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.

该提案旨在创建 3D 衰老和阿尔茨海默病大脑计划，旨在弥合阿尔茨海默氏病 (AD) 已知危险因素与该疾病的症状表现之间的分歧，并在持续努力中解决几个关键差距。显着的差距在于：i）与衰老相关的认知能力下降的神经生物学如何为增强复原力提供见解； ii) 了解AD易感位点的分子机制和AD靶基因的多样性以及这些基因如何引起细胞效应； iii) 使用当前皮质组织测序方法来暗示导致疾病的细胞亚型时的关键拓扑和形态测量信息。为了解决这些差距，我们提出了一个综合计划，系统地生成和分析多个相互关联的参考数据集，其中包括不同的个体，以（a）表征AD蛋白病、脑淀粉样血管病（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）识别导致认知能力下降的那些方面， 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来捕获一系列不同神经病理学的影响。我们将建立三个大容量分子图谱：1）通过对神经病理学负担最小的个体的整个生命周期进行采样来研究衰老本身对大脑的影响，从而研究衰老的大脑； 2) 淀粉样蛋白和 tau 蛋白病的影响，包括具体的代表性病例，以捕获 β-淀粉样蛋白和 tau 单独以及与 α-突触核蛋白和 TDP-43 蛋白病组合的独立和协同作用； 3) CAA 的影响对淀粉样蛋白病的一个非常不同的方面及其对神经血管单位的影响产生了新的见解。然后，我们将建立 300 名不同个体的分子数据参考数据集，以评估与病理和认知结果相关的空间分子特征。在开发这些图集和参考数据集的同时，我们将优化空间转录组学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在现有基线能力的基础上增强数据生成。我们将通过 NIA 资助的 AD 知识门户分发所有协议和数据，该门户已经托管来自相同队列和参与者的多组学数据，以加速数据的重新利用。最后，我们将创建 MAAP-Brain，一个 3D 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，都可以与我们的数据和结果进行交互。该项目团队汇集了一批具有高度互补性的才华横溢的初级和高级科学家，它建立在多个交叉的长期合作研究项目的基础上，这些项目使其能够很好地实现所有可交付成果，以增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。