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Updated: Jul 28, 2025
Fabrication of Amyloid-β-Secreting Alginate Microbeads for Use in Modelling Alzheimer's Disease
Published on: July 6, 2019
β2-Microglobulin coaggregates with Aβ and contributes to amyloid pathology and cognitive deficits in Alzheimer's
Yini Zhao1,2, Qiuyang Zheng1,2, Yujuan Hong1
1State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China.
Abstract:
Extensive studies indicate that β-amyloid (Aβ) aggregation is pivotal for Alzheimer's disease (AD) progression; however, cumulative evidence suggests that Aβ itself is not sufficient to trigger AD-associated degeneration, and whether other additional pathological factors drive AD pathogenesis remains unclear. Here, we characterize pathogenic aggregates composed of β2-microglobulin (β2M) and Aβ that trigger neurodegeneration in AD. β2M, a component of major histocompatibility complex class I (MHC class I), is upregulated in the brains of individuals with AD and constitutes the amyloid plaque core. Elevation of β2M aggravates amyloid pathology independent of MHC class I, and coaggregation with β2M is essential for Aβ neurotoxicity. B2m genetic ablation abrogates amyloid spreading and cognitive deficits in AD mice. Antisense oligonucleotide- or monoclonal antibody-mediated β2M depletion mitigates AD-associated neuropathology, and inhibition of β2M-Aβ coaggregation with a β2M-based blocking peptide ameliorates amyloid pathology and cognitive deficits in AD mice. Our findings identify β2M as an essential factor for Aβ neurotoxicity and a potential target for treating AD.
Insights
Beta-2 microglobulin (β2M) aggregates with amyloid-beta (Aβ) to drive Alzheimer's disease (AD) neurodegeneration. Targeting β2M shows promise for treating AD pathology and cognitive decline.
Area of Science:
- Neuroscience
- Immunology
- Biochemistry
Background:
- Alzheimer's disease (AD) pathogenesis involves amyloid-beta (Aβ) aggregation, but additional factors driving neurodegeneration are unclear.
- Beta-2 microglobulin (β2M), a component of MHC class I, is found in amyloid plaques and upregulated in AD brains.
Purpose of the Study:
- To investigate the role of β2M in Aβ-induced neurodegeneration in Alzheimer's disease.
- To identify β2M as a potential therapeutic target for AD.
Main Methods:
- Characterization of pathogenic β2M-Aβ aggregates.
- Genetic ablation of B2m in AD mouse models.
- Pharmacological inhibition of β2M using antisense oligonucleotides, monoclonal antibodies, and blocking peptides.
Main Results:
- β2M coaggregation with Aβ is essential for Aβ neurotoxicity and aggravates amyloid pathology independently of MHC class I.
- B2m genetic ablation prevented amyloid spreading and cognitive deficits in AD mice.
- β2M depletion and inhibition of β2M-Aβ coaggregation ameliorated AD neuropathology and cognitive deficits.
Conclusions:
- β2M is an essential factor contributing to Aβ neurotoxicity in Alzheimer's disease.
- Targeting β2M or its coaggregation with Aβ represents a promising therapeutic strategy for AD.
