Novel Approaches to Understand the Pathogenesis and Treat Alzheimer's Disease

了解发病机制和治疗阿尔茨海默病的新方法

• 批准号: 10621825
• 负责人: THOMAS M WISNIEWSKI
• 金额: $ 235.85万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621825
• 关键词: Acceleration; Address; Advisory Committees; Affect; Age of Onset; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Amyloid; Amyloid beta-Protein; Animal Model; Animals; Apolipoprotein E; Apolipoproteins; Area; Automobile Driving; Awareness; Behavior; Behavior assessment; Behavioral; Binding; Bioinformatics; Biological Markers; Biometry; Biostatistical Methods; Blood Vessels; Cerebral Amyloid Angiopathy; Clinical; Collaborations; Communities; Complex; Consensus; Coupling; Data; Data Analyses; Databases; Deposition; Development; Disease Progression; Education; Ensure; Experimental Designs; Genotype; Goals; Hemorrhage; Image; Immunology; Immunotherapy; Interdisciplinary Study; Label; Late Onset Alzheimer Disease; Magnetic Resonance Imaging; Methodology; Methods; Mitochondria; Molecular Conformation; Pathogenesis; Pathology; Peptoids; Pharmaceutical Chemistry; Play; Progress Reports; Protein Conformation; Protein Isoforms; Proteins; Proteome; Proteomics; Recording of previous events; Research; Research Personnel; Rodent Model; Role; Safety; Sampling; Senile Plaques; Synaptic plasticity; Techniques; Technology; Testing; Therapeutic; Transgenic Mice; Transgenic Organisms; United States National Institutes of Health; Work; abeta deposition; abeta oligomer; aged; amyloid pathology; apolipoprotein E-3; apolipoprotein E-4; brain parenchyma; clinically relevant; data management; data sharing; genetic risk factor; glucose metabolism; human data; human tissue; immunoregulation; innovation; insight; laser capture microdissection; meetings; microPET; mouse model; neuroimaging; neuropathology; novel; novel strategies; novel therapeutics; operation; power analysis; programs; protein oligomer; response; side effect; small molecule; synergism; tau Proteins; therapeutic development; therapeutically effective; therapy outcome; treatment response

OVERALL PROGRAM SUMMARY/ABSTRACT In this P01 proposal entitled: “Novel Approaches to Understand the Pathogenesis and Treat Alzheimer’s Disease”, we seek to gain a better understanding of the heterogeneous pathogenesis of AD and how it is influenced by apolipoprotein (apo) E isotypes. The apoE4 allele is the major genetic risk factor for late-onset AD and has been strongly associated with increased amyloid plaques deposition in brain parenchyma and advanced vascular amyloid pathology; as well as, enhanced Aβ oligomerization. ApoE is also involved in synaptic plasticity, glucose metabolism, mitochondrial function, and vascular integrity. Currently, there is no consensus on how different apoE genotypes contribute to the pathogenesis of AD. The interrelated studies proposed in the three projects of this P01 will help elucidate this complex role of apoE in AD. Hence this P01 is addressing an issue of great significance. We propose an integrated, multidisciplinary research endeavor that brings together investigators with an extensive history of successful collaboration, who have expertise in diverse areas including proteomics, bioinformatics, neuropathology, AD mouse models, immunology, µMRI, µPET, medicinal chemistry and biomarker studies. Across all projects we will apply our innovative proteomic methods (with the assistance of the proteomics/neuropathology Core B) and use of common AD models and behavioral assessments (with the assistance of the transgenic/behavioral Core C), along with state-of-the-art biomarker technology using SIMOA and P01 investigator developed µMRI methodologies, to ensure synergism across all P01 studies. Scientific rigor of the P01 will be ensure by the Biostatistics and Bioinformatics Core (Core D). The three projects of this P01 are focused on the differential role apolipoprotein E (apoE) isoforms play in: 1) AD plaque and vessel amyloid development as assessed by unbiased proteomics across the full spectrum of AD pathology (Project 1); 2) innovative therapeutic approaches that target the Aβ/apoE interaction (Project 2); and 3) responses to our novel therapeutic immunomodulation that targets abnormal conformation (Project 3). Combined our efforts are anticipated to enhance our understanding of the differential effects of apoE isotypes on AD pathogenesis and accelerate the discovery of effective therapeutic approaches that address these diverse roles.

总体数据摘要/摘要 在P01提案中，题为：“了解发病机制和治疗阿尔茨海默氏症的新方法 疾病”，我们寻求更好地了解AD的异质性发病机制， 受载脂蛋白（apo）E同种型影响。apoE 4等位基因是晚发性脑梗死的主要遗传危险因素， AD与脑实质中淀粉样蛋白斑块沉积增加密切相关， 晚期血管淀粉样病变;以及增强的Aβ寡聚化。ApoE也参与了 突触可塑性、葡萄糖代谢、线粒体功能和血管完整性。目前尚无 就不同的apoE基因型如何促进AD的发病机制达成共识。相关研究 本P01的三个项目中提出的新方法将有助于阐明apoE在AD中的复杂作用。因此，P01是 解决一个重要问题我们提出了一个综合的，多学科的研究奋进， 汇集了具有广泛成功合作历史的调查人员，他们拥有以下方面的专业知识： 包括蛋白质组学、生物信息学、神经病理学、AD小鼠模型、免疫学、µMRI、 µPET、药物化学和生物标志物研究。在所有项目中，我们将应用我们的创新蛋白质组学 方法（在蛋白质组学/神经病理学核心B的帮助下）和使用常见的AD模型， 行为评估（在转基因/行为核心C的帮助下），沿着最先进的 使用SIMOA和P01的生物标志物技术，研究者开发了µMRI方法，以确保协同作用 在所有P01研究中。生物统计学和生物信息学核心将确保P01的科学严谨性 (Core D）。本P01的三个项目集中在载脂蛋白E（apoE）亚型的差异作用 发挥作用：1）AD斑块和血管淀粉样蛋白的发展，如通过无偏倚的蛋白质组学评估的， AD病理学谱（项目1）; 2）靶向Aβ/apoE相互作用的创新治疗方法 （项目2）;和3）对我们的靶向异常构象的新型治疗性免疫调节的反应 （项目3）。我们的共同努力预计将提高我们对不同影响的理解， apoE同种型在AD发病机制中的作用，并加速发现有效的治疗方法， 发挥这些不同的作用。

项目成果

High-fat diet-induced atherosclerosis promotes neurodegeneration in the triple transgenic (3 × Tg) mouse model of Alzheimer's disease associated with chronic platelet activation.

高脂肪饮食诱导的动脉粥样硬化会促进与慢性血小板活化相关的阿尔茨海默病三重转基因 (3 × Tg) 小鼠模型中的神经变性

• DOI: 10.1186/s13195-021-00890-9
• 发表时间: 2021-08-28
• 期刊: Alzheimer's research & therapy
• 作者: Wang M;Lv J;Huang X;Wisniewski T;Zhang W
• 通讯作者: Zhang W

Life stressors significantly impact long-term outcomes and post-acute symptoms 12-months after COVID-19 hospitalization.

• DOI: 10.1016/j.jns.2022.120487
• 发表时间: 2022-12-15
• 期刊: JOURNAL OF THE NEUROLOGICAL SCIENCES
• 影响因子: 4.4
• 作者: Frontera, Jennifer A.;Sabadia, Sakinah;Yang, Dixon;de Havenon, Adam;Yaghi, Shadi;Lewis, Ariane;Lord, Aaron S.;Melmed, Kara;Thawani, Sujata;Balcer, Laura J.;Wisniewski, Thomas;Galetta, Steven L.
• 通讯作者: Galetta, Steven L.

ADAMTS18 Deficiency Affects Neuronal Morphogenesis and Reduces the Levels of Depression-like Behaviors in Mice.

ADAMTS18 缺乏会影响小鼠神经元形态发生并降低抑郁样行为水平

• DOI: 10.1016/j.neuroscience.2018.12.025
• 发表时间: 2019-02-10
• 期刊: Neuroscience
• 影响因子: 3.3
• 作者: Zhu R;Pan YH;Sun L;Zhang T;Wang C;Ye S;Yang N;Lu T;Wisniewski T;Dang S;Zhang W
• 通讯作者: Zhang W

Pilot study evaluating everolimus molecular mechanisms in tuberous sclerosis complex and focal cortical dysplasia.

• DOI: 10.1371/journal.pone.0268597
• 发表时间: 2022
• 期刊: PloS one
• 影响因子: 3.7

Demographic and social determinants of cognitive dysfunction following hospitalization for COVID-19.

• DOI: 10.1016/j.jns.2022.120146
• 发表时间: 2022-07-15
• 期刊: Journal of the neurological sciences
• 影响因子: 4.4
• 作者: Valdes E;Fuchs B;Morrison C;Charvet L;Lewis A;Thawani S;Balcer L;Galetta SL;Wisniewski T;Frontera JA
• 通讯作者: Frontera JA