研究领域

本课题组致力于解析唐氏综合征和阿尔茨海默病这两类重要的认知障碍疾病的共患病机制和潜在药物靶点，近期在Cell, Nature Neuroscience, Nature Medicine, Journal of Clinical Investigation, Science Advances, National Science Review, Molecular Psychiatry, PLOS Biology等国际学术期刊上发表系列研究论文，系统解析了这类疾病的分子机制与治疗靶点。课题组利用基因修饰、电生理、药理学、多组学分析等相关技术，以临床样本和疾病动物模型为研究对象，深入阐明认知障碍疾病的分子机制，为临床诊断和靶向药物的开发提供模型和理论依据。主要方向包括：

1. 免疫调节异常参与认知障碍疾病的分子机制；

2. 蛋白转运和降解障碍导致认知障碍疾病的作用机制；

3. 能量代谢障碍参与认知障碍疾病的分子机制；

4. 认知障碍疾病药物靶点的研究和小分子药物的筛选。

学习经历

2009~2013 美国Sanford-Burnham医学研究所Biomedical Sciences专业  博士；

2005~2008 上海交通大学药学院药理学专业  硕士研究生；

2001~2005 重庆医科大学药学院药学专业    理学学士。

工作经历

2015~至今 双色球结果  教授；

2014~2015 美国Sanford-Burnham医学研究所  博士后；

2013~2014 美国加州大学圣地亚哥分校（UCSD）神经科学系、霍华德•休斯医学研究所（HHMI）  博士后；

2013~2013 美国Sanford-Burnham医学研究所  博士后；

2008~2009 美国Sanford-Burnham医学研究所  访问学者。

代表性成果

1. Gao Y, Hong Y, Huang L, Zheng S, Zhang H, Wang S, Yao Y, Zhao Y, Zhu L, Xu Q, Chai X, Zeng Y, Zeng Y, Zheng L, Zhou Y, Luo H, Zhang X, Zhang H, Zhou Y, Fu G, Sun H, Huang TY, Zheng Q, Xu H, Wang X*. β2-microglobulin functions as an endogenous NMDAR antagonist to impair synaptic function. Cell. 2023;186(5):1026-1038.

2. Zhao Y, Zheng Q, Hong Y, Gao Y, Hu J, Lang M, Zhang H, Zhou Y, Luo H, Zhang X, Sun H, Yan XX, Huang TY, Wang YJ, Xu H, Liu C, Wang X*. β2-microglobulin coaggregates with Aβ and contributes to amyloid pathology and cognitive deficits in Alzheimer’s disease model mice. Nat Neurosci. 2023. 2023;26(7):1170-1184.（封面文章）

3. Zhang H^#, Zheng Q^#, Guo T^#, Zhang S^#, Zheng S, Wang R, Deng Q, Yang G, Zhang S, Tang L, Qi Q, Zhu L, Zhang X-F, Luo H, Zhang X, Sun H, Gao Y, Zhang H, Zhou Y, Han A, Zhang C-S, Xu H, Wang X*. Metabolic reprogramming in astrocytes results in neuronal dysfunction in intellectual disability. Mol Psychiatry. 2022. DOI: 10.1038/s41380-022-01521-x.

4. Zheng Q^#, Song B^#, Li G^#, Cai F^#, Wu M, Zhao Y, Jiang L, Guo T, Shen M, Hou H, Zhou Y, Zhao Y, Di A, Zhang L, Zeng F, Zhang X-F, Luo H, Zhang X, Zhang H, Zeng Z, Huang T, Dong C, Qing H, Zhang Y, Zhang Q, Wang X, Wu Y, Xu H*, Song W*, and Wang X*. USP25 inhibition ameliorates Alzheimer’s pathology through regulating APP processing and Aβ generation. J Clin Invest. 2022;132(5): e15217

5. Zhang H^#, Hong Y^#, Yang W, Wang R, Yao T, Wang J, Liu K, Yuan H, Xu C, Zhou Y, Li G, Zhang L, Luo H, Zhang X, Du D, Sun H, Zheng Q, Zhang Y-W, Zhao Y, Zhou Y, Xu H, Wang X*. SNX14 deficiency-induced defective axonal mitochondrial transport in Purkinje cells underlies cerebellar ataxia and can be reversed by valproate. Natl Sci Rev. 2021;8(7): nwab024.

6. Zheng Q#, Li G#, Wang S, Zhou Y, Liu K, Gao Y, Zhou Y, Zheng L, Zhu L, Deng Q, Wu M, Di A, Zhang L, Zhao Y, Zhang H, Sun H, Dong C, Xu H, Wang X*. Trisomy 21-induced dysregulation of microglial homeostasis in Alzheimer’s brains is mediated by USP25. Sci Adv. 2021;7(1): eabe1340.

7. Zeng F#, Ma X#, Zhu L#, Xu Q, Zeng Y, Gao Y, Li G, Guo T, Zhang H, Tang X, Wang Z, Ye Z, Zheng L, Zhang H, Zheng Q, Li K, Lu J, Qi X, Luo H, Zhang X, Wang Z, Zhou Y, Yao Y, Ke R, Zhou Y, Liu Y, Sun H, Huang T, Shao Z, Xu H, and Wang X*. The deubiquitinase USP6 affects memory and synaptic plasticity through modulating NMDA receptor stability. PLoS Biol. 2019;17(12): e3000525.

8. Wang X, Zhao Y, Zhang X, Badie H, Zhou Y, Mu Y, Loo LS, Cai L, Thompson RC, Yang B, Chen Y, Johnson PF, Wu C, Bu G, Mobley WC, Zhang D, Gage FH, Ranscht B, Zhang YW, Lipton SA, Hong W, Xu H*. Loss of sorting nexin 27 contributes to excitatory synaptic dysfunction via modulation of glutamate receptor recycling in Down's syndrome. Nat Med. 2013;19(4):473-80. （封面文章）

承担的重要课题

1. 国家自然科学基金杰出青年科学基金项目，82325018，2024-01至2028-12，主持；

2. 国家自然科学基金区域联合基金重点项目，U21A20358，2022-01至2025-12，主持；

3. 科技部重点研发计划课题，2021YFA1101401，2021-12至2026-06，主持；

4. 科技部科技创新2030—“脑科学与类脑研究”重大项目，2021ZD0202402，2021-12至2026-11，骨干；

5. 福建省自然科学基金重点项目，2021J02004，2021-11至2024-11，主持；

6. 广东省基础与应用基础研究基金区域联合基金重点项目，2021B1515120081，2021-10至2024-09，主持；

7. 国家自然科学基金优秀青年科学基金项目，81822014，2019-1至2021-12，主持；

8. 国家自然科学基金面上项目，31871077，2019-1至2022-12，主持；

9. 福建省自然科学基金杰出青年基金项目，2017J06021，2017-4至2020-4，主持；

10. 国家自然科学基金面上项目，81571176，2016-1至2019-12，主持。

获奖及荣誉

1. 国家杰出青年科学基金获得者，2023年；

2. 第十七届福建省青年科技奖，2023年；

3. 厦门市科技进步一等奖，2018年；

4. 厦门市首批杰出青年人才，2018年；

5. 基金委优秀青年科学基金获得者，2018年；

6. 福建省引进高层次创新人才计划专家，2017年；

7. 福建省杰出青年基金获得者，2017年；

8. 闽江学者特聘教授，2016年；

9. 国家高层次青年人才，2016年；

10. 美国阿尔茨海默病协会青年学者奖（Young Scholar Award of Alzheimer's Association），2010年。

所有论文列表

1. Zhong L*, Sheng X, Wang W, Li Y, Zhuo R, Wang K, Zhang L, Hu DD, Hong Y, Chen L, Rao H, Li T, Chen M, Lin Z, Zhang YW, Wang X, Yan XX, Chen X, Bu G, Chen XF*. TREM2 receptor protects against complement-mediated synaptic loss by binding to complement C1q during neurodegeneration. Immunity. 2023;56(8):1794-1808.e8.   PMID: 37442133

2. Zhao Y, Zheng Q, Hong Y, Gao Y, Hu J, Lang M, Zhang H, Zhou Y, Luo H, Zhang X, Sun H, Yan XX, Huang TY, Wang YJ, Xu H, Liu C, Wang X*. β2-microglobulin coaggregates with Aβ and contributes to amyloid pathology and cognitive deficits in Alzheimer’s disease model mice. Nat Neurosci. 2023.   PMID: 37264159

3. Gao Y, Hong Y, Huang L, Zheng S, Zhang H, Wang S, Yao Y, Zhao Y, Zhu L, Xu Q, Chai X, Zeng Y, Zeng Y, Zheng L, Zhou Y, Luo H, Zhang X, Zhang H, Zhou Y, Fu G, Sun H, Huang TY, Zheng Q, Xu H, Wang X*. β2-microglobulin functions as an endogenous NMDAR antagonist to impair synaptic function. Cell. 2023.   PMID: 36868208

4. Zhang H^#, Zheng Q^#, Guo T^#, Zhang S^#, Zheng S, Wang R, Deng Q, Yang G, Zhang S, Tang L, Qi Q, Zhu L, Zhang X-F, Luo H, Zhang X, Sun H, Gao Y, Zhang H, Zhou Y, Han A, Zhang C-S, Xu H, Wang X*. Metabolic reprogramming in astrocytes results in neuronal dysfunction in intellectual disability. Mol Psychiatry. 2022.   PMID: 35338313

5. Zheng Q^#, Song B^#, Li G^#, Cai F^#, Wu M, Zhao Y, Jiang L, Guo T, Shen M, Hou H, Zhou Y, Zhao Y, Di A, Zhang L, Zeng F, Zhang X-F, Luo H, Zhang X, Zhang H, Zeng Z, Huang T, Dong C, Qing H, Zhang Y, Zhang Q, Wang X, Wu Y, Xu H*, Song W*, and Wang X*. USP25 inhibition ameliorates Alzheimer’s pathology through regulating APP processing and Aβ generation. J Clin Invest. 2022;132(5): e15217.  PMID: 35229730

6. Tang XY, Xu L, Wang J, Hong Y, Wang Y, Zhu Q, Wang D, Zhang XY, Liu CY, Fang KH, Han X, Wang S, Wang X, Xu M, Bhattacharyya A, Guo X*, Lin M*, Liu Y*. DSCAM/PAK1 pathway suppression reverses neurogenesis deficits in iPSC-derived cerebral organoids from patients with Down syndrome. J Clin Invest. 2021;131(12): e135763.  PMID: 33945512

7. Zhang H^#, Hong Y^#, Yang W, Wang R, Yao T, Wang J, Liu K, Yuan H, Xu C, Zhou Y, Li G, Zhang L, Luo H, Zhang X, Du D, Sun H, Zheng Q, Zhang Y-W, Zhao Y, Zhou Y, Xu H, Wang X*. SNX14 deficiency-induced defective axonal mitochondrial transport in Purkinje cells underlies cerebellar ataxia and can be reversed by valproate. Natl Sci Rev. 2021;8(7): nwab024.  PMID: 34691693

8. Zheng Q^#, Li G^#, Wang S, Zhou Y, Liu K, Gao Y, Zhou Y, Zheng L, Zhu L, Deng Q, Wu M, Di A, Zhang L, Zhao Y, Zhang H, Sun H, Dong C, Xu H, Wang X*. Trisomy 21-induced dysregulation of microglial homeostasis in Alzheimer’s brains is mediated by USP25. Sci Adv. 2021;7(1): eabe1340.  PMID: 33523861

9. Huo Y^#, Gao Y^#, Zheng Q, Zhao D, Guo T, Zhang S, Zeng Y, Cheng Y, Gu H, Zhang L, Zhu B, Luo H, Zhang X, Zhou Y, Zhang YW, Sun H, Xu H, Wang X*. Overexpression of Human SNX27 Enhances Learning and Memory Through Modulating Synaptic Plasticity in Mice. Front Cell Dev Biol. 2020;8:595357.  PMID: 33330482

10. Lin C^#, Jiang M^#, Liu L^#, Chen X, Zhao Y, Chen L, Hong Y, Wang X, Hong C, Yao X, Ke R*. Imaging of individual transcripts by amplification-based single-molecule fluorescence in situ hybridization. N Biotechnol. 2021;61:116-123.  PMID: 33301924

11. Zhao D, Zhou Y, Huo Y, Meng J, Xiao X, Han L, Zhang X, Luo H, Can D, Sun H, Huang TY, Wang X, Zhang J, Liu FR, Xu H, Zhang YW*. RPS23RG1 modulates tau phosphorylation and axon outgrowth through regulating p35 proteasomal degradation. Cell Death Differ. 2021;28(1):337-348.  PMID: 32908202

12. Rong Z, Cheng B, Zhong L, Ye X, Li X, Jia L, Li Y, Shue F, Wang N, Cheng Y, Huang X, Liu CC, Fryer JD, Wang X, Zhang YW, Zheng H*. Activation of FAK/Rac1/Cdc42-GTPase signaling ameliorates impaired microglial migration response to Aβ 42 in triggering receptor expressed on myeloid cells 2 loss-of-function murine models. FASEB J. 2020;34(8):10984-10997.  PMID: 32613609

13. Lin C, Jiang M, Duan S, Qiu J, Hong Y, Wang X, Chen X, Ke R*. Visualization of individual microRNA molecules in fixed cells and tissues using target-primed padlock probe assay. Biochem Biophys Res Commun. 2020;526(3):607-611.  PMID: 32247612

14. Zeng F^#, Ma X^#, Zhu L^#, Xu Q, Zeng Y, Gao Y, Li G, Guo T, Zhang H, Tang X, Wang Z, Ye Z, Zheng L, Zhang H, Zheng Q, Li K, Lu J, Qi X, Luo H, Zhang X, Wang Z, Zhou Y, Yao Y, Ke R, Zhou Y, Liu Y, Sun H, Huang T, Shao Z, Xu H, and Wang X*. The deubiquitinase USP6 affects memory and synaptic plasticity through modulating NMDA receptor stability. PLoS Biol. 2019;17(12): e3000525.  PMID: 31841517

15. Zhang H^#, Zhu L^#, Wang F^#, Wang R, Hong Y, Chen Y, Zhu B, Gao Y, Luo H, Zhang X, Sun H, Zhou Y*, Yao Y*, Wang X*. Novel KCNJ10 Compound Heterozygous Mutations Causing EAST/SeSAME-Like Syndrome Compromise Potassium Channel Function. Front Genet. 2019;10:912.  PMID: 31781151

16. Lin KM^#, Su G^#, Wang F, Zhang X, Wang Y, Ren J, Wang X*, Yao Y*, Zhou Y*. A de novo SCN8A heterozygous mutation in a child with epileptic encephalopathy: a case report. BMC Pediatr. 2019;19(1):400.  PMID: 31672125

17. Zeng Y, Wang N, Guo T, Zheng Q, Wang S, Wu S, Li X, Wu J, Chen Z, Xu H, Wang X*, Lin B*. Snx27 Deletion Promotes Recovery From Spinal Cord Injury by Neuroprotection and Reduces Macrophage/Microglia Proliferation. Front Neurol. 2018;9:1059.  PMID: 30619032

18. Zhao D, Meng J, Zhao Y, Huo Y, Liu Y, Zheng N, Zhang M, Gao Y, Chen Z, Sun H, Wang X, Jing C, Zhang T, Zhang X, Luo H, Wang X, Zhang J, Liu FR, Li Y, Bu G, Wen L, Huang TY, Xu H, Zhang YW. RPS23RG1 Is Required for Synaptic Integrity and Rescues Alzheimer's Disease-Associated Cognitive Deficits. Biol Psychiatry. 2018. pii: S0006-3223(18)31782-7.  PMID: 30292394

19. Zhang H, Huang T, Hong Y, Yang W, Zhang X, Luo H, Xu H, Wang X*. The Retromer Complex and Sorting Nexins in Neurodegenerative Diseases. Front Aging Neurosci. 2018;10:79.  PMID: 29632483

20. Zhao Y, Li X, Huang T, Jiang LL, Tan Z, Zhang M, Cheng IH, Wang X, Bu G, Zhang YW, Wang Q, Xu H. Intracellular trafficking of TREM2 is regulated by presenilin 1. Exp Mol Med. 2017;49(12):e405.  PMID: 29611543

21. Zheng H, Jia L, Liu CC, Rong Z, Zhong L, Yang L, Chen XF, Fryer JD, Wang X, Zhang YW, Xu H, Bu G*. TREM2 Promotes Microglial Survival by Activating Wnt/β-catenin Pathway. J Neurosci. 2017;37(7):1772-1784.   PMID: 28077724

22. Zheng Q, Huang T, Zhang L, Zhou Y, Luo H, Xu H, Wang X*. Dysregulation of Ubiquitin-Proteasome System in Neurodegenerative Diseases. Front Aging Neurosci. 2016;8:303.   PMID: 28018215

23. Wang X*, Zhou Y, Wang J, Tseng IC, Huang T, Zhao Y, Zheng Q, Gao Y, Luo H, Zhang X, Bu G, Hong W, Xu H*. SNX27 Deletion Causes Hydrocephalus by Impairing Ependymal Cell Differentiation and Ciliogenesis. J Neurosci. 2016;36(50):12586-12597.  PMID: 27974614

24. Huang TY, Zhao Y, Li X, Wang X, Tseng IC, Thompson R, Tu S, Willnow TE, Zhang YW, Xu H*. SNX27 and SORLA Interact to Reduce Amyloidogenic Subcellular Distribution and Processing of Amyloid Precursor Protein. J Neurosci. 2016;36(30):7996-8011.   PMID: 27466343

25. Zhang X, Hu J, Zhong L, Wang N, Yang L, Liu CC, Li H, Wang X, Zhou Y, Zhang Y, Xu H, Bu G*, Zhuang J*. Quercetin stabilizes apolipoprotein E and reduces brain Aβ levels in amyloid model mice. Neuropharmacology. 2016;108:179-192.   PMID: 27114256

26. Zhao Y, Tseng IC, Heyser CJ, Rockenstein E, Mante M, Adame A, Zheng Q, Huang T, Wang X, Arslan PE, Chakrabarty P, Wu C, Bu G, Mobley WC, Zhang YW, St George-Hyslop P, Masliah E, Fraser P, Xu H*. Appoptosin-Mediated Caspase Cleavage of Tau Contributes to Progressive Supranuclear Palsy Pathogenesis. Neuron. 2015;87(5):963-75.   PMID: 26335643

27. Aquizu N, Cantagrel V, Zaki M, Al-Gazali L, Wang X, et al. Biallelic mutations in SNX14 lead to a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction. Nat Genet. 2015;47(5):528-34.   PMID: 25848753

28. Wang X, Huang T, Zhao Y, Thompson RC, Bu G, Zhang YW, Hong W, Xu H*. Sorting nexin 27 regulates Aβ production through modulating γ-secretase activity. Cell Rep. 2014;9(3):1023-33.   PMID: 25437557

29. Wang X, Huang T, Bu G, Xu H*. Dysregulation of protein trafficking in neurodegeneration. Mol Neurodegener. 2014;9(1):31.   PMID: 25152012

30. Wang X, Zhao Y, Zhang X, Badie H, Zhou Y, Mu Y, Loo LS, Cai L, Thompson RC, Yang B, Chen Y, Johnson PF, Wu C, Bu G, Mobley WC, Zhang D, Gage FH, Ranscht B, Zhang YW, Lipton SA, Hong W, Xu H*. Loss of sorting nexin 27 contributes to excitatory synaptic dysfunction via modulation of glutamate receptor recycling in Down's syndrome. Nat Med. 2013;19(4):473-80.  PMID: 23524343

31. Zhao Y, Wang Y, Yang J, Wang X, Zhao Y, Zhang X, Zhang YW*. Sorting nexin 12 interacts with BACE1 and regulates BACE1-mediated APP processing. Mol Neurodegener. 2012; 7(30).   PMID: 22709416

32. Liu Y, Zhang YW, Wang X, Zhang H, You X, Liao FF, Xu H*. Intracellular trafficking of Presenilin 1 is regulated by β-amyloid precursor protein and phospholipase D1. J Biol Chem. 2009; 284(18):12145-52.   PMID: 19276086

33. Nie H, Li Z, Lukas RJ, Shen Y, Song L, Wang X, Yin M*. Construction of SH-EP1-alpha4beta2-hAPP695 cell line and effects of nicotinic agonists on beta-amyloid in the cells. Cell Mol Neurobiol. 2008;28(1):103-12.   PMID: 17912626