第396次SKLBE 学术论坛

以下为第396次SKLBE 学术论坛信息，请阅。

   报告题目：   Delta-secretase in the Pathogenesis of Neurodegenerative Diseasesand its Drug Discovery

   报告人：      Prof. Keqiang YE

   单位：         Department of Pathology and Laboratory Medicine，Emory University School of Medicine，USA

   地点：        逸夫楼第一会议室

   时间：        2018-1-17 10:00-11:30

   主持人：     张立新研究员

报告人简介：

Dr. Keqiang Ye is a tunured professor in Department of Pathology and Laboratory Medicine, Emory Univerisity, USA. He earned his PhD at Emory University, Atlanta, GA. He served as a member of American Association for Cancer Research and Neuroscience Society. He served as a reviewer of peer reviewed journals in the area of neuroscicence, cell biology and lipidomics. He received many awards like ACS research scholar and Sontag Distinuished scientist middots award.

报告摘要：

Delta-secretase, a lysosomal asparagine endopepti- dase (AEP), simultaneously cleaves both APP and tau, controlling the onset of pathogenesis of Alzheimer’s disease (AD). However, how this protease is post-translationally regulated remains unclear. Serine-arginine protein kinase 2 (SRPK2) phosphorylates delta-secretase enhances its enzymatic activity. SRPK2 phosphorylates serine 226 on delta-secretase and accelerates its autocatalytic cleavage, leading to its cytoplasmic translocation and escalated enzymatic activities. Delta-secretase is highly phosphorylated in human AD brains, tightly correlated with SRPK2 activity. The BDNF mimetic compound 7,8-dihydroxyflavone (7,8-DHF), a potent small molecular TrkB agonist, displays prominent therapeutic efficacy against Alzheimer’s disease (AD). However, 7,8-DHF has only modest oral bioavailability and a moderate pharmacokinetic (PK) profile. To alleviate these preclinical obstacles, a prodrug strategy was used to elevate 7,8-DHF oral bioavailability and brain exposure, and found that the optimal prodrug R13 has favorable properties and dose-dependently reverses the cognitive defects in an AD mouse model. A large number of 7,8-DHF derivatives were synthesized via ester or carbamate group modification on the catechol ring in the parent compound. Using in vitro absorption, distribution, metabolism, and excretion assays, Combined with in vivo PK studies, a prodrug was identified, R13, that prominently up-regulates 7,8-DHF PK profiles. Chronic oral administra- tion of R13 activated TrkB signaling and prevented Aβ deposition in 5XFAD AD mice, inhibiting the pathological cleavage of APP and Tau by AEP. Moreover, R13 inhibited the loss of hippocampal synapses and ameliorated memory deficits in a dose-dependent manner.