Resveratrol regulates the alternative splicing of tau exon 10 to improve learning and memory in hTau mice

[Speaker] Wei Qian:1
[Co-author] Shuo Qian:1, Jianlan Gu:1, Qin Huang:1
1:Department of Biochemistry, Medical School, Nantong University, China

Background: Equal amount of 3R-tau and 4R-tau from normal alternative splicing of tau exon 10 is quite essential for normal brain function. The imbalance of 3R-tau to 4R-tau from abnormal alternative splicing of tau exon 10 , leads to hyperphosphorylation and aggregation of tau and consequently neurofibrillary degeneration. 9G8, one of the SR proteins, may bind to the proximal downstream intron and inhibit inclusion of tau exon 10 . A great many of acetylation sites have been revealed on the splicing proteins including SR proteins. But to date, the location and function of acetylation modification of SR protein remain illusive. Sirt1, one member in mammalian Sirtuin family, is connected closely with age-related diseases such as AD. Resveratrol, a polyphenol found in wines, was reported to be an activator of Sirt1 in vivo and in vitro. Methods: By co-immunoprecipitation, GST pull down and confocal, we studied the interaction between Sirt1 and 9G8. Employing mini-tau gene, pCI/SI9-SI10 which consists of exons 9, 10, 11, a part of intron 9 and intron 10 and RT-PCR, we explored whether and how Sirt1 regulates tau exon 10 inclusion inhibited by 9G8 in cultured cells. By animal behavioral research, we examine the effect of resveratrol on learning and memory in human tau transgenic mice. Results: We observed that Sirt1 interacts with and deacetylates 9G8 to regulate alternative splicing of tau exon 10 repressed by 9G8. Overexpression or knocking down of Sirt1 affected its role in suppression 9G8-mediated tau exon 10 inclusion. Resveratrol enhanced learning and memory in Htau mice. Conclusion: Abnormal expression of Sirt1 in Alzheimer's disease brain may cause dysregulation of tau exon 10 splicing through 9G8, which may initiate or accelerate tau pathology in AD brain. Resveratrol, Which acts on Sirt1 to alleviate the defects of learning and memory in hTtau mice. may serve as a new drug target for Alzheimer's Disease.
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