Downregulating PTBP1 Fails to Convert Astrocytes into Hippocampal Neurons and to Alleviate Symptoms in Alzheimer's Mouse Models

作者全名："Guo, Tiantian; Pan, Xinjia; Jiang, Guangtong; Zhang, Denghong; Qi, Jinghui; Shao, Lin; Wang, Zhanxiang; Xu, Huaxi; Zhao, Yingjun"

作者地址："[Guo, Tiantian; Pan, Xinjia; Jiang, Guangtong; Zhang, Denghong; Qi, Jinghui; Shao, Lin; Wang, Zhanxiang; Xu, Huaxi; Zhao, Yingjun] Xiamen Univ, Fujian Provincial Key Lab Neurodegen Disease & Agi, Inst Neurosci,Sch Med, Ctr Brain Sci,Affiliated Hosp 1, Xiamen 361005, Fujian, Peoples R China; [Xu, Huaxi] Chongqing Med Univ, Inst Brain Sci & Dis, Chongqing 400016, Peoples R China"

通信作者："Xu, HX; Zhao, YJ (通讯作者)，Xiamen Univ, Fujian Provincial Key Lab Neurodegen Disease & Agi, Inst Neurosci,Sch Med, Ctr Brain Sci,Affiliated Hosp 1, Xiamen 361005, Fujian, Peoples R China.; Xu, HX (通讯作者)，Chongqing Med Univ, Inst Brain Sci & Dis, Chongqing 400016, Peoples R China."

来源：JOURNAL OF NEUROSCIENCE

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:000864792800012

JCR分区：Q1

影响因子：5.3

年份：2022

卷号：42

期号：38

开始页：7309

结束页：7317

文献类型：Article

关键词：Alzheimer?s disease; astrocyte; cell fate conversion; glia; transdifferentiation

摘要："Conversion of astroglia into functional neurons has been considered a promising therapeutic strategy for neurodegenerative diseases. Recent studies reported that downregulation of the RNA binding protein, polypyrimidine tract-binding protein 1 (PTBP1), converts astrocytes into neurons in situ in multiple mouse brain regions, consequently improving pathologic pheno-types associated with Parkinson's disease, RGC loss, and aging. Here, we demonstrate that PTBP1 downregulation using an astrocyte-specific AAV-mediated shRNA system fails to convert hippocampal astrocytes into neurons in both male and female wild-type (WT) and b-amyloid (53FAD) and tau (PS19) Alzheimer's disease (AD) mouse models and fails to reverse synap-tic/cognitive deficits and AD-associated pathology in male mice. Similarly, PTBP1 downregulation cannot convert astrocytes into neurons in the striatum and substantia nigra in both male and female WT mice. Together, our study suggests that cell fate conversion strategy for neurodegenerative disease therapy through manipulating one single gene, such as PTBP1, war-rants more rigorous scrutiny."

基金机构：Ministry of Science and Technology of the People?s Republic of China; National Natural Science Foundation of China; Xiamen University; [2021YFA1101401]; [2021ZD0202402]; [82071213]; [92049202]; [92149303]

基金资助正文："This study was supported by Ministry of Science and Technology of the People?s Republic of China Grants 2021YFA1101401 (Y.Z.) and 2021ZD0202402 (H.X.) ; the National Natural Science Foundation of China Grants 82071213 (Y.Z.) , 92049202, and 92149303 (H.X.) ; and start-up funding from Xiamen University (Y.Z.) . We thank Baoying Xie, Haiping Zheng, Yixian Gao, Xiang You, Qingfeng Liu, Lei Huang, and Jingru Huang at Xiamen University for technical assistance."