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.

该建议是为了创建3D衰老和阿尔茨海默氏症脑计划，它解决了正在进行的努力，以弥合已知的阿尔茨海默氏病（AD）危险因素（AD）与疾病综合表现的差异。显着差距是：i）与衰老相关的认知下降的神经生物学如何可以为增强弹性提供见解； ii）了解AD敏感性的分子机制局部和AD靶基因的多样化以及这些基因如何引起细胞作用； iii）当使用当前的皮质组织上的测序方法来实施导致疾病的细胞亚型时，关键的拓扑和形态计量学信息。为了解决这些差距，我们提出了一项全面的计划，以系统地生成和分析包括不同的个人在内的多个相互联系的参考数据集，以（a）为特征，特征是蛋白质病的个体和协同效应，蛋白质病，脑淀粉样蛋白血管病（CAA）以及对这些较低的neecular nelecular nelecorture nelecortute ne neecortexext（be）（CAA）的质量和细胞（均具有）（be）的neexexex和neexexexexext（B）（B）。 AD的临床有意义的结果。为此，我们的程序针对三个大脑区域，以捕获一系列不同神经病理学的影响。我们将建立三个大体积分子图谱：1）通过对神经病理学最少的个体的整个寿命进行采样，以研究大脑中衰老自身的影响； 2）淀粉样蛋白和tau蛋白质病的影响，包括特定的代表性病例，以捕获单独的β-淀粉样蛋白和tau的独立和协同作用，并与α-突触核蛋白和TDP-43蛋白质病结合使用； 3）CAA对淀粉样蛋白病的一个非常不同方面的新见解及其对神经血管单元的影响。然后，我们将在300名潜水员个体中建立一个分子数据的参考数据集，以便评估与病理和认知结果有关的空间分子特征。与这些地图酶和参考数据集的开发并行，我们将优化用于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，并促进现有的基线功能增强数据生成。我们将通过NIA资助的AD知识门户进行分发所有协议和数据，该门户已经托管了来自同一同类群体和参与者的多域数据，以加速数据的重新利用。最后，我们将创建一个3D交互式数据可视化器Maap-Brain，以便所有研究人员，尤其是非计算科学家都可以与我们的数据和结果进行互动。该计划团队汇集了高度完整的才华横溢的初级和高级科学家，它基于多个相交的长期协作研究计划的基础，这些计划将其定位得很好，以实现其所有可交付成果，以促进我们对复杂的临床空间分子特征的理解，这些特征有助于老化和AD，这将为更广阔的科学社区提供所需的资源。