A TIMEM252-dependent Microvascular Endophenotype in Alzheimer’s Disease

阿尔茨海默病中依赖于 TIMEM252 的微血管内表型

• 批准号: 10214327
• 负责人: Zhen Zhao
• 金额: $ 230.28万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10214327
• 关键词: Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Anatomy; Antisense Oligonucleotides; Astrocytes; Bioinformatics; Blood - brain barrier anatomy; Blood Circulation; Blood Vessels; Brain; CRISPR/Cas technology; Caspase; Cell Death; Cells; Cerebrovascular Disorders; Cerebrovascular system; Collaborations; Craniocerebral Trauma; Data; Data Set; Development; Edema; Electron Microscopy; Endoplasmic Reticulum; Endothelial Cells; Endothelium; Event; Extravasation; Functional disorder; Gender; Gene Delivery; Goals; Homeostasis; Human; Hypoxia; Impaired cognition; Impairment; In Vitro; Injury; Integral Membrane Protein; Intercellular Junctions; Intervention; Knockout Mice; Link; Magnetic Resonance Imaging; Membrane; Metabolic; Metabolic stress; Mitochondria; Modeling; Molecular; Molecular Profiling; Molecular Target; Mus; Mutation; Neurologic; Neurological Models; Neuronal Dysfunction; Neurons; Nutrient; Pathogenesis; Pathologic; Pathway interactions; Phenotype; Physiological; Plasma Proteins; Poison; Proteins; Role; Sampling; Stress; Stroke; Structure; System; Testing; Tg2576; Therapeutic Intervention; Traumatic Brain Injury; Up-Regulation; Validation; Vascular Diseases; adeno-associated viral vector; age group; age related; base; behavior test; brain endothelial cell; cerebrovascular; cognitive development; cognitive function; endophenotype; endothelial dysfunction; improved; in silico; in vivo; insight; mild traumatic brain injury; multimodality; multiple datasets; nervous system disorder; neuropathology; normal aging; novel; prevent; seal; single cell analysis; single-cell RNA sequencing; small molecular inhibitor; stroke model; tool; transcriptomics; wasting

Cerebrovascular dysfunction and blood-brain barrier (BBB) impairment are very common in neurological disorders, including age-related Alzheimer’s disease and related Dementia (AD/ADRD), head injuries including traumatic brain injury (TBI) and stroke. Microvascular injury and BBB breakdown often result in a cascade of events including extravasation of plasma proteins that are toxic to neuronal cells, parenchymal edema, hypoxia, metabolic stress including endoplasmic reticulum (ER) dysfunction, accumulation of metabolic wastes, activation of microglial and astrocytes, and eventually neuronal dysfunctions. Our central hypothesis is microvascular injury among different pathological conditions such as aging and AD can be attributed to an intrinsic molecular driver on BBB dysfunctions, which ultimately influence neuropathology and the development of cognitive impairment. Based on our preliminary data from comprehensive bioinformatic analysis and validations in multiple models of neurological disorders, we hypothesize that specific TMEM252 upregulation in BBB is a common molecular signature for microvascular injury. Mechanistically, TMEM252 may drive the microvascular injury endophenotype by inducing ER-dependent BBB dysfunctions. Hence, we propose to determine whether TMEM252 upregulation is a key event of microvascular injury and a common mechanism in aging and AD. More specifically, we will first provide a mechanistically understand TMEM252 functions in BBB (AIM 1), then understand the role of TMEM252 in age- and AD-associated microvascular injury using TMEM252-deficient mice (AIM 2), and finally examine the potential of targeting TMEM252 as an intervention for microvascular injury and BBB dysfunction in vivo (AIM 3). By phenotypically characterizing Tmem252 deficient model and its cross with Tg2576 model at multiple physiological levels, we hope to define a TMEM252-dependent link to vascular dysfunctions in aging and AD. As this molecular signature of microvascular injury was based on scRNA-seq analysis of multiple datasets obtained in TBI and aging mice, and cross-examined in human and mouse aging and AD samples, we expect that the propose project will provide very unique information regarding the common microvascular injury endophenotype across many neurological conditions. The data to be gathered from this study will expand our understanding of microvascular injury, as well as capture the nuance of the vascular changes between normal aging and AD. The successful completion of this study will provide new insights into the role of ER dysfunctions in microvascular injury, and novel molecular target for potential therapeutic intervention of microvascular injury in aging, AD and beyond.

脑血管功能障碍和血脑屏障(BBB)损害在神经科非常常见 疾病，包括与年龄相关的阿尔茨海默病和相关痴呆症(AD/ADRD)，头部损伤包括 创伤性脑损伤(TBI)和中风。微血管损伤和血脑屏障的破坏通常会导致一系列 事件包括对神经细胞有毒的血浆蛋白外溢，实质水肿，缺氧， 代谢应激包括内质网功能障碍、代谢废物堆积、激活 小胶质细胞和星形胶质细胞，最终导致神经元功能障碍。我们的中心假设是微血管损伤 不同的病理条件，如衰老和阿尔茨海默病，可以归因于内在的分子驱动因素 血脑屏障功能障碍，最终影响神经病理和认知障碍的发展。 基于我们综合生物信息学分析的初步数据和在多种模型中的验证 神经紊乱，我们假设BBB中特异的TMEM252上调是一种常见的分子 微血管损伤的签名。从机制上讲，TMEM252可能驱动微血管损伤的表型。 通过诱导内质网依赖的血脑屏障功能障碍。因此，我们建议确定TMEM252是否上调 是微血管损伤的关键事件，也是衰老和阿尔茨海默病的共同机制。更具体地说，我们将首先 从机制上理解TMEM252在血脑屏障(AIM 1)中的作用，进而理解TMEM252的作用 在年龄和AD相关的微血管损伤中使用TMEM252缺陷小鼠(AIM 2)，最后检查 靶向TMEM252作为干预微血管损伤和体内BBB功能障碍的可能性(AIM 3)。 通过表型表征Tem252缺陷模型及其与Tg2576模型的杂交 在生理水平上，我们希望定义TMEM252依赖于衰老和AD的血管功能障碍。 因为这种微血管损伤的分子特征是基于对多个数据集的scRNA-seq分析 在脑损伤和衰老小鼠中获得，并在人和小鼠衰老和AD样本中交叉验证，我们预计 建议的项目将提供关于常见微血管损伤的非常独特的信息 在许多神经疾病中表现为内表型。从这项研究中收集的数据将扩大我们的 了解微血管损伤，以及捕捉正常之间血管变化的细微差别 衰老和AD。这项研究的成功完成将为内质网功能障碍的作用提供新的见解 在微血管损伤中的作用，以及微血管损伤潜在治疗干预的新分子靶点 在衰老、阿尔茨海默病及以后。

项目成果

Microglia innate immune response contributes to the antiviral defense and blood-CSF barrier function in human choroid plexus organoids during HSV-1 infection.

• DOI: 10.1002/jmv.28472
• 发表时间: 2023-02
• 期刊: JOURNAL OF MEDICAL VIROLOGY
• 影响因子: 12.7
• 作者: Qiao, Haowen;Chiu, Yuanpu;Liang, Xinyan;Xia, Shangzhou;Ayrapetyan, Mariam;Liu, Siqi;He, Cuiling;Song, Ruocen;Zeng, Jianxiong;Deng, Xiangxue;Yuan, Weiming;Zhao, Zhen
• 通讯作者: Zhao, Zhen

Anti-malaria drug artesunate prevents development of amyloid-β pathology in mice by upregulating PICALM at the blood-brain barrier.

• DOI: 10.1186/s13024-023-00597-5
• 发表时间: 2023-01-27
• 期刊: Molecular neurodegeneration
• 影响因子: 15.1

Microglia and its Genetics in Alzheimer's Disease.

• DOI: 10.2174/1567205018666211105140732
• 发表时间: 2021
• 期刊: CURRENT ALZHEIMER RESEARCH
• 影响因子: 2.1
• 作者: Liang, Xinyan;Wu, Haijian;Colt, Mark;Guo, Xinying;Pluimer, Brock;Zeng, Jianxiong;Dong, Shupeng;Zhao, Zhen
• 通讯作者: Zhao, Zhen

Vascular inflammation in the central nervous system.

• DOI: 10.4103/1673-5374.332140
• 发表时间: 2022-08
• 期刊: Neural regeneration research
• 影响因子: 6.1
• 作者: Guo X;Zhao Z
• 通讯作者: Zhao Z

Mild traumatic brain injury induces microvascular injury and accelerates Alzheimer-like pathogenesis in mice.

• DOI: 10.1186/s40478-021-01178-7
• 发表时间: 2021-04-23
• 期刊: Acta neuropathologica communications
• 影响因子: 7.1
• 作者: Wu Y;Wu H;Zeng J;Pluimer B;Dong S;Xie X;Guo X;Ge T;Liang X;Feng S;Yan Y;Chen JF;Sta Maria N;Ma Q;Gomez-Pinilla F;Zhao Z
• 通讯作者: Zhao Z