β2-Microglobulin coaggregates with Aβ and contributes to amyloid pathology and cognitive deficits in Alzheimer's disease model mice

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.