Acetylcholinesterase and Acetylcholinesterase–Amyloid-beta complexes (AChE and AChE–Aβ complexes)

Acetylcholinesterase (AChE) is a serine hydrolase primarily responsible for the termination of nerve impulse transmission by the rapid hydrolysis of the neurotransmitter acetylcholine (UniProt P22303). In the context of Alzheimer's disease, AChE interacts with amyloid-beta (Aβ) peptides to form stable AChE–Aβ complexes, which have been shown to significantly accelerate the rate of Aβ fibrillogenesis and increase the neurotoxicity of the resulting aggregates (Inestrosa et al., 1996, PubMed). This interaction is primarily mediated by the peripheral anionic site (PAS) of the enzyme, a region distinct from the catalytic active site (CAS) (NIH, PubChem). Therapeutic agents such as Donepezil and Galantamine are designed to inhibit the catalytic activity to improve cognitive function, while newer dual-binding inhibitors target the PAS to disrupt the formation of these toxic complexes (StatPearls, 2023). The presence of AChE within amyloid plaques suggests that these complexes play a structural role in the stabilization of plaques in the brain (PubMed). Targeting the AChE–Aβ complex offers a dual approach: symptomatic relief through cholinergic modulation and potential disease-modifying effects by reducing amyloid deposition.

Other names

AChEAcetylcholine esteraseAChE-Aβ complexAChE-amyloid-beta complexTrue cholinesterase

Reversible or pseudo-irreversible inhibition of the catalytic active site (CAS) to prevent acetylcholine breakdown; blockade of the peripheral anionic site (PAS) to inhibit AChE-mediated amyloid-beta aggregation and fibril formation (PubMed, StatPearls).