文献类型：期刊文献

中文题名：Hippocampus-targeted BDNF gene therapy to rescue cognitive impairments of Alzheimer's disease in multiple mouse models

作者：Siqi Tang[1];Wenshu Luo[2];Shihao Wu[3];Meng Yuan[3];Jiashuo Wen[3];Guoshen Zhong[3];Leshan Shen[4];Wei Jiang[2,4];Cheng Cheng[2,4];Xia Wu[1];Xiao Xiao[1,2]

机构：[1]School of Pharmacy,East China University of Science and Technology,Shanghai 200237,China;[2]Belief Biomed Inc,Shanghai 200237,China;[3]School of Medicine,Yunnan University,Kunming,Yunnan 650106,China;[4]School of Bioengineering,East China University of Science and Technology,Shanghai 200237,China

年份：2026

卷号：13

期号：2

起止页码：453

中文期刊名：Genes & Diseases

外文期刊名：基因与疾病(英文)

基金：supported by the National Key Research and Development Program of China(No.2021YFC2700803);the National Natural Science Foundation of China(No.82471501,82360226).

语种：英文

中文关键词：AAVT42;Alzheime’s disease;Brain-derived neurotrophic factor;Cognitive impairment;Hippocampal RNA sequencing

摘要：Brain-derived neurotrophic factor(BDNF)can protect neurons from apoptosis and maintain normal synaptic structures,indicating a significant potential for Alzheimer's disease(AD)treatment.However,the method of in vivo BDNF delivery requires further optimization,and the therapeutic efficacy of BDNF in AD animal models needs to be further evaluated.Here,we demonstrated that a newly engineered adeno-associated virus(AAV)serotype termed AAVT42 showed better tropism for neurons than AAV9 in the central nervous system(CNS).We analyzed the therapeutic potentials of AAVT42-delivered BDNF in three AD mouse models:amyloid precursor protein/presenilin-1(APP/PS1),rTg4510,and 3×Tg.Long-term BDNF expression in the hippocampus mitigated neuronal degeneration or loss in these AD mice,and alleviated their cognitive impairment,with no discernible effect on amyloid-βdeposition or tau phosphorylation.Furthermore,transcriptomic analysis in 3×Tg mice revealed that BDNF orchestrated the up-regulation of genes associated with neuronal structural organization and synaptic transmissions,such as Neuropeptide Y(Npy),Corticotropin-releasing hormone(Crh),Tachykinin precursor 1(Tac1),and the down-regulation of Bone morphogenetic proteins(Bmps).Our study highlighted the efficacy of AAVT42 in gene delivery to CNS and validated the therapeutic benefits of BDNF in treating AD,which will be useful for future translational research on AD treatment using an AAV delivery system.