期刊
CEREBRAL CORTEX
卷 27, 期 7, 页码 3553-3567出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/cercor/bhw177
关键词
acetylcholine; Alzheimer's disease; cognition; pathology; RNA metabolism
资金
- Canadian Institutes of Health Research [MOP 93651, MOP 136930, MOP 126000, MOP 89919]
- National Sciences and Engineering Research Council of Canada [402524-2013]
- Brain Canada
- Canadian Foundation for Innovation
- Ontario research fund
- European Research Council [321501]
- Legacy Heritage Science Initiative (LHSI) of the Israel Science Foundation [378/11]
- Alzheimer's Society of Canada
- Kuwait University
- Science without borders program (Brazil)
- Marie Curie Actions Intra European Fellowship
- European Commission
The relationship between long-term cholinergic dysfunction and risk of developing dementia is poorly understood. Here we used mice with deletion of the vesicular acetylcholine transporter (VAChT) in the forebrain to model cholinergic abnormalities observed in dementia. Whole-genome RNA sequencing of hippocampal samples revealed that cholinergic failure causes changes in RNAmetabolism. Remarkably, key transcripts related to Alzheimer's disease are affected. BACE1, for instance, shows abnormal splicing caused by decreased expression of the splicing regulator hnRNPA2/B1. Resulting BACE1 overexpression leads to increased APP processing and accumulation of soluble A beta(1-42). This is accompanied by age-related increases in GSK3 activation, tau hyperphosphorylation, caspase-3 activation, decreased synaptic markers, increased neuronal death, and deteriorating cognition. Pharmacological inhibition of GSK3 hyperactivation reversed deficits in synaptic markers and tau hyperphosphorylation induced by cholinergic dysfunction, indicating a key role for GSK3 in some of these pathological changes. Interestingly, in human brains there was a high correlation between decreased levels of VAChT and hnRNPA2/B1 levels with increased tau hyperphosphorylation. These results suggest that changes in RNA processing caused by cholinergic loss can facilitate Alzheimer's-like pathology in mice, providing a mechanism by which decreased cholinergic tone may increase risk of dementia.
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