N-Acetylcholinesterase-Induced Apoptosis in Alzheimer's Disease

• DOI: 10.1371/journal.pone.0003108
• Publication Date: 2008-08-29T20:35:57Z
• Authors: Debra Toiber; Amit Berson; David Greenberg; Naomi Melamed-Book; Sophia Diamant; Hermona Soreq
• Keywords: Neurons; 0301 basic medicine; Science; Q; Cell Membrane; R; Brain; Genetic Variation; Apoptosis; tau Proteins; Models, Biological; 3. Good health; Glycogen Synthase Kinase 3; 03 medical and health sciences; Proto-Oncogene Proteins c-bcl-2; Alzheimer Disease; Caspases; Acetylcholinesterase; Medicine; Humans; Receptors, Cholinergic; Phosphorylation; Research Article

Alzheimer's disease (AD) involves loss of cholinergic neurons and Tau protein hyper-phosphorylation. Here, we report that overexpression of an N-terminally extended "synaptic" acetylcholinesterase variant, N-AChE-S is causally involved in both these phenomena.In transfected primary brain cultures, N-AChE-S induced cell death, morphological impairments and caspase 3 activation. Rapid internalization of fluorescently labeled fasciculin-2 to N-AChE-S transfected cells indicated membranal localization. In cultured cell lines, N-AChE-S transfection activated the Tau kinase GSK3, induced Tau hyper-phosphorylation and caused apoptosis. N-AChE-S-induced cell death was suppressible by inhibiting GSK3 or caspases, by enforced overexpression of the anti-apoptotic Bcl2 proteins, or by AChE inhibition or silencing. Moreover, inherent N-AChE-S was upregulated by stressors inducing protein misfolding and calcium imbalances, both characteristic of AD; and in cortical tissues from AD patients, N-AChE-S overexpression coincides with Tau hyper-phosphorylation.Together, these findings attribute an apoptogenic role to N-AChE-S and outline a potential value to AChE inhibitor therapeutics in early AD.