Changes in readthrough acetylcholinesterase expression modulate amyloid-beta pathology

Amit Berson, Marlen Knobloch, Mor Hanan, Sophia Diamant, Michal Sharoni, Daniel Schuppli, Brian C. Geyer, Rivka Ravid, Tsafrir Leket-Mor, Roger M. Nitsch, Hermona Soreq

Research output: Contribution to journalArticle

87 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)109-119
Number of pages11
JournalBrain
Volume131
Issue number1
DOIs
StatePublished - Jan 2008

Keywords

  • Acetylcholinesterase
  • Alternative splicing
  • Alzheimer's disease
  • β-Amyloid

ASJC Scopus subject areas

  • Clinical Neurology

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    Berson, A., Knobloch, M., Hanan, M., Diamant, S., Sharoni, M., Schuppli, D., Geyer, B. C., Ravid, R., Leket-Mor, T., Nitsch, R. M., & Soreq, H. (2008). Changes in readthrough acetylcholinesterase expression modulate amyloid-beta pathology. Brain, 131(1), 109-119. https://doi.org/10.1093/brain/awm276