Fibrillar amyloid-beta aggregate (fAβ) (fAβ)

Fibrillar amyloid-beta (Aβ) aggregates are insoluble, beta-sheet-rich protein assemblies that constitute the hallmark extracellular senile plaques in Alzheimer's disease and the vascular deposits in cerebral amyloid angiopathy (CAA). These aggregates arise from the misfolding and polymerization of Aβ monomers, particularly the 42-amino acid isoform (Aβ42), which is highly prone to aggregation (Hardy & Higgins, 1992, Science). In the brain parenchyma, dense-core plaques are surrounded by dystrophic neurites and activated glia, contributing to neuroinflammation and synaptic dysfunction (Selkoe & Hardy, 2016, EMBO Molecular Medicine). Vascular amyloid deposits weaken the walls of cerebral blood vessels, increasing the risk of microhemorrhages and stroke. Therapeutic intervention focuses on the use of monoclonal antibodies, such as aducanumab and donanemab, which bind to these fibrillar structures to promote their clearance through microglial-mediated phagocytosis (Sevigny et al., 2016, Nature). However, the removal of vascular amyloid is frequently associated with amyloid-related imaging abnormalities (ARIA), representing a significant clinical challenge in the development of anti-amyloid therapies (Sperling et al., 2011, Alzheimer's & Dementia).

Other names

Amyloid-beta plaqueSenile plaqueNeuritic plaqueDense-core plaqueVascular amyloidCerebral amyloid angiopathy depositAβ fibril

Monoclonal antibodies target specific epitopes on the fibrillar amyloid-beta aggregate, marking them for clearance by microglial cells via Fc-gamma receptor-mediated phagocytosis, or by directly promoting the dissolution of the fibrillar structure (Sevigny et al., 2016, Nature; Mintun et al., 2021, NEJM).