期刊
PLOS ONE
卷 11, 期 7, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0159435
关键词
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资金
- Alzheimer's Association [R01AG026146]
- CART-Rotary funds
- BioMotiv LLC
- Sujana Biotech LLC
- OptiKira LLC
- Rexceptor Inc
- Renovo Neural Inc
Amyloid precursor protein (APP) is cleaved by gamma-secretase to simultaneously generate amyloid beta (A beta) and APP Intracellular Domain (AICD) peptides. A beta plays a pivotal role in Alzheimer's disease (AD) pathogenesis but recent studies suggest that amyloid-independent mechanisms also contribute to the disease. We previously showed that AICD transgenic mice (AICD-Tg) exhibit AD-like features such as tau pathology, aberrant neuronal activity, memory deficits and neurodegeneration in an age-dependent manner. Since AD is a tauopathy and tau has been shown to mediate A beta-induced toxicity, we examined the role of tau in AICD-induced pathological features. We report that ablating endogenous tau protects AICD-Tg mice from deficits in adult neurogenesis, seizure severity, short-term memory deficits and neurodegeneration. Deletion of tau restored abnormal phosphorylation of NMDA receptors, which is likely to underlie hyperexcitability and associated excitotoxicity in AICD-Tg mice. Conversely, overexpression of wild-type human tau aggravated receptor phosphorylation, impaired adult neurogenesis, memory deficits and neurodegeneration. Our findings show that tau is essential for mediating the deleterious effects of AICD. Since tau also mediates A beta-induced toxic effects, our findings suggest that tau is a common downstream factor in both amyloid-dependent and-independent pathogenic mechanisms and therefore could be a more effective drug target for therapeutic intervention in AD.
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