Advances in understanding the β-amyloid precursor protein intracellular domain

老年性痴呆症(Alzheimer's disease,AD)一个重要的病理学特征,是在神经细胞外形成由β-淀粉样蛋白(β-amyloid,Aβ)组成的淀粉样斑(amyloid plaques)。β-淀粉样蛋白前体蛋白(β-amyloid procursor protein,APP)经β-分泌酶和γ-分泌酶依次水解后产生Aβ和APP胞内结构域(APP intracellular domain,AICD)。现在已经知道Aβ在AD的发病机制中起着关键作用,但是关于AICD的生理及病理功能还不清楚。近年来研究发现AICD可以与细胞内多种蛋白相互作用,而且AICD在基因转录、细胞凋亡以及APP的加工和运输过程中均有调节功能。本文针对这一领域的研究进展,对AICD的生理及病理功能进行探讨。One of the neuropathologic hallmarks of Alzheimer’s disease (AD) is the presence of senile plaques which consist of β-amyloid peptide (Aβ) in the brain. Aβ is derived from β-amyloid precursor protein (APP) through sequential cleavages by the β-secretase and the γ-secretase. In addition to Aβ, γ-cleavage releases the intracellular domain of APP (AICD). However, although it is well-established that Aβ is the prime culprit for AD pathogenesis, the physio/pathological functions of AICD remain largely elusive. Here we review recent progress toward elucidating the functional roles of AICD, which include modulating intracellular trafficking/processing of APP, inducing apoptosis, and regulating gene expression at transcriptional level.国家自然科学基金(30672198);; 福建省高等学校新世纪优秀人才支持计

Novel Pathways Regulating Function and Metabolism of ß-Amyloid Precursor Protein in Alzheimer's Disease

阿尔茨海默病(AD)是最常见的老年人痴呆病症，AD病人最显著的病理特征是细胞外的淀粉样斑和细胞内的神经纤维缠结(NFT)。淀粉样斑是由β-淀粉样蛋白(Aβ)组成，而NFT由细胞骨架蛋白tau组成。Aβ是由淀粉样前体蛋白(APP)经β-分泌酶和γ-分泌酶依次切割而成；而NFT的形成与tau蛋白异常磷酸化有关。多种证据表明，大脑中Aβ的过度产生和聚集是AD的主要原因：Aβ具有神经毒性并可触发级联反应引起细胞死亡。Alzheimer’s disease (AD) is the most common neurodegenera-tive disorder worldwide, defined by two classical hallmark pa-thologies: extracellular senile plaques and intraneuronal neu-rofibrillary tangles (NFTs) (1,2). NFTs are composed of the hyperphosphorylated microtubule-associated protein tau that is abnormally phosphorylated primarily by glycogen synthase ki-nase-3 (GSK-3) and cyclin D kinase 5 (Cdk5) (2). Senile plaques are composed of heterogeneous small peptides collectively called β-amyloid (Aβ), derived from the β-amyloid precursor pro-tein (APP) through sequential cleavage by β- and γ-secretases. APP is synthesized in the endoplasmic reticulum (ER) and trans-ported through the Golgi/trans-Golgi network (TGN) to the plasma membrane, where it can be cleaved by α-secretase to produce sAPPα. Non-cleaved APP is re-internalized and is subjected to amyloidogenic processing for Aβ generation (1). Multiple lines of evidence suggest that overproduction/aggregation of Aβ in the brain is the primary cause of AD: Aβ is highly toxic to neurons and can trigger a cascade of pathogenic events leading to cell death. Therefore, detailed delineation of the function, process-ing, and regulated trafficking of APP is crucial for understanding the mechanism underlying AD pathogenesis and for developing AD therapeutic strategies

Transcriptional regulation of PEN-2, a key component of the γ-secretase complex, by CREB

Gamma-secretase, which is responsible for the intramembranous cleavage of Alzheimer's P-amyloid precursor protein (APP), the signaling receptor Notch, and many other substrates, is a multiprotein complex consisting of at least four components: presenilin (PS), nicastrin, APH-1, and PEN-2. Despite the fact that PEN-2 is known to mediate endoproteolytic cleavage of full-length PS and APH-1 and nicastrin are required for maintaining the stability of the complex, the detailed physiological function of each component remain elusive. Unlike that of PS, the transcriptional regulation of PEN-2, APH-1, and nicastrin has not been investigated. Here, we characterized the upstream regions of the human PEN-2 gene and identified a 238-bp fragment located 353 bp upstream of the translational start codon as the key region necessary for the promoter activity. Further analysis revealed a CREB binding site located in the 238-bp region that is essential for the transcriptional activity of the PEN-2 promoter. Mutation of the CREB site abolished the transcriptional activity of the PEN-2 promoter. Electrophoretic mobility shift assays and chromatin immunoprecipitation analysis showed the binding of CREB to the PEN-2 promoter region both in vitro and in vivo. Activation of the CREB transcriptional factor by forskolin dramatically promoted the expression of PEN-2 mRNA and protein, whereas the other components of the gamma-secretase complex remained unaffected. Forskolin treatment slightly increases the secretion of soluble APP alpha and A beta without affecting Notch cleavage. These results demonstrate that expression of PEN-2 is regulated by CREB and suggest that the specific control of PEN-2 expression may imply additional physiological functions uniquely assigned to PEN-2

Deficiency in LRP6-Mediated Wnt Signaling Contributes to Synaptic Abnormalities and Amyloid Pathology in Alzheimer’s Disease

该课题是卜国军教授课题组与美国梅奥医学中心、以及厦门大学神经科学研究所教授许华曦课题组等多位科学家合作完成的。由许华曦和卜国军领导的厦门大学神经科学研究所暨福建省神经退行性疾病及衰老研究重点实验室近年来在神经退行性疾病研究领域取得了一系列优秀的成果，先后在NatMed、NatStructMolBiol、NatRevNeurol、Neuron、ProcNatlAcadSciUSA等国际高水平杂志上以厦门大学为第一署名或通讯单位发表了30多篇SCI论文，总影响因子达250多。Alzheimer’s disease (AD) is an age-related neurological disorder characterized by synaptic loss and dementia. The low-density lipoprotein receptor-related protein 6 (LRP6) is an essential coreceptor for Wnt signaling, and its genetic variants have been linked to AD risk. Here we report that neuronal LRP6-mediated Wnt signaling is critical for synaptic function and cognition. Conditional deletion of Lrp6 gene in mouse forebrain neurons leads to age-dependent deficits in synaptic integrity and memory. Neuronal LRP6 deficiency in an amyloid mouse model also leads to exacerbated amyloid pathology due to increased APP processing to amyloid-β. In humans, LRP6 and Wnt signaling are significantly downregulated in AD brains, likely by a mechanism that depends on amyloid-β. Our results define a critical pathway in which decreased LRP6-mediated Wnt signaling, synaptic dysfunction, and elevated Aβ synergistically accelerate AD progression and suggest that restoring LRP6-mediated Wnt signaling can be explored as a viable strategy for AD therapy

Soluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer's disease model

阿尔茨海默病（Alzheimer’s Disease, AD）是一种以渐进性认知功能丧失为主要特征的神经退行性疾病，是最为常见的老年痴呆类型。随着全球人口老龄化的加剧，AD正在成为二十一世纪最大的疾病之一。该研究首次揭示sTREM2在AD中具有重要的保护功能，提出sTREM2或可用于AD治疗的新观点，同时也进一步佐证了小胶质细胞在AD治疗中的核心作用，研究为AD等神经退行性疾病的防治开辟了新思路、提供了新靶点。 厦门大学医学院博士后钟力和硕士研究生徐颖为论文共同第一作者，陈小芬教授和卜国军教授为该论文的共同通讯作者。厦门大学的文磊、孙灏、卓仁恭等教授和美国Sanford-Burnham-Prebys医学研究所的许华曦教授共同参与了该项目的研究。【Abstract】Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial surface receptor genetically linked to the risk for Alzheimer’s disease (AD). A proteolytic product, soluble TREM2 (sTREM2), is abundant in the cerebrospinal fluid and its levels positively correlate with neuronal injury markers. To gain insights into the pathological roles of sTREM2, we studied sTREM2 in the brain of 5xFAD mice, a model of AD, by direct stereotaxic injection of recombinant sTREM2 protein or by adeno-associated virus (AAV)-mediated expression. We found that sTREM2 reduces amyloid plaque load and rescues functional deficits of spatial memory and long-term potentiation. Importantly, sTREM2 enhances microglial proliferation, migration, clustering in the vicinity of amyloid plaques and the uptake and degradation of Aβ. Depletion of microglia abolishes the neuroprotective effects of sTREM2. Our study demonstrates a protective role of sTREM2 against amyloid pathology and related toxicity and suggests that increasing sTREM2 can be explored for AD therapy.Research by the authors was supported by grants from the National Natural Science Foundation of China 81370459, 31400914 (to X.C.), 81701079 (to L.Z.), 81373999, 81774377 (to L.W.), and 81601227 (to R.Z.), grants from the Natural Science Foundation of Guangdong Province 2016A030306005 (to X.C.), 2016A030310371 (to R.Z.), grants from the Fundamental Research Funds for the Central Universities 20720180055 (to X.C.), grants from the Alzheimer's Association AARG-18-56635 (to X.C.), and C4C-15-369446 (to H.X.). NIH grants RF1AG056130 (to G.B. and H.X.), R01AG035355 (to G.B.), R37AG027924 (to G.B.), and RF1AG056114 (to H.X.), grants from the Postdoctoral Science Foundation of China 2016M600503 and 2017T100469 (to L.Z.), a grant from the Tanz Family Funds (to H.X.), and a grant from the Natural Science Foundation of Fujian Province 2016J05203 (to R.Z.).该工作得到国家自然科学基金、厦门大学校长基金、广东省自然科学杰出青年基金、美国阿尔茨海默氏症协会基金和中国博士后科学基金等的资助

Menin Deficiency Leads to Depressive-like Behaviors in Mice by Modulating Astrocyte-Mediated Neuroinflammation

厦门大学医学院、神经科学研究所张杰教授团队发现了抑郁症新的致病基因MEN1，并阐明了MEN1调控星形胶质细胞炎症导致抑郁发生发展的新机制，为抑郁症的诊治提供了新靶点和方向。抑郁症是严重威胁人类健康的重大神经系统疾病，危及全球30%的人口。但对其发病机制并不清楚。张杰教授团队发现，在慢性不可预测以及LPS处理的模拟抑郁小鼠模型中，多发性内分泌肿瘤蛋白(menin)在大脑中的表达显著降低，并且在星形胶质细胞中降低最明显。为了研究menin是否参与了小鼠抑郁表型的产生，研究团队制作了多种神经系统menin条件性敲除小鼠。通过对这些小鼠行为学的检测，锁定了只有在星形胶质细胞中敲除menin后，小鼠才会表现出抑郁样表型。证实了menin可能是通过调控星形胶质细胞的功能促进了抑郁的发生。 MEN1基因的突变会导致多发性内分泌肿瘤，而内分泌的紊乱和抑郁等精神疾病有着密切的联系。下丘脑-垂体-肾上腺轴（HPA轴）的功能紊乱直接参与了抑郁的产生。基于此研究团队推测MEN1的基因突变是否也会导致抑郁的发生。通过和中国医学科学院基础所的许琪教授合作，研究团队对1000多例重度抑郁患者和800多例对照人群进行了MEN1基因的外显子测序。通过测序发现MEN1的一个SNP s375804228和抑郁的发生有着显著关联。该SNP导致menin第503位的氨基酸由G突变成D。通过功能研究进一步证实该突变可以阻断menin和p65的结合，从而过度激活NF-κB-IL-1β通路，导致神经炎症的发生。 张杰，厦门大学特聘教授、博士生导师。国家优秀青年科学基金；教育部新世纪优秀人才；福建省杰出青年科学基金；厦门市五四青年奖章等获得者。2011年8月加入厦门大学医学院神经科学研究所担任教授至今。张杰博士主要从事重大神经系统疾病（老年痴呆、帕金森、抑郁症、自闭症、术后认知障碍、胶质瘤）等的发病机制和药物开发研究。至今以第一作者或者通讯作者在国际知名期刊发表研究论文21篇。其中回国独立开展研究工作以后，作为通讯作者在 Neuron，Cell Reports, PNAS, The Journal of Neuroscience, Clinical Cancer Research，Cell Death and Disease, JBC, Chemistry，Chem. Biol. Drug Des.等杂志上发表多篇研究论文。【Abstract】Astrocyte dysfunction and inflammation are associated with the pathogenesis of major depressive disorder (MDD). However, the mechanisms underlying these effects remain largely unknown. Here, we found that multiple endocrine neoplasia type 1 (Men1; protein: menin) expression is attenuated in the brain of mice exposed to CUMS (chronic unpredictable mild stress) or lipopolysaccharide. Astrocyte-specific reduction of Men1 (GcKO) led to depressive-like behaviors in mice. We observed enhanced NF-κB activation and IL-1β production with menin deficiency in astrocytes, where depressive-like behaviors in GcKO mice were restored by NF-κB inhibitor or IL-1β receptor antagonist. Importantly, we identified a SNP, rs375804228, in human MEN1, where G503D substitution is associated with a higher risk of MDD onset. G503D substitution abolished menin-p65 interactions, thereby enhancing NF-κB activation and IL-1β production. Our results reveal a distinct astroglial role for menin in regulating neuroinflammation in depression, indicating that menin may be an attractive therapeutic target in MDD.We thank Prof. Guanghui Jin (Xiamen University) and Prof. Xianxin Hua (University of Pennsylvania) for providing the Men1-floxp mice. This work was supported by the National Natural Science Foundation of China (grants 81522016, 81271421, and 31571055 to J.Z.; 81625008 and 31430048 to Q.X.; 81630026 to Z.Y.; 81771163 and U1405222 to H.X.; U1505227 to G.B.; 81472725 to W.M.), the Natural Science Foundation of Fujian Province of China (grant 2013J01147 and 2014J06019 to J.Z.), the Fundamental Research Funds for the Central Universities (grants 20720150062 and 20720180049 to J.Z.), the National Key Research and Development Program of China (2016YFC1305903), and CAMS Innovation Fund for Medical Sciences (grant 2016I2M1004 to Q.X.).研究工作得到国家自然科学基金项目（81522016、81271421、31571055）以及厦门大学校长基金等资助

CDK5-dependent BAG3 degradation modulates synaptic protein turnover

阿尔茨海默病（AD）是严重威胁人类健康的重大神经系统疾病，AD的发生发展与衰老密切相关，目前临床治疗方法十分有限。因此迫切需要从AD致病早期入手，发现和鉴定导致AD神经功能紊乱的机制和靶点，为AD的早期防治提供基础。张杰教授及其团队从高通量磷酸化蛋白质组学入手，系统研究了CDK5在神经细胞中的磷酸化底物，鉴定出了在蛋白质量控制中发挥重要功能的BAG3蛋白是CDK5的全新底物。课题组从磷酸化蛋白质组学入手，发现和阐明了细胞周期蛋白激酶5（CDK5）通过调控BAG3在维持突触蛋白水平调控中的作用机制，及其在阿尔茨海默病（AD）发生发展中的机理。 该研究是多个团队历时8年合作完成的，香港中文大学的周熙文教授、美国匹兹堡大学的Karl Herrup教授、美国Sanford-Burnham研究所的许华曦教授、美国梅奥医学中心的卜国军教授，厦门大学医学院的文磊教授、张云武教授、赵颖俊教授、薛茂强教授，军事医学科学院的袁增强教授等都参与了该工作。 厦门大学医学院2012级博士生周杰超等为文章的第一作者，张杰教授为通讯作者。Background Synaptic protein dyshomeostasis and functional loss is an early invariant feature of Alzheimer’s disease (AD), yet the unifying etiological pathway remains largely unknown. Knowing that cyclin-dependent kinase 5 (CDK5) plays critical roles in synaptic formation and degeneration, its phosphorylation targets were re-examined in search for candidates with direct global impacts on synaptic protein dynamics, and the associated regulatory network was also analyzed. Methods Quantitative phospho-proteomics and bioinformatics analyses were performed to identify top-ranked candidates. A series of biochemical assays were used to investigate the associated regulatory signaling networks. Histological, electrochemical and behavioral assays were performed in conditional knockout, shRNA-mediated knockdown and AD-related mice models to evaluate its relevance to synaptic homeostasis and functions. Results Among candidates with known implications in synaptic modulations, BCL2-associated athanogene-3 (BAG3) ranked the highest. CDK5-mediated phosphorylation on Ser297/Ser291 (Mouse/Human) destabilized BAG3. Loss of BAG3 unleashed the selective protein degradative function of the HSP70 machinery. In neurons, this resulted in enhanced degradation of a number of glutamatergic synaptic proteins. Conditional neuronal knockout of Bag3 in vivo led to impairment of learning and memory functions. In human AD and related-mouse models, aberrant CDK5-mediated loss of BAG3 yielded similar effects on synaptic homeostasis. Detrimental effects of BAG3 loss on learning and memory functions were confirmed in these mice, and such were reversed by ectopic BAG3 re-expression. Conclusions Our results highlight that neuronal CDK5-BAG3-HSP70 signaling axis plays a critical role in modulating synaptic homeostasis. Dysregulation of the signaling pathway directly contributes to synaptic dysfunction and AD pathogenesis.This work was supported by the National Science Foundation in China (Grant: 31571055, 81522016, 81271421 to J.Z.; 81801337 to L.L; 81774377 and 81373999 to L.W.); Fundamental Research Funds for the Central Universities of China-Xiamen University (Grant: 20720150062, 20720180049 and 20720160075 to J.Z.); Fundamental Research Funds for Fujian Province University Leading Talents (Grant JAT170003 to L.L); Hong Kong Research Grants Council (HKUST12/CRF/13G, GRF660813, GRF16101315, AoE/M-05/12 to K.H.; GRF16103317, GRF16100718 and GRF16100219 to H.-M,C.); Offices of Provost, VPRG and Dean of Science, HKUST (VPRGO12SC02 to K.H.); Chinese University of Hong Kong (CUHK) Improvement on Competitiveness in Hiring New Faculty Funding Scheme (Ref. 133), CUHK Faculty Startup Fund and Alzheimer’s Association Research Fellowship (AARF-17-531566) to H.-M, C. 该研究受到了国家自然科学基金、厦门大学校长基金、福建省卫生教育联合攻关基金等的资助

Appoptosin-Mediated Caspase Cleavage of Tau Contributes to Progressive Supranuclear Palsy Pathogenesis

在该研究中，许教授课题组鉴定了一个在Tau疾病中起关键致病作用的新蛋白Appoptosin。Tau疾病是一类具有共同病理特征：即随着疾病的进程，在脑中会产生Tau蛋白异常聚集和缠结的神经退行性疾病，包括阿尔茨海默症（老年性痴呆）、额颞痴呆、以及进行性核上麻痹（PSP）等。虽然人们推测Tau蛋白异常很可能是导致这些疾病中神经元和脑功能受损的关键因素，但是并不清楚它究竟是如何诱发疾病的。尤其是PSP患者在平衡、眼球运动以及思维上都存在严重的障碍，但迄今为止，人们对该疾病的致病机制几乎一无所知。许教授的研究团队通过对PSP患者的检测，发现一个与该疾病相关的DNA单核苷酸突变（SNP）可以引起Appoptosin蛋白水平的增高，并增加Tau蛋白的过度磷酸化以及caspase-3酶介导的Tau蛋白切割，从而导致Tau蛋白的异常聚集和突触功能障碍。更为重要的是，在阿尔茨海默症和额颞痴呆患者的脑组织中，同样发现了致病蛋白Appoptosin和Tau蛋白异常切割的增加，进一步证明了Appoptosin介导的途径在Tau疾病的发病机制中起到了关键性作用。该研究为进一步阐明神经退行性疾病的病理机制指引了新的研究方向，为痴呆和运动功能障碍的临床治疗提供了全新的治疗靶点和思路，具有重要的临床意义。Progressive supranuclear palsy (PSP) is a movement disorder characterized by tau neuropathology where the underlying mechanism is unknown. An SNP (rs1768208 C/T) has been identified as a strong risk factor for PSP. Here, we identified a much higher T-allele occurrence and increased levels of the pro-apoptotic protein appoptosin in PSP patients. Elevations in appoptosin correlate with activated caspase-3 and caspase-cleaved tau levels. Appoptosin overexpression increased caspase-mediated tau cleavage, tau aggregation, and synaptic dysfunction, whereas appoptosin deficiency reduced tau cleavage and aggregation. Appoptosin transduction impaired multiple motor functions and exacerbated neuropathology in tau-transgenic mice in a manner dependent on caspase-3 and tau. Increased appoptosin and caspase-3-cleaved tau were also observed in brain samples of patients with Alzheimer’s disease and frontotemporal dementia with tau inclusions. Our findings reveal a novel role for appoptosin in neurological disorders with tau neuropathology, linking caspase-3-mediated tau cleavage to synaptic dysfunction and behavioral/motor defects

SNX14 deficiency-induced defective axonal mitochondrial transport in Purkinje cells underlies cerebellar ataxia and can be reversed by valproate

共济失调是一类以运动协调性紊乱为主要特征的神经系统症状，临床表现包括步态不稳、丧失平衡、吞咽困难、眼球运动异常、肌张力受损等。厦门大学医学院神经科学研究所王鑫教授团队首次从轴突线粒体运输这一全新视角揭示了一类遗传性共济失调的发病机制，并发现抗癫痫药--丙戊酸大幅度减缓模型小鼠的疾病进程，具有较强的转化应用价值，有望为共济失调提供新的治疗手段。 该研究工作由王鑫教授指导完成，厦门大学医学院助理教授张洪峰和博士生洪育娟共同完成主要实验工作。Loss-of-function mutations in SNX14 cause autosomal recessive spinocerebellar ataxia 20, which is a form of early-onset cerebellar ataxia that lacks molecular mechanisms and mouse models. We generated Snx14-deficient mouse models and observed severe motor deficits and cell-autonomous Purkinje cell degeneration. SNX14 deficiency disrupted microtubule organization and mitochondrial transport in axons by destabilizing the microtubule-severing enzyme spastin, which is implicated in dominant hereditary spastic paraplegia with cerebellar ataxia, and compromised axonal integrity and mitochondrial function. Axonal transport disruption and mitochondrial dysfunction further led to degeneration of high-energy-demanding Purkinje cells, which resulted in the pathogenesis of cerebellar ataxia. The antiepileptic drug valproate ameliorated motor deficits and cerebellar degeneration in Snx14-deficient mice via the restoration of mitochondrial transport and function in Purkinje cells. Our study revealed an unprecedented role for SNX14-dependent axonal transport in cerebellar ataxia, demonstrated the convergence of SNX14 and spastin in mitochondrial dysfunction, and suggests valproate as a potential therapeutic agent.We thank Tim Huang for helpful discussion, Wei Mo for sharing mouse lines, Li Zhong for sharing reagents, Aidong Han, Luming Yao, Caiming Wu, Mingxia Zhu, Qingfeng Liu, Lin Zhu, Shuo Zhang, Haiping Zheng, and Changchuan Xie for technical assistance, and Cui Li for providing bioinformatics software. We also thank Novogene Co., Ltd. and PTM Biolab Co., Ltd. for technical assistance in the transcriptomic and proteomic analyses, respectively. 厦门大学医学院许华曦、赵颖俊、张云武、杜丹教授在研究过程中给予大力帮助和支持。本研究工作得到国家重点研发计划项目、国家自然科学基金、福建省自然科学基金、厦门大学校长基金的资助和支持

Trisomy 21-induced Dysregulation of Microglial Homeostasis in Alzheimer’s Brains is Mediated by USP25

阿尔茨海默病（Alzheimer’s disease, AD）是一种最为常见的与记忆、认知能力退化相关的渐进性神经退行性疾病。唐氏综合征（Down’s syndrome, DS）是早发型阿尔茨海默病的一个重要风险因素，作为最常见的智力障碍遗传疾病，厦门大学医学院神经科学研究所王鑫教授团队揭示了治疗阿尔茨海默病和唐氏综合征新的治疗靶点，并且在小鼠模型上利用USP25小分子抑制剂成功地改善了阿尔茨海默病小鼠的认知功能，缓解了神经退行性病变的病理进程。该研究工作由王鑫教授指导完成，厦门大学医学院助理教授郑秋阳和博士生李桂林完成主要实验工作，王世华、朱琳、高月、邓青芳、张洪峰、张丽珊、吴美玲、狄安洁参与了部分研究工作。厦门大学医学院许华曦、赵颖俊和孙灏教授在研究过程中给予大力帮助和支持，清华大学董晨教授提供了Usp25基因敲除小鼠，厦门大学附属妇女儿童医院周裕林教授和郑良楷博士帮助收集了脑组织样品。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 5×FAD 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 5×FAD 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.This work was supported by the National Natural Science Foundation of China (31871077, 81822014, and 81571176 to X.W.; 81701130 to Q.Z.), the National Key R&D Program of China (2016YFC1305900 to X.W.), the Natural Science Foundation of Fujian Province of China (2017J06021 to X.W.), the Fundamental Research Funds for the Chinese Central Universities (20720150061 to X.W.), and the BrightFocus Foundation (A2018214F to Yingjun Zhao). 该研究工作得到国家重点研发计划项目、国家自然科学基金、福建省自然科学基金、厦门大学校长基金的资助和支持