PCSK6 exacerbates Alzheimer's disease pathogenesis by promoting MT5-MMP maturation

作者全名："Xu, Mingliang; Li, Junjie; Xia, Lei; Du, Yehong; Wu, Bin; Shi, Xiuyu; Tian, Na; Pang, Yayan; Yi, Lilin; Chen, Mulan; Song, Weihong; Dong, Zhifang"

作者地址："[Xu, Mingliang; Li, Junjie; Xia, Lei; Du, Yehong; Wu, Bin; Shi, Xiuyu; Tian, Na; Pang, Yayan; Yi, Lilin; Chen, Mulan; Song, Weihong; Dong, Zhifang] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Dept Infect,Childrens Hosp,Chongqing Key Lab Child, Minist Educ,Key Lab Child Dev & Disorders,Pediat R, Chongqing 400014, Peoples R China; [Xu, Mingliang] Southwest Med Univ, Dept Anesthesiol, Affiliated Hosp, Luzhou 646000, Sichuan, Peoples R China; [Song, Weihong] Univ British Columbia, Dept Psychiat, Townsend Family Labs, Vancouver, BC V6T 1Z3, Canada; [Song, Weihong] Wenzhou Med Univ, Sch Mental Hlth, Zhejiang Clin Res Ctr Mental Disorders,Oujiang Lab, Inst Aging,Key Lab Alzheimers Dis Zhejiang Prov, Wenzhou 325000, Zhejiang, Peoples R China; [Song, Weihong] Wenzhou Med Univ, Affiliated Kangning Hosp, Wenzhou 325000, Zhejiang, Peoples R China"

通信作者："Dong, ZF (通讯作者)，Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Dept Infect,Childrens Hosp,Chongqing Key Lab Child, Minist Educ,Key Lab Child Dev & Disorders,Pediat R, Chongqing 400014, Peoples R China."

来源：EXPERIMENTAL NEUROLOGY

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:001164682700001

JCR分区：Q1

影响因子：4.6

年份：2024

卷号：374

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：PCSK6; Learning and memory; Alzheimer's; MT5-MMP

摘要："Proprotein convertase subtilisin/kexin type 6 (PCSK6) is a calcium-dependent serine proteinase that regulates the proteolytic activity of various precursor proteins and facilitates protein maturation. Dysregulation of PCSK6 expression or function has been implicated in several pathological processes including nervous system diseases. However, whether and how PCSK6 is involved in the pathogenesis of Alzheimer's disease (AD) remains unclear. In this study, we reported that the expression of PCSK6 was significantly increased in the brain tissues of postmortem AD patients and APP23/PS45 transgenic AD model mice, as well as N2AAPP cells. Genetic knockdown of PCSK6 reduced amyloidogenic processing of APP in N2AAPP cells by suppressing the activation of membrane-type 5-matrix metalloproteinase (MT5-MMP), referred to as q-secretase. We further found that PCSK6 cleaved and activated MT5-MMP by recognizing the RRRNKR sequence in its N-terminal propeptide domain in N2A cells. The mutation or knockout of this cleavage motif prevented PCSK6 from interacting with MT5-MMP and performing cleavage. Importantly, genetic knockdown of PCSK6 with adeno-associated virus (AAV) reduced A beta production and ameliorated hippocampal long-term potentiation (LTP) and long-term spatial learning and memory in APP23/PS45 transgenic mice. Taken together, these results demonstrate that genetic knockdown of PCSK6 effectively alleviate AD-related pathology and cognitive impairments by inactivating MT5MMP, highlighting its potential as a novel therapeutic target for AD treatment."

基金机构："National Natural Science Foundation of China [32371030, 82371194, 82071395, 82001158]; Natural Science Foundation of Chongqing [2022NSCQ-LZX0010]; CQMU Program for Youth Innovation in Future Medicine [W0044]"

基金资助正文："<BOLD>Acknowledgements</BOLD> This work was supported by the National Natural Science Foundation of China (32371030, 82371194, 82071395 and 82001158) , the Natural Science Foundation of Chongqing (2022NSCQ-LZX0010) and CQMU Program for Youth Innovation in Future Medicine (W0044) ."