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

项目摘要/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不能很好地模拟的干预。这 尽管负荷占阿尔茨海默病(AD)的90%以上，但缺乏强有力的模型存在 这些病例构成了疾病负担的主要部分。女性携带者的风险特别高。 ε4载脂蛋白等位基因的突变，这种风险与绝经过渡(MT)有关。猕猴 很好地模拟了负荷的临床前阶段；这一物种概括了淀粉样蛋白和 人类随年龄增长而出现的tau病理，表现为相当于轻度的伴随记忆损害 人类的认知障碍。此外，雌性猕猴接受MT，只有一只 猕猴载脂蛋白亚型，相当于人类的ε4等位基因；因此所有雌性猕猴都处于兴奋状态 有负荷性病理的风险。因此，猕猴为研究临床前大脑提供了一个独特的机会 在大脑结构和功能上与人类非常相似的物种中，衰老和负荷的变化 人类。人们早就知道，在人类的临床前负荷阶段，淀粉样蛋白和tau 病理学显示了特定的起源部位和(尤其是tau)扩散的模式；机制 在这些疾病的空间特征背后，人们还不知道。为了更好地理解 关于灵长类动物大脑老化的神经化学，我们将研究MT前后的雌性猕猴，以及年龄 匹配的男性对照组，提供受试者内代谢物水平的空间图谱(空间代谢组)， 大脑皮层和小脑的蛋白质表达(空间蛋白质组)和现存的病理学。代谢物 蛋白质组将从相同的样本中获得，从而使跨组整合能够理解空间 整个大脑的生化途径活动的模式。组织病理学数据将来自 同一个体的对侧半球。我们将使用空间主成分分析和一种新颖的 多重对应分析的空间适应性以识别单个生物标记物和组合 说明大脑皮质空间位置的生物标记物，并识别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)空间相关联的组合 病理模式。这些关键数据将对早期衰老和关键的 负荷的前驱阶段，提供了识别赋予风险或弹性的生化因素的可能性 在局部大脑回路上。促进韧性的因素是干预的机会，而风险因素保持不变 早期诊断和筛查的可能性；如果我们要了解这两种结果，这两种结果将是至关重要的 并有效地解决这种毁灭性大脑疾病最普遍的形式。

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.