Amyloid-beta protofibrils and aggregates (Aβ protofibrils)

Amyloid-beta (Aβ) protofibrils and aggregates are misfolded protein assemblies derived from the amyloid precursor protein (APP) that play a central role in the pathogenesis of Alzheimer's disease (Hardy & Higgins, 1992). These structures range from small, soluble oligomers and protofibrils to large, insoluble extracellular plaques, with protofibrils being particularly neurotoxic by disrupting synaptic function and promoting neuroinflammation (Walsh & Selkoe, 2007). The amyloid cascade hypothesis suggests that the accumulation of these species is the primary driver of neurodegeneration, leading to subsequent tau tangle formation and neuronal death. Therapeutic strategies primarily involve monoclonal antibodies designed to selectively bind these aggregated forms to facilitate their clearance from the brain via microglial phagocytosis (Budd Haeberlein et al., 2022). Clinical success with drugs like lecanemab and donanemab has validated Aβ protofibrils and plaques as viable targets for slowing cognitive decline in early-stage Alzheimer's patients (van Dyck et al., 2023; Sims et al., 2023). However, targeting these aggregates is associated with safety risks such as amyloid-related imaging abnormalities (ARIA), which require careful monitoring during treatment (Sperling et al., 2011).

Other names

Amyloid-beta oligomersAβ protofibrilsAmyloid-beta plaquesAβ aggregatesSoluble Aβ protofibrilsFibrillar amyloid-beta

Monoclonal antibodies bind to specific epitopes on amyloid-beta protofibrils or insoluble plaques, promoting their clearance by microglia through Fc receptor-mediated phagocytosis and preventing the further accumulation of neurotoxic aggregates (van Dyck et al., 2023; Mintun et al., 2021).