Amyloid-beta peptide aggregates (Aβ aggregates)

Amyloid-beta (Aβ) peptide aggregates, encompassing soluble oligomers, protofibrils, and insoluble fibrils that form senile plaques, are central pathological hallmarks of Alzheimer's disease [Selkoe & Hardy, 2016, EMBO Mol Med]. These aggregates are derived from the proteolytic cleavage of the amyloid precursor protein (APP) by beta- and gamma-secretases, leading to the accumulation of Aβ40 and Aβ42 isoforms in the brain parenchyma [Haass et al., 2012, Cold Spring Harb Perspect Med]. In their aggregated forms, Aβ peptides exert potent neurotoxic effects by disrupting synaptic signaling, inducing oxidative stress, and triggering chronic neuroinflammation via microglial activation [Walsh & Selkoe, 2007, J Neurochem; Heneka et al., 2015, Lancet Neurol]. Therapeutic strategies primarily focus on passive immunotherapy using monoclonal antibodies designed to recognize specific conformational epitopes of these aggregates to promote their clearance from the central nervous system [Sevigny et al., 2016, Nature]. Recent clinical successes with drugs like lecanemab and donanemab have validated Aβ aggregates as a viable therapeutic target for slowing cognitive decline in early-stage Alzheimer's patients [van Dyck et al., 2023, NEJM; Sims et al., 2023, JAMA]. However, targeting these aggregates is associated with significant safety risks, most notably amyloid-related imaging abnormalities (ARIA), which require careful monitoring [Sperling et al., 2011, Alzheimers Dement].

Other names

Aβ aggregatesBeta-amyloid plaquesSenile plaquesAmyloid-beta oligomersAbetaAmyloid-beta protofibrils

Passive immunotherapy using monoclonal antibodies that bind to specific conformational epitopes on Aβ aggregates (such as protofibrils or plaques), facilitating their clearance from the brain via Fc-receptor-mediated microglial phagocytosis [Sevigny et al., 2016; van Dyck et al., 2023].