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.

总体方案摘要/摘要

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.

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

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

Localized proteomic differences in the choroid plexus of Alzheimer's disease and epilepsy patients.

• DOI: 10.3389/fneur.2023.1221775
• 发表时间: 2023
• 期刊: Frontiers in neurology
• 影响因子: 3.4