Amyloid-beta 42 (Aβ42) fibrils and oligomers (Aβ42)

Amyloid-beta 42 (Aβ42) is a 42-amino acid peptide produced through the sequential cleavage of the Amyloid Precursor Protein (APP) by BACE1 and the γ-secretase complex (UniProt P05067). In its monomeric form, Aβ42 is thought to play roles in synaptic plasticity and antimicrobial defense, but its pathological aggregation into soluble oligomers and insoluble fibrils is a defining characteristic of Alzheimer's disease (Hardy & Higgins, 1992, Science). These aggregated species, particularly soluble oligomers and protofibrils, are highly neurotoxic and contribute to synaptic loss, oxidative stress, and the formation of neurofibrillary tangles (NIH/NIA, 2023). The "amyloid cascade hypothesis" posits that the accumulation of these Aβ42 aggregates in the brain parenchyma is the initiating event in Alzheimer's pathogenesis (PubMed: 1564440). Therapeutic strategies have successfully utilized monoclonal antibodies, such as Lecanemab and Donanemab, to target these aggregates for removal by the brain's immune cells (van Dyck et al., 2023, NEJM). These treatments aim to slow cognitive decline by reducing the overall amyloid burden and preventing further neuronal damage (FDA, 2023). However, targeting these aggregates is associated with Amyloid-Related Imaging Abnormalities (ARIA), which require careful monitoring via MRI (FDA Label for Leqembi). Despite these challenges, Aβ42 aggregates remain the most validated therapeutic target for disease-modifying therapies in early-stage Alzheimer's disease (Nature Reviews Drug Discovery, 2023).

Other names

Abeta42Beta-amyloid 1-42Aβ42 aggregatesAmyloid-beta peptide 42Soluble Aβ42 oligomersInsoluble Aβ42 fibrilsAβ42 protofibrils

Monoclonal antibodies bind to specific epitopes on Aβ42 oligomers, protofibrils, or insoluble fibrils to facilitate Fc-receptor-mediated phagocytosis by microglia and promote the clearance of amyloid plaques from the brain (Sevigny et al., 2016, Nature; FDA Label for Leqembi).