Amyloid-beta pathological aggregates (oligomers, fibrils, and pores) (Aβ aggregates)

Amyloid-beta (Aβ) pathological aggregates, encompassing soluble oligomers, insoluble fibrils, and membrane-associated conducting pores, are primary drivers of neurotoxicity in Alzheimer's disease (Selkoe & Hardy, 2016). These species are formed through the sequential cleavage of the amyloid precursor protein (APP) by beta- and gamma-secretases, leading to the accumulation of Aβ peptides that misfold into beta-sheet-rich structures (Haass & Selkoe, 2007). Soluble oligomers and protofibrils are particularly detrimental, as they impair synaptic transmission and can insert into neuronal membranes to form unregulated ion channels, or "pores," that disrupt calcium homeostasis (Arispe et al., 1993; Lal et al., 2007). Insoluble fibrils constitute the core of senile plaques, which serve as reservoirs of toxicity and focal points for microglial activation and neuroinflammation (Hardy & Higgins, 1992). Therapeutic interventions, most notably monoclonal antibodies like lecanemab and donanemab, target these aggregated forms to promote their clearance from the brain or prevent their interaction with neuronal receptors (van Dyck et al., 2023; Sims et al., 2023). While targeting these species has shown efficacy in slowing cognitive decline, it is also associated with safety concerns such as amyloid-related imaging abnormalities (ARIA) (Sperling et al., 2011).

Other names

Amyloid-beta oligomersAmyloid-beta fibrilsAmyloid-beta poresAβ protofibrilsAmyloid-beta 42 aggregatesAmyloid-beta ion channelsAβ aggregates

Monoclonal antibodies bind to specific conformational epitopes of Aβ aggregates to facilitate microglial-mediated phagocytosis, neutralize soluble toxic species, and promote plaque clearance.