Changes in readthrough acetylcholinesterase expression modulate amyloid-beta pathology.
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.
The Eric Roland Center for Neurodegenerative Diseases, Institute of Life Sciences, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel.
Amit
A
Berson
Marlen
M
Knobloch
Mor
M
Hanan
Sophia
S
Diamant
Michal
M
Sharoni
Daniel
D
Schuppli
Brian C
BC
Geyer
Rivka
R
Ravid
Tsafrir S
TS
Mor
Roger M
RM
Nitsch
Hermona
H
Soreq
D000110:Acetylcholinesterase / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing; D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000187:drug effects; D000818:Animals; D001253:Astrocytes / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003712:Dendrites / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006624:Hippocampus / Q000201:enzymology; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D012333:RNA, Messenger; D011994:Recombinant Proteins; D000110:Acetylcholinesterase