N-acetylcholinesterase-induced apoptosis in Alzheimer's disease.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
Together, these findings attribute an apoptogenic role to N-AChE-S and outline a potential value to AChE inhibitor therapeutics in early AD.
Toiber
Debra
D
Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel.
Berson
Amit
A
Greenberg
David
D
Melamed-Book
Naomi
N
Diamant
Sophia
S
Soreq
Hermona
H