A spatially resolved joint cortical metabolome and proteome in aging and menopause for the rhesus macaque

恒河猴衰老和更年期的空间分辨联合皮质代谢组和蛋白质组

基本信息

批准号：
10701771
负责人：
Anita A Disney
金额：
$ 78.92万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10701771
关键词：
Address Affect Age Aging Aldehydes Alleles Alzheimer like pathology Alzheimer&apos s Disease Alzheimer&apos s disease pathology Amyloid Amyloid beta-Protein Animal Model Animals Apolipoproteins Area Arginine Atlases Biochemical Biochemical Pathway Bioinformatics Biological Biological Markers Blood - brain barrier anatomy Brain Brain Diseases Brain Mapping Brain region Cerebellum Characteristics Code Complex Data Diagnosis Dimensions Disease Disease Progression Early Diagnosis Female Freezing Functional Magnetic Resonance Imaging Genes Genome Histologic Histology Human Individual Inflammatory Intervention Joints Late Onset Alzheimer Disease Link Liquid Chromatography Literature Location Macaca Macaca mulatta Maps Measures Memory impairment Menopause Methionine Methods Modeling Monkeys Organ Outcome Pathologic Pathology Pathway Analysis Pathway interactions Pattern Perimenopause Phase Positioning Attribute Postmenopause Pre-Clinical Model Primates Principal Component Analysis Process Protein Isoforms Proteins Proteome Proteomics Publishing Purines Randomized Research Resolution Risk Risk Factors Sampling Site Statistical Methods Synapses Testing Time Transgenic Animals Transgenic Model Visual Cortex Visualization age related aged aging brain amyloid pathology analytical tool biomarker identification burden of illness dimensional analysis early screening frontal lobe high risk human model innovation insight male mass spectrometric imaging metabolome metabolomics mild cognitive impairment multidimensional data neurochemistry neuropathology normal aging novel novel strategies pre-clinical preclinical study promote resilience protein expression protein metabolism resilience small molecule tandem mass spectrometry tau Proteins tau aggregation tau-1 tool

项目摘要

PROJECT SUMMARY / ABSTRACT The preclinical phase of late-onset Alzheimer’s disease (LoAD) is a crucial time period for diagnosis and intervention that is not well-modeled by the transgenic animal models commonly used in aging research. This lack of strong models exists despite the fact that LoAD accounts for well over 90% of Alzheimer’s disease (AD) cases and thus represents the bulk of the disease burden. At particularly high risk for LoAD are female carriers of the ε4 apolipoprotein allele, a risk that has been linked to the menopause transition (MT). Macaque monkeys well-model the preclinical phase of LoAD; this species recapitulates patterns of accumulation of amyloid and tau pathology seen with aging in humans, and shows accompanying memory impairment equivalent to mild cognitive impairment in humans. Furthermore, female macaques undergo the MT, and there is only one macaque apolipoprotein isoform, equivalent to the human ε4 allele; all female macaques are therefore at high risk for LoAD-like pathology. The macaque monkey thus offers a unique opportunity to study preclinical brain changes in aging and LoAD, in a species with a brain that is structurally and functionally very similar to that of humans. It has long been known that in humans during the preclinical phase of LoAD, amyloid and tau pathology show characteristic sites of origin and (particularly for tau) patterns of spread; the mechanisms behind these spatial features of the disease are not yet known. In order to understand the spatial neurochemistry of the aging primate brain, we will study peri- and post-MT female macaques, and age- matched male controls, delivering within-subject spatial atlases of metabolite levels (spatial metabolome), protein expression (spatial proteome), and extant pathology for the cortex and cerebellum. The metabolome and proteome will be obtained from the same samples, allowing trans-omic integration to understand spatial patterns of biochemical pathway activity across the brain. The histopathological data will come from the opposite hemisphere of the same individual. We will use spatial principal components analysis and a novel spatial adaptation of multiple correspondence analysis to identify individual biomarkers and combinations of biomarkers that account for spatial position in the cortex, and to identify biomarkers and biomarker combinations that are associated with observed (in an individual) and predicted (from the literature) spatial patterns of pathology. These crucial data will yield unprecedented insights into early aging and the critical prodromal phase of LoAD, offering possibility of identifying biochemical factors that confer risk or resilience upon local brain circuits. Factors promoting resilience are opportunities for intervention, while risk factors hold the possibility for early diagnosis and screening; both of these outcomes will be crucial if we are to understand and effectively address the most prevalent form of this devastating brain disease.

项目概要/摘要晚发性阿尔茨海默病（LoAD）的临床前阶段是诊断和治疗的关键时期。衰老研究中常用的转基因动物模型无法很好地模拟干预措施。尽管 LoAD 占阿尔茨海默病 (AD) 的 90% 以上，但仍缺乏强大的模型女性携带者是 LoAD 的高危人群。 ε4 载脂蛋白等位基因，这种风险与猕猴的更年期过渡 (MT) 有关。很好地模拟了 LoAD 的临床前阶段；该物种概括了淀粉样蛋白的积累模式 tau 蛋白病理学随人类衰老而出现，并显示伴随的记忆障碍相当于轻度此外，雌性猕猴会经历 MT，而且只有一种。猕猴载脂蛋白亚型，相当于人类 ε4 等位基因，因此所有雌性猕猴都处于高水平；因此，猕猴为研究临床前大脑提供了独特的机会。大脑在结构和功能上与人类非常相似的物种在衰老和负载负荷方面的变化人们早就知道，在 LoAD 的临床前阶段，淀粉样蛋白和 tau 蛋白在人类中存在。病理学显示特征性起源位点和（特别是 tau）传播模式；这些疾病背后的空间特征尚不清楚，以便了解。衰老灵长类大脑的神经化学，我们将研究 MT 前后的雌性猕猴，以及年龄匹配的男性对照，提供受试者内代谢物水平的空间图谱（空间代谢组），蛋白质表达（空间蛋白质组）以及皮质和小脑的现有病理学代谢组。蛋白质组将从相同的样本中获得，从而允许跨组学整合来理解空间整个大脑的生化通路活动模式。组织病理学数据将来自我们将使用空间主成分分析和新颖的方法。多重对应分析的空间适应，以识别单个生物标志物和组合解释皮层空间位置的生物标记，并识别生物标记和生物标记与观察到的（在个体中）和预测的（来自文献）空间相关的组合这些重要的数据将对早期衰老和关键的病理模式产生前所未有的见解。 LoAD 的前驱阶段，提供识别赋予风险或恢复力的生化因素的可能性促进复原力的因素是干预的机会，而风险因素则存在。如果我们要了解，早期诊断和筛查的可能性至关重要；并有效解决这种破坏性脑部疾病的最普遍形式。