Exploring How Acetylcholinesterase Influences Neural Signaling Beyond Neurotransmitter Hydrolysis and Its Paradoxical Role in Neurodegeneration

Acetylcholinesterase (AChE) is traditionally known for its catalytic role in hydrolyzing acetylcholine at synaptic junctions, thereby terminating cholinergic signaling. However, emerging evidence suggests that AChE also participates in non-classical roles extending far beyond neurotransmitter clearance. These roles encompass cell adhesion, apoptosis modulation, neurite outgrowth, and participation in neuroinflammatory processes. Intriguingly, AChE displays paradoxical behavior in neurodegenerative diseases such as Alzheimer’s and Parkinson’s, where its overexpression and aberrant splicing variants contribute to neuronal damage despite the concurrent loss of cholinergic tone. This review explores the dualistic and complex role of AChE in the central nervous system (CNS), shedding light on its signaling roles beyond catalysis, the molecular basis of its neurotoxic versus neuroprotective profiles, and its therapeutic implications in managing neurodegeneration. Keywords: Acetylcholinesterase, Non-classical signaling, Neurodegeneration, Synaptic plasticity, Cholinergic dysfunction