Trisomy 21-induced dysregulation of microglial homeostasis in Alzheimer's brains is mediated by USP25

被引：50

作者：

Zheng, Qiuyang ^{[1
]}

Li, Guilin ^{[1
]}

Wang, Shihua ^{[1
,2
]}

Zhou, Ying ^{[3
]}

Liu, Ke ^{[3
]}

Gao, Yue ^{[1
]}

Zhou, Yulin ^{[4
]}

Zheng, Liangkai ^{[4
]}

Zhu, Lin ^{[1
]}

Deng, Qingfang ^{[1
]}

Wu, Meiling ^{[1
]}

Di, Anjie ^{[1
]}

Zhang, Lishan ^{[1
]}

Zhao, Yingjun ^{[1
]}

Zhang, Hongfeng ^{[1
]}

Sun, Hao ^{[1
]}

Dong, Chen ^{[5
]}

Xu, Huaxi ^{[1
,6
]}

Wang, Xin ^{[1
]}

机构：

[1] Xiamen Univ, Sch Med, Inst Neurosci, State Key Lab Cellular Stress Biol,Fujian Prov Ke, Xiamen 361005, Fujian, Peoples R China

[2] Xizang Minzu Univ, Sch Med, Xianyang 712082, Shaanxi, Peoples R China

[3] Xiamen Univ, Sch Med, Dept Translat Med, Xiamen 361005, Fujian, Peoples R China

[4] Xiamen Univ, Women & Childrens Hosp, Sch Med, Xiamen 361003, Fujian, Peoples R China

[5] Tsinghua Univ, Sch Med, Inst Immunol, Beijing 100084, Peoples R China

[6] Xiamen Univ, Affiliated Hosp 1, Ctr Brain Sci, Sch Med, Xiamen 361003, Fujian, Peoples R China

来源：

SCIENCE ADVANCES | 2021年 / 7卷 / 01期

基金：

中国国家自然科学基金; 国家重点研发计划;

关键词：

DOWN-SYNDROME; DEUBIQUITINATING ENZYME; NEGATIVE REGULATION; INFLAMMATION; DISEASE; SYSTEM; REGION;

D O I：

10.1126/sciadv.abe1340

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Down syndrome (DS), caused by trisomy of chromosome 21, is the most significant risk factor for early-onset Alzheimer's disease (AD); however, underlying mechanisms linking DS and AD remain unclear. Here, we show that triplication of homologous chromosome 21 genes aggravates neuroinflammation in combined murine DS-AD models. Overexpression of USP25, a deubiquitinating enzyme encoded by chromosome 21, results in microglial activation and induces synaptic and cognitive deficits, whereas genetic ablation of Usp25 reduces neuroinflammation and rescues synaptic and cognitive function in 5xFAD mice. Mechanistically, USP25 deficiency attenuates microglia-mediated proinflammatory cytokine overproduction and synapse elimination. Inhibition of USP25 reestablishes homeostatic microglial signatures and restores synaptic and cognitive function in 5xFAD mice. In summary, we demonstrate an unprecedented role for trisomy 21 and pathogenic effects associated with microgliosis as a result of the increased USP25 dosage, implicating USP25 as a therapeutic target for neuroinflammation in DS and AD.

引用

页数：13

共 57 条

[21] Early amyloid deposition in the medial temporal lobe of young Down syndrome patients: A regional quantitative analysis [J].

Leverenz, JB ;

Raskind, MA .

EXPERIMENTAL NEUROLOGY, 1998, 150 (02) :296-304

[22] Microglia and macrophages in brain homeostasis and disease [J].

Li, Qingyun ;

Barres, Ben A. .

NATURE REVIEWS IMMUNOLOGY, 2018, 18 (04) :225-242

[23] Positive and negative regulation of APP amyloidogenesis by sumoylation [J].

Li, YH ;

Wang, H ;

Wang, S ;

Quon, D ;

Liu, YW ;

Cordell, B .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (01) :259-264

[24] Duplication of the entire 22.9 Mb human chromosome 21 syntenic region on mouse chromosome 16 causes cardiovascular and gastrointestinal abnormalities [J].

Li, Zhongyou ;

Yu, Tao ;

Morishima, Masae ;

Pao, Annie ;

LaDuca, Jeffrey ;

Conroy, Jeffrey ;

Nowak, Norma ;

Matsui, Sei-Ichi ;

Shiraishi, Isao ;

Yu, Y. Eugene .

HUMAN MOLECULAR GENETICS, 2007, 16 (11) :1359-1366

[25] featureCounts: an efficient general purpose program for assigning sequence reads to genomic features [J].

Liao, Yang ;

Smyth, Gordon K. ;

Shi, Wei .

BIOINFORMATICS, 2014, 30 (07) :923-930

[26] Complement C3aR Inactivation Attenuates Tau Pathology and Reverses an Immune Network Deregulated in Tauopathy Models and Alzheimer's Disease [J].

Litvinchuk, Alexandra ;

Wan, Ying-Wooi ;

Swartzlander, Dan B. ;

Chen, Fading ;

Cole, Allysa ;

Propson, Nicholas E. ;

Wang, Qian ;

Zhang, Bin ;

Liu, Zhandong ;

Zheng, Hui .

NEURON, 2018, 100 (06) :1337-+

[27] Deficiency in LRP6-Mediated Wnt Signaling Contributes to Synaptic Abnormalities and Amyloid Pathology in Alzheimer's Disease [J].

Liu, Chia-Chen ;

Tsai, Chih-Wei ;

Deak, Ferenc ;

Rogers, Justin ;

Penuliar, Michael ;

Sung, You Me ;

Maher, James N. ;

Fu, Yuan ;

Li, Xia ;

Xu, Huaxi ;

Estus, Steven ;

Hoe, Hyang-Sook ;

Fryer, John D. ;

Kanekiyo, Takahisa ;

Bu, Guojun .

NEURON, 2014, 84 (01) :63-77

[28] Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 [J].

Love, Michael I. ;

Huber, Wolfgang ;

Anders, Simon .

GENOME BIOLOGY, 2014, 15 (12)

[29] Polymorphisms in BACE2 may affect the age of onset Alzheimer's dementia in Down syndrome [J].

Mok, Kin Y. ;

Jones, Emma L. ;

Hanney, Marisa ;

Harold, Denise ;

Sims, Rebecca ;

Williams, Julie ;

Ballard, Clive ;

Hardy, John .

NEUROBIOLOGY OF AGING, 2014, 35 (06) :1513.e1-1513.e5

[30] Antiamyloidogenic and neuroprotective functions of cathepsin B: implications for Alzheimer's disease [J].

Mueller-Steiner, Sarah ;

Zhou, Yungui ;

Arai, Hideaki ;

Roberson, Erik D. ;

Sun, Binggui ;

Chen, Jennifer ;

Wang, Xin ;

Yu, Guiqiu ;

Esposito, Luke ;

Mucke, Lennart ;

Gan, Li .

NEURON, 2006, 51 (06) :703-714

← 1 2 3 4 5 6 →