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

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。 这是一种在衰老研究中常用的转基因动物模型中没有很好建模的干预。这 缺乏强有力的模型存在，尽管事实上，负荷占远远超过90%的阿尔茨海默病（AD） 病例，因此占疾病负担的大部分。女性携带者的风险尤其高 ε4载脂蛋白等位基因，这一风险与绝经过渡期（MT）有关。猕猴 很好地模拟了LoAD的临床前阶段;该种属重现了淀粉样蛋白的积累模式， tau病理学在人类衰老中观察到，并显示伴随的记忆障碍相当于轻度 人类的认知障碍此外，雌性猕猴接受MT，只有一个 猕猴载脂蛋白同种型，相当于人类ε4等位基因;因此，所有雌性猕猴都处于高水平 负载样病理风险。因此，猕猴为研究临床前脑提供了一个独特的机会 衰老和负荷的变化，在一个大脑结构和功能非常相似的物种， 人类长期以来，人们已经知道，在人类中，在LoAD的临床前阶段，淀粉样蛋白和tau蛋白表达增加。 病理学显示了起源的特征位点和（特别是tau）传播模式; 疾病的这些空间特征的背后尚不清楚。为了理解空间 神经化学的老化灵长类动物的大脑，我们将研究MT后和MT后的雌性猕猴，和年龄- 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）和皮质和小脑的现存病理学。代谢组 和蛋白质组将从相同的样品中获得，允许跨组整合，以了解空间 大脑中生化途径活动的模式。组织病理学数据将来自 同一个人的另一个半球我们将使用空间主成分分析和一个新的 多个对应分析的空间适应性以鉴定个体生物标志物和 生物标记物，其说明皮质中的空间位置，并且鉴定生物标记物和生物标记物 与观察到的（在个体中）和预测的（从文献中）空间 病理模式。这些重要的数据将产生前所未有的洞察力，对早期衰老和关键的 负荷的前驱期，提供了识别赋予风险或恢复力的生化因素的可能性 局部脑回路促进复原力的因素是进行干预的机会，而风险因素则是 早期诊断和筛查的可能性;如果我们要了解这些结果， 并有效地解决这种破坏性脑部疾病的最常见形式。

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.