Amyloid-beta peptide 42 (Aβ42)

Amyloid-beta peptide 42 (Aβ42) is a 42-amino acid peptide produced by the proteolytic cleavage of the Amyloid Precursor Protein (APP) by beta-secretase (BACE1) and gamma-secretase [UniProt: P05067]. While Aβ40 is the more common isoform, Aβ42 is more hydrophobic and significantly more prone to forming toxic oligomers and insoluble fibrils that constitute the core of senile plaques in Alzheimer's disease [PMID: 1564512]. According to the amyloid cascade hypothesis, the accumulation and aggregation of Aβ42 in the brain parenchyma trigger a series of pathological events, including neuroinflammation, tau protein hyperphosphorylation, and synaptic dysfunction, ultimately leading to neuronal death and cognitive decline [PMID: 1564512]. Therapeutic strategies targeting Aβ42 include monoclonal antibodies designed to clear existing aggregates or prevent their formation, as well as enzyme inhibitors intended to reduce peptide production. Recent clinical trials for drugs like lecanemab and donanemab have demonstrated that reducing amyloid burden can modestly slow cognitive decline in early Alzheimer's patients [PMID: 36351264]. However, these therapies are associated with serious safety risks, particularly Amyloid-Related Imaging Abnormalities (ARIA), which require careful monitoring via MRI [PMID: 33531306].

Other names

Amyloid-beta 1-42Abeta42Beta-amyloid 42Aβ1-42Amyloid beta-protein 42

Monoclonal antibodies bind to specific epitopes on Aβ42 (monomers, protofibrils, or plaques) to promote microglial-mediated clearance or prevent aggregation. Small molecule inhibitors like BACE1 inhibitors aim to block the initial cleavage of APP to prevent Aβ42 formation [PMID: 30612306].