TY - JOUR
T1 - Changes in readthrough acetylcholinesterase expression modulate amyloid-beta pathology
AU - Berson, Amit
AU - Knobloch, Marlen
AU - Hanan, Mor
AU - Diamant, Sophia
AU - Sharoni, Michal
AU - Schuppli, Daniel
AU - Geyer, Brian C.
AU - Ravid, Rivka
AU - Leket-Mor, Tsafrir
AU - Nitsch, Roger M.
AU - Soreq, Hermona
N1 - Funding Information:
The funding was provided by The German Israel Project DIP-G 3.2, European Community’s Network of Excellence (LSH-2004-1.1.5-3) and STREP (LSHG-CT 2006-037277), the Hebrew University’s Eric Roland Center for Neurodegenerative Diseases and the Interdisciplinary Center for Neuronal Computation (ICNC), to H.S; The Defense Advance Research Project Agency (#N66001-01-C-8015) to T.S.M and H.S. The authors wish to thank Dr Naomi Melamed-Book for confocal microscopy assistance and Mr Erez Podoloy for structural advice.
PY - 2008/1
Y1 - 2008/1
N2 - 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 β (Aβ) induced toxicity. In vitro, highly purified AChE-R dose-dependently suppressed the formation of insoluble Aβ oligomers and fibrils and abolished Aβ 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 Aβ-induced damages and revealing a previously unforeseen linkage between cholinergic and amyloidogenic events.
AB - 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 β (Aβ) induced toxicity. In vitro, highly purified AChE-R dose-dependently suppressed the formation of insoluble Aβ oligomers and fibrils and abolished Aβ 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 Aβ-induced damages and revealing a previously unforeseen linkage between cholinergic and amyloidogenic events.
KW - Acetylcholinesterase
KW - Alternative splicing
KW - Alzheimer's disease
KW - β-Amyloid
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U2 - 10.1093/brain/awm276
DO - 10.1093/brain/awm276
M3 - Article
C2 - 18056160
AN - SCOPUS:37549022563
SN - 0006-8950
VL - 131
SP - 109
EP - 119
JO - Brain
JF - Brain
IS - 1
ER -