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

<h4>Background</h4>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 phen...

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Autores principales:	Debra Toiber, Amit Berson, David Greenberg, Naomi Melamed-Book, Sophia Diamant, Hermona Soreq
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2008
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2018499a57c049bf8580dad94ba61bb7
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spelling	oai:doaj.org-article:2018499a57c049bf8580dad94ba61bb72021-11-25T06:18:46ZN-acetylcholinesterase-induced apoptosis in Alzheimer's disease.1932-620310.1371/journal.pone.0003108https://doaj.org/article/2018499a57c049bf8580dad94ba61bb72008-09-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18769671/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Methodology and principal findings</h4>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.<h4>Conclusions</h4>Together, these findings attribute an apoptogenic role to N-AChE-S and outline a potential value to AChE inhibitor therapeutics in early AD.Debra ToiberAmit BersonDavid GreenbergNaomi Melamed-BookSophia DiamantHermona SoreqPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 3, Iss 9, p e3108 (2008)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Debra Toiber Amit Berson David Greenberg Naomi Melamed-Book Sophia Diamant Hermona Soreq N-acetylcholinesterase-induced apoptosis in Alzheimer's disease.
description	<h4>Background</h4>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.<h4>Methodology and principal findings</h4>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.<h4>Conclusions</h4>Together, these findings attribute an apoptogenic role to N-AChE-S and outline a potential value to AChE inhibitor therapeutics in early AD.
format	article
author	Debra Toiber Amit Berson David Greenberg Naomi Melamed-Book Sophia Diamant Hermona Soreq
author_facet	Debra Toiber Amit Berson David Greenberg Naomi Melamed-Book Sophia Diamant Hermona Soreq
author_sort	Debra Toiber
title	N-acetylcholinesterase-induced apoptosis in Alzheimer's disease.
title_short	N-acetylcholinesterase-induced apoptosis in Alzheimer's disease.
title_full	N-acetylcholinesterase-induced apoptosis in Alzheimer's disease.
title_fullStr	N-acetylcholinesterase-induced apoptosis in Alzheimer's disease.
title_full_unstemmed	N-acetylcholinesterase-induced apoptosis in Alzheimer's disease.
title_sort	n-acetylcholinesterase-induced apoptosis in alzheimer's disease.
publisher	Public Library of Science (PLoS)
publishDate	2008
url	https://doaj.org/article/2018499a57c049bf8580dad94ba61bb7
work_keys_str_mv	AT debratoiber nacetylcholinesteraseinducedapoptosisinalzheimersdisease AT amitberson nacetylcholinesteraseinducedapoptosisinalzheimersdisease AT davidgreenberg nacetylcholinesteraseinducedapoptosisinalzheimersdisease AT naomimelamedbook nacetylcholinesteraseinducedapoptosisinalzheimersdisease AT sophiadiamant nacetylcholinesteraseinducedapoptosisinalzheimersdisease AT hermonasoreq nacetylcholinesteraseinducedapoptosisinalzheimersdisease
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N-acetylcholinesterase-induced apoptosis in Alzheimer's disease.

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