Abstract
BackgroundAlzheimer'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.Methodology and Principal FindingsIn 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.ConclusionsTogether, these findings attribute an apoptogenic role to N-AChE-S and outline a potential value to AChE inhibitor therapeutics in early AD.
Highlights
In Alzheimer’s disease (AD), premature death of cholinergic neurons is associated with accumulation of neurofibrillary tangles, constituting of hyper-phosphorylated Tau [1]
Together, these findings attribute an apoptogenic role to N-AChE-S and outline a potential value to AChE inhibitor therapeutics in early AD
Some argue for attenuation of the disease process under treatment with AChE inhibitors [4,5]; others develop alternative AD therapeutics, including inhibitors of the Tau kinase, Glycogen Synthase Kinase 3 (GSK3) [6,7], or of other key proteins of the apoptotic pathway, but it is still unclear if these different approaches reflect a single targeted cascade and if so, what triggers this cascade
Summary
In Alzheimer’s disease (AD), premature death of cholinergic neurons is associated with accumulation of neurofibrillary tangles, constituting of hyper-phosphorylated Tau [1]. Recent reports demonstrated AChE accumulation in apoptotic cells, and AChE inhibition and general silencing were found to prevent apoptosome formation and cell death [9,10]. Such cell death may occur through activation of the endoplasmic reticulum (ER), mitochondrial stress and/or cell surface death receptors [11,12]. Alzheimer’s disease (AD) involves loss of cholinergic neurons and Tau protein hyper-phosphorylation. We report that overexpression of an N-terminally extended ‘‘synaptic’’ acetylcholinesterase variant, N-AChE-S is causally involved in both these phenomena
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