Pathogenic protein oligomers

Pathogenic protein oligomers are soluble, intermediate assemblies of misfolded proteins that serve as the primary neurotoxic agents in various neurodegenerative diseases, collectively known as proteinopathies (Haass & Selkoe, 2007, Nature Reviews Molecular Cell Biology). These oligomers are formed from proteins such as amyloid-beta, tau, and alpha-synuclein, which transition from their native monomeric states into toxic, non-fibrillar clusters (Benilova et al., 2012, Nature Neuroscience). Unlike large, insoluble plaques or tangles, oligomers are highly diffusible and can spread throughout the brain, acting as seeds that induce further protein misfolding in a prion-like manner (Jucker & Walker, 2013, Nature). They exert toxicity by disrupting cell membranes, impairing synaptic plasticity, and triggering chronic neuroinflammation and oxidative stress (Walsh & Selkoe, 2007, Journal of Neurochemistry). Therapeutic interventions targeting these species include monoclonal antibodies, such as lecanemab, which are designed to selectively recognize and clear oligomeric or protofibrillar forms while sparing monomeric proteins (van Dyck et al., 2023, New England Journal of Medicine). Small molecule inhibitors, such as anle138b, are also being developed to stabilize monomers or disrupt the nucleation process required for oligomer formation (Wagner et al., 2013, Acta Neuropathologica). Despite their promise as targets, the transient and heterogeneous nature of oligomers makes them difficult to characterize and monitor in clinical settings (Sperling et al., 2011, Alzheimer's & Dementia). Successful targeting of these species is currently the leading strategy for disease-modifying therapies in Alzheimer's and Parkinson's diseases (Selkoe, 2019, Science).

Other names

Toxic oligomersSoluble protein aggregatesAmyloid oligomersMisfolded protein assembliesProtofibrilsSoluble amyloid-beta oligomersTau oligomersAlpha-synuclein oligomers

Monoclonal antibodies bind to and promote the clearance of oligomeric species via microglial phagocytosis; small molecules inhibit the primary and secondary nucleation of monomers into oligomers or stabilize non-toxic monomeric forms to prevent aggregation.