Amyloid-beta aggregate and fibril (Aβ aggregate) (Aβ aggregate)

Amyloid-beta (Aβ) aggregates and fibrils are pathological protein assemblies derived from the proteolytic cleavage of the amyloid precursor protein (APP) by beta- and gamma-secretases (O'Brien & Wong, 2011, Annual Review of Neuroscience). In Alzheimer's disease, these peptides, particularly the 42-amino acid isoform (Aβ42), undergo a conformational shift from soluble monomers into toxic oligomers, protofibrils, and eventually insoluble fibrils that form extracellular senile plaques (Hardy & Higgins, 1992, Science). These aggregates are central to the amyloid cascade hypothesis, which posits that Aβ accumulation triggers a sequence of events including tau hyperphosphorylation, neuroinflammation, and synaptic loss, ultimately leading to neurodegeneration (Jack et al., 2013, Lancet Neurology). Beyond Alzheimer's, Aβ aggregates also deposit in the walls of cerebral blood vessels, leading to cerebral amyloid angiopathy (CAA) and increasing the risk of hemorrhagic stroke (Viswanathan & Greenberg, 2011, Annals of Neurology). Therapeutic strategies primarily utilize monoclonal antibodies designed to recognize specific aggregated states of Aβ to facilitate their clearance via microglial phagocytosis or to prevent the recruitment of further monomers into existing fibrils (Sevigny et al., 2016, Nature). Drugs such as Lecanemab and Donanemab have demonstrated the ability to reduce plaque burden and modestly slow cognitive decline in early-stage patients (van Dyck et al., 2023, NEJM). However, targeting these aggregates is associated with significant safety risks, most notably Amyloid-Related Imaging Abnormalities (ARIA), which manifest as brain edema or microhemorrhages (Sperling et al., 2011, Alzheimer's & Dementia). Monitoring efficacy and patient selection for these therapies relies heavily on biomarkers such as Amyloid PET imaging and the measurement of Aβ42/Aβ40 ratios in cerebrospinal fluid or plasma (Hansson et al., 2019, JAMA Neurology).

Other names

Amyloid-beta plaquesAβ oligomersAβ fibrilsSenile plaquesBeta-amyloid aggregatesAmyloid-beta protofibrils

Monoclonal antibodies bind to specific conformational or linear epitopes on amyloid-beta aggregates, protofibrils, or plaques to facilitate their clearance via microglial-mediated phagocytosis or to prevent further peptide aggregation.