Microglia
Published on: November 9, 2018
Microglia convert aggregated amyloid-β into neurotoxic forms through the shedding of microvesicles
11] Department of Biotechnology and Translational Medicine, University of Milano, via Vanvitelli 32, Milano 20129, Italy [2] Department of Medicine, CNR Institute of Neuroscience, via Vanvitelli 32, Milano 20129, Italy.
Abstract:
Alzheimer's disease (AD) is characterized by extracellular amyloid-β (Aβ) deposition, which activates microglia, induces neuroinflammation and drives neurodegeneration. Recent evidence indicates that soluble pre-fibrillar Aβ species, rather than insoluble fibrils, are the most toxic forms of Aβ. Preventing soluble Aβ formation represents, therefore, a major goal in AD. We investigated whether microvesicles (MVs) released extracellularly by reactive microglia may contribute to AD degeneration. We found that production of myeloid MVs, likely of microglial origin, is strikingly high in AD patients and in subjects with mild cognitive impairment and that AD MVs are toxic for cultured neurons. The mechanism responsible for MV neurotoxicity was defined in vitro using MVs produced by primary microglia. We demonstrated that neurotoxicity of MVs results from (i) the capability of MV lipids to promote formation of soluble Aβ species from extracellular insoluble aggregates and (ii) from the presence of neurotoxic Aβ forms trafficked to MVs after Aβ internalization into microglia. MV neurotoxicity was neutralized by the Aβ-interacting protein PrP and anti-Aβ antibodies, which prevented binding to neurons of neurotoxic soluble Aβ species. This study identifies microglia-derived MVs as a novel mechanism by which microglia participate in AD degeneration, and suggest new therapeutic strategies for the treatment of the disease.
Insights
Microglia-released microvesicles (MVs) in Alzheimer's disease (AD) promote toxic soluble amyloid-beta (Aβ) formation and directly harm neurons. Neutralizing these MVs with PrP or antibodies offers potential new AD therapies.
Area of Science:
- Neuroscience
- Cell Biology
- Pathology
Background:
- Alzheimer's disease (AD) involves amyloid-beta (Aβ) plaques, neuroinflammation, and neurodegeneration.
- Soluble Aβ species are considered more neurotoxic than insoluble fibrils.
- Microglia activation is a key feature of AD pathogenesis.
Purpose of the Study:
- To investigate the role of microvesicles (MVs) from reactive microglia in AD neurodegeneration.
- To elucidate the mechanisms underlying MV-mediated neurotoxicity.
- To explore potential therapeutic interventions targeting these MVs.
Main Methods:
- Analysis of myeloid MVs in AD patients and mild cognitive impairment subjects.
- In vitro studies using MVs from primary microglia to assess neuronal toxicity.
- Investigating the interaction of MVs with Aβ species and neuronal cells.
- Testing the efficacy of Aβ-binding protein PrP and anti-Aβ antibodies in neutralizing MV neurotoxicity.
Main Results:
- Elevated levels of myeloid MVs observed in AD and mild cognitive impairment patients.
- Microglia-derived MVs demonstrated direct neurotoxicity in cultured neurons.
- MV lipids promoted soluble Aβ formation, and MVs carried toxic Aβ species.
- PrP and anti-Aβ antibodies neutralized MV neurotoxicity by preventing soluble Aβ binding to neurons.
Conclusions:
- Microglia-derived MVs represent a novel mechanism contributing to AD neurodegeneration.
- These MVs facilitate the spread of toxic soluble Aβ species.
- Targeting microglia-derived MVs presents a promising therapeutic strategy for AD.
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