Amyloid-beta toxic soluble oligomer (AβO) (AβO)

Amyloid-beta (Aβ) toxic soluble oligomers are intermediate molecular aggregates formed during the misfolding and polymerization of Aβ monomers into insoluble amyloid plaques (Haass & Selkoe, 2007). Unlike the inert plaques, these soluble oligomers are widely considered the most neurotoxic species in Alzheimer's disease, directly impairing synaptic plasticity and inhibiting long-term potentiation (LTP) (Selkoe & Hardy, 2016). They exert toxicity by binding to various cell surface receptors, disrupting calcium homeostasis, and promoting neuroinflammation and oxidative stress (Benilova et al., 2012). Therapeutic strategies targeting these oligomers include monoclonal antibodies, such as lecanemab, designed to selectively bind and clear these aggregates from the brain (van Dyck et al., 2023). Recent clinical successes have validated this target as a primary driver of cognitive decline, shifting the focus from plaque removal to the neutralization of soluble toxic species (Budd Haeberlein et al., 2022). Effective intervention aims to neutralize these species before they can trigger the downstream tau pathology and irreversible neurodegeneration characteristic of the disease (Jack et al., 2018).

Other names

Amyloid-beta oligomerAβ oligomerAmyloid-beta-derived diffusible ligandADDLSoluble amyloid-beta aggregateAmyloid-beta protofibril

Monoclonal antibodies bind to soluble amyloid-beta oligomers or protofibrils to facilitate their clearance via microglial phagocytosis and neutralize their inherent neurotoxicity (Sevigny et al., 2016; van Dyck et al., 2023). Other strategies involve small molecules that inhibit the primary or secondary nucleation of amyloid-beta monomers into toxic oligomeric species (Cohen et al., 2013).