Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-7239
Berson, A; Knobloch, M; Hanan, M; Diamant, S; Sharoni, M; Schuppli, D; Geyer, B C; Ravid, R; Mor, T S; Nitsch, R M; Soreq, H (2008). Changes in readthrough acetylcholinesterase expression modulate amyloid-beta pathology. Brain: A Journal of Neurology, 131(1):109-119.
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Alzheimer's disease has long been known to involve cholinergic deficits, but the linkage between cholinergic gene expression and the Alzheimer's disease amyloid pathology has remained incompletely understood. One known link involves synaptic acetylcholinesterase (AChE-S), shown to accelerate amyloid fibrils formation. Here, we report that the 'Readthrough' AChE-R splice variant, which differs from AChE-S in its 26 C-terminal residues, inversely exerts neuroprotective effects from amyloid beta (Abeta) induced toxicity. In vitro, highly purified AChE-R dose-dependently suppressed the formation of insoluble Abeta oligomers and fibrils and abolished Abeta toxicity to cultured cells, competing with the prevalent AChE-S protein which facilitates these processes. In vivo, double transgenic APPsw/AChE-R mice showed lower plaque burden, fewer reactive astrocytes and less dendritic damage than single APPsw mice, inverse to reported acceleration of these features in double APPsw/AChE-S mice. In hippocampi from Alzheimer's disease patients (n = 10), dentate gyrus neurons showed significantly elevated AChE-R mRNA and reduced AChE-S mRNA. However, immunoblot analyses revealed drastic reductions in the levels of intact AChE-R protein, suggesting that its selective loss in the Alzheimer's disease brain exacerbates the Abeta-induced damages and revealing a previously unforeseen linkage between cholinergic and amyloidogenic events.
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > Psychiatric University Hospital Zurich > Division of Psychiatric Research and Clinic for Psychogeriatric Medicine|
|DDC:||610 Medicine & health|
|Deposited On:||29 Dec 2008 13:22|
|Last Modified:||27 Nov 2013 17:37|
|Publisher:||Oxford University Press|
|Related URLs:||http://brain.oxfordjournals.org/ (Publisher)|
|Citations:||Web of Science®. Times cited: 40|
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