Changes in readthrough acetylcholinesterase expression modulate amyloid-beta pathology

Alzheimers disease has long been known to involve cholinergic deficits, but the linkage between cholinergic gene expression and the Alzheimers 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 (A beta) induced toxicity. In vitro, highly purified AChE-R dose-dependently suppressed the formation of insoluble A beta oligomers and fibrils and abolished A beta 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 Alzheimers 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 Alzheimers disease brain exacerbates the A beta-induced damages and revealing a previously unforeseen linkage between cholinergic and amyloidogenic events.