Defining the effect of Alzheimer pathologies on the aged brain in 3 dimensions

从 3 个维度定义阿尔茨海默病病理对衰老大脑的影响

• 批准号: 10555892
• 负责人: PHILIP L DE JAGER
• 金额: $ 651.82万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555892
• 关键词: 3-Dimensional; Acceleration; Address; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Antibodies; Architecture; Atlases; Autopsy; BRAIN initiative; Blood Vessels; Brain; Brain Diseases; Brain imaging; Brain region; Caregivers; Cell Aging; Cells; Central Nervous System Diseases; Cerebral Amyloid Angiopathy; Clinical; Cognitive; Cognitive aging; Communities; Complement; Complex; Data; Data Set; Development; Disease; Elderly; Environment; Foundations; Frustration; Funding; Gene Combinations; Generations; Genes; Growth; Human; Image; Impaired cognition; Indirect Immunofluorescence; Individual; Knowledge; Knowledge Portal; Location; Longevity; Magnetic Resonance Imaging; Medicine; Methodology; Microscopic; Molecular; Multiomic Data; Neocortex; Neurobiology; Outcome; Output; Participant; Pathologic; Pathology; Patients; Positioning Attribute; Proteomics; Protocols documentation; RNA; Research; Research Personnel; Resources; Rest; Risk Factors; Sampling; Scientist; Senile Plaques; Senior Scientist; Severities; Signal Transduction; Surface; Susceptibility Gene; Talents; Techniques; Thinness; Tissues; United States National Institutes of Health; Variant; age effect; aging brain; alpha synuclein; brain tissue; cell community; cell type; cohort; effective therapy; insight; neocortical; neuropathology; neurovascular unit; new therapeutic target; programs; promote resilience; protein TDP-43; single nucleus RNA-sequencing; tau Proteins; therapeutic development; transcriptomics; two-dimensional

This proposal, to create the 3D Aging & Alzheimer Brain Program, addresses several critical gaps in ongoing efforts to bridge the divide between known risk factors for Alzheimer’s disease (AD) and the syndromic manifestations of the disease. The significant gaps are in: i) how the neurobiology of aging-related cognitive decline may provide insights into enhancing resilience; ii) understanding the molecular mechanisms of AD susceptibility loci and diversification of AD target genes and how these genes cause a cellular effect; and iii) key topological and morphometric information when using current sequencing approaches on cortical tissue to implicate cellular subtypes contributing to disease. To address these gaps, we propose a comprehensive program to systematically generate and analyze multiple interconnected reference data sets, that includes diverse individuals, to (a) characterize the individual and synergistic effects that AD proteinopathies, cerebral amyloid angiopathy (CAA), and aging itself have on the molecular and cellular architecture of the older neocortex and (b) identify those aspects that contribute to cognitive decline, the clinically meaningful outcome of AD. To this end, our Program targets three brain regions to capture the effects of a range of different neuropathologies. We will establish three large-volume molecular atlases of: 1) the aging brain by sampling the entire lifespan in individuals with minimal neuropathologic burden to investigate the effect of aging itself in the brain; 2) the impact of amyloid and tau proteinopathies, including specific representative cases to capture the independent and synergistic effects of β-amyloid and tau alone and in combination with α-synuclein and TDP-43 proteinopathies; and 3) the impact of CAA to yield new insights into a very different aspect of amyloid proteinopathy and its impact on the neurovascular unit. We will then establish a reference dataset of molecular data in 300 diverse individuals to enable the assessment of spatial molecular features in relation to pathological and cognitive outcomes. In parallel to the development of these atlases and reference datasets, we will optimize experimental protocols for spatial transcriptomics and iterative indirect immunofluorescence imaging (4i) to facilitate large-scale projects and enable enhanced data generation over existing, baseline capabilities. We will distribute all protocols and data through the NIA-funded AD Knowledge portal, which already hosts multiomic data from the same cohorts and participants, to accelerate repurposing of the data. Finally, we will create MAAP-Brain, a 3-D interactive data visualizer, so that all investigators and particularly non-computational scientists, can interact with our data and results. The Program team brings together a highly complementary cast of talented junior and senior scientists, and it rests on a foundation of multiple intersecting long-term collaborative research programs that position it well to achieve all its deliverables towards advancing our understanding of the complex clinico-spatial-molecular features that contribute to aging and AD, which will provide needed resources to the broader scientific community.

这项创建3D老龄化和阿尔茨海默病大脑计划的提案，解决了正在努力弥合阿尔茨海默病(AD)已知风险因素与该疾病症状表现之间的鸿沟的几个关键空白。主要的差距在于：i)与衰老相关的认知衰退的神经生物学如何为增强复原力提供见解；ii)理解AD易感基因和AD靶基因多样化的分子机制，以及这些基因如何导致细胞效应；iii)在使用当前的皮质组织测序方法来推断导致疾病的细胞亚型时，关键的拓扑和形态计量信息。为了解决这些差距，我们提出了一个全面的计划，以系统地生成和分析包括不同个体在内的多个相互关联的参考数据集，以(A)表征AD蛋白病变、大脑淀粉样血管病变(CAA)和衰老本身对老年新皮质的分子和细胞结构的个体和协同效应，以及(B)确定导致认知功能下降的那些方面，这是AD具有临床意义的结果。为此，我们的计划针对三个大脑区域，以捕捉一系列不同神经病理的影响。我们将建立三个大容量分子图谱，包括：1)通过采样神经病理负担最小的个人的整个寿命来研究衰老本身在大脑中的影响；2)淀粉样蛋白和tau蛋白病变的影响，包括特定的代表性病例，以捕捉β-淀粉样蛋白和tau蛋白单独以及与α-突触核蛋白和Tdp-43蛋白病变联合的独立和协同作用；以及3)CAA的影响，使人们对淀粉样蛋白病变的一个非常不同的方面及其对神经血管单位的影响有新的见解。然后，我们将建立300个不同个体的分子数据的参考数据集，以便能够评估与病理和认知结果相关的空间分子特征。在开发这些地图集和参考数据集的同时，我们将优化空间转录和迭代间接免疫荧光成像(4I)的实验方案，以促进大规模项目，并使数据生成能力超过现有的基线能力。我们将通过NIA资助的AD知识门户分发所有协议和数据，该门户已经托管了来自相同队列和参与者的多组数据，以加快数据的再利用。最后，我们将创建MAAP-Brain，一个3-D交互式数据可视化工具，以便所有研究人员，特别是非计算科学家，可以与我们的数据和结果互动。该计划团队汇集了一批高度互补的有才华的初级和高级科学家，它建立在多个交叉的长期合作研究计划的基础上，这些计划使其能够很好地实现其所有交付成果，从而促进我们对导致衰老和AD的复杂临床-空间-分子特征的理解，这将为更广泛的科学界提供所需的资源。