Acetylcholinesterase peripheral anionic site (AChE PAS)

Acetylcholinesterase (AChE) is a primary enzyme in the nervous system responsible for terminating cholinergic signaling by hydrolyzing the neurotransmitter acetylcholine [1.3.1]. Beyond its classical catalytic role, AChE possesses a peripheral anionic site (PAS) located at the entrance of its active-site gorge, which is involved in several non-cholinergic functions [1.3.3, 1.5.1]. The PAS acts as a molecular chaperone that interacts with beta-amyloid (Aβ) peptides, significantly accelerating their aggregation into neurotoxic fibrils and the formation of senile plaques, which are pathological hallmarks of Alzheimer's disease [1.1.1, 1.2.1, 1.5.2]. This interaction interface between the AChE PAS and Aβ represents a critical therapeutic target for disease-modifying strategies in neurodegeneration [1.3.1, 1.4.2]. Drugs targeting this site, such as dual-site inhibitors like donepezil, aim to provide both symptomatic relief by increasing acetylcholine levels and potential disease-modifying effects by disrupting the pro-amyloidogenic activity of the enzyme [1.3.2, 1.4.1]. Research continues to focus on developing multi-target-directed ligands (MTDLs) that can block this interface to slow the progression of Alzheimer's disease [1.3.1, 1.4.3].

Other names

AChE peripheral anionic sitePASAChE-Abeta interfaceAChE-amyloid binding domainPeripheral anionic binding siteAChE-induced beta-amyloid aggregation interface

Inhibition of the chaperone-like activity of the acetylcholinesterase peripheral anionic site (PAS) to prevent the nucleation and elongation of beta-amyloid fibrils, while simultaneously inhibiting the catalytic hydrolysis of acetylcholine to improve cholinergic neurotransmission [1.2.1, 1.3.1, 1.4.2].