Amyloid-beta (Aβ) fibrils (Aβ fibrils)

Aggregated amyloid-beta (Aβ) fibrils are insoluble, misfolded protein structures that serve as the hallmark pathological feature of Alzheimer's disease (Hardy & Higgins, 1992, Science). These fibrils are primarily composed of the 42-amino acid amyloid-beta peptide (Aβ42), which is produced through the proteolytic cleavage of the amyloid precursor protein (APP) by beta- and gamma-secretases (Selkoe & Hardy, 2016, EMBO Molecular Medicine). In the brain, these fibrils accumulate into extracellular deposits known as senile plaques, which are thought to disrupt neuronal communication and trigger a cascade of neurotoxic events, including oxidative stress and neuroinflammation. As a therapeutic target, Aβ fibrils are the focus of several FDA-approved monoclonal antibodies, such as lecanemab and donanemab, which are designed to bind specifically to aggregated forms of the peptide (van Dyck et al., 2023, NEJM; Sims et al., 2023, JAMA). These therapies work by recruiting microglia to clear existing plaques and preventing the further deposition of new fibrils, thereby slowing cognitive decline in early-stage patients. However, targeting these aggregates is associated with significant safety concerns, most notably Amyloid-Related Imaging Abnormalities (ARIA), which involve brain edema or microhemorrhages (Sperling et al., 2011, Alzheimer's & Dementia).

Other names

Aggregated amyloid-betaAmyloid-beta plaquesSenile plaquesAβ aggregatesAmyloid-beta peptide aggregates

Monoclonal antibody-mediated clearance via microglial phagocytosis, inhibition of fibril elongation, and plaque solubilization.