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.