Amyloid-beta (Aβ) fibril and plaque (Aβ fibril/plaque)

Amyloid-beta (Aβ) fibrils and plaques are insoluble, misfolded protein aggregates that serve as a primary pathological hallmark of Alzheimer's disease (AD). These structures are formed through the sequential cleavage of the amyloid precursor protein (APP) by beta-secretase and gamma-secretase, leading to the release of Aβ monomers that subsequently aggregate into oligomers, protofibrils, and eventually insoluble fibrils and dense plaques (Hardy & Higgins, 1992). While soluble oligomers and protofibrils are often considered the most neurotoxic species, the deposition of insoluble plaques is associated with widespread neuroinflammation and synaptic loss. Therapeutic agents like aducanumab and donanemab are designed with high selectivity for these aggregated forms, showing lower affinity for soluble monomers or smaller oligomeric species compared to agents like lecanemab (Sevigny et al., 2016; Mintun et al., 2021). By binding to these plaques, the antibodies facilitate their clearance via microglial phagocytosis, aiming to reduce the amyloid burden and slow cognitive decline in patients with early-stage AD. However, the removal of vascular amyloid can lead to amyloid-related imaging abnormalities (ARIA), which remains a significant safety concern in clinical practice (Sperling et al., 2011).

Other names

Amyloid-beta aggregateInsoluble amyloid-betaSenile plaqueNeuritic plaqueAβ plaqueFibrillar amyloid-betaAmyloid-beta deposit

Monoclonal antibodies bind to conformational or linear epitopes (such as the N-terminus or pyroglutamate-modified residues) exposed on aggregated amyloid-beta fibrils and plaques. This binding triggers microglial-mediated clearance via Fc-gamma receptor-mediated phagocytosis and subsequent lysosomal degradation, leading to the reduction of brain amyloid burden (Sevigny et al., 2016; Mintun et al., 2021).