Amyloid beta aggregation pathway

The Amyloid beta aggregation pathway refers to the cellular and molecular sequence in which amyloid precursor protein (APP) is processed by β-secretase and γ-secretase, yielding amyloid beta (Aβ) peptides, primarily Aβ40 and the highly aggregation-prone Aβ42. These peptides can accumulate and misfold into oligomers, fibrils, and ultimately insoluble amyloid plaques in the brain's extracellular space. The aggregation process is implicated in disrupting synaptic communication, activating immune and inflammatory pathways, and causing cell death. The pathway is a major therapeutic target in Alzheimer’s disease, with interventions aiming to inhibit aggregation, promote clearance, or block the production of toxic Aβ species. Notably, toxic soluble oligomers, rather than dense fibrils or plaques, are now considered the principal neurotoxic species. While drug development has focused on interventions that interfere with this pathway, no therapies have yet fully halted disease progression. Safety challenges include inflammatory responses, neurovascular complications, and imaging abnormalities associated with anti-amyloid therapies.

Other names

Beta-amyloid aggregation pathwayAmyloidogenic pathwayBeta-amyloid pathway

Inhibition of Aβ aggregation (direct interaction or binding to oligomeric intermediates); Promotion of Aβ clearance (antibody-mediated elimination); Blockade of Aβ production (secretase inhibitors); Disruption of oligomer/fibril formation (β-breaker peptides and small molecules)