Senescence, NAD+ decrease and Alzheimer's disease and related dementias Alzheimer's disease and related dementias

衰老、NAD 减少与阿尔茨海默病和相关痴呆症 阿尔茨海默病和相关痴呆症

• 批准号: 10187413
• 负责人: Eric M. Verdin
• 金额: $ 58.2万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10187413
• 关键词: 3xTg-AD mouse; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Apolipoprotein E; Astrocytes; Behavioral; Biological Assay; Brain; Cell Aging; Cell Culture Techniques; Cell physiology; Cells; Coculture Techniques; Consumption; Cytometry; DNA Repair; Dementia; Disease Progression; Endothelial Cells; Enzymes; Exhibits; Flow Cytometry; Goals; Human; Human Amyloid Precursor Protein; Hydrolase; Immune; In Vitro; Inflammatory; Interleukin-1; Interleukin-10; Knockout Mice; Lead; Learning; Link; LoxP-flanked allele; Measures; Metabolic; Metabolic dysfunction; Metabolism; Microglia; Modeling; Mus; NADH; Neurons; Normal Cell; Pathway interactions; Patients; Phenotype; Play; Population; Proteins; Proteomics; Publishing; Reporter; Research Design; Role; Sampling; Sirtuins; TNF gene; Testing; Time; Tissue Sample; Tissues; Transgenic Mice; Wild Type Mouse; age related; brain cell; brain tissue; cell type; cofactor; cognitive function; cytokine; extracellular; improved; in vivo; induced pluripotent stem cell; knock-down; macrophage; metabolome; metabolomics; mouse model; mutant; novel; novel therapeutics; overexpression; phenotypic biomarker; presenilin-1; presenilin-2; protein expression; relating to nervous system; restoration; senescence; single cell sequencing; transcriptomics

PROJECT SUMMARY Aging and Alzheimer's disease (AD) and related dementia are accompanied by striking changes in systemic and cellular metabolism. Several recently published results support the model that changes in NAD metabolism plays a role in AD and that restoration of NAD levels via NAD boosters protect against disease progression. The enzyme CD38 consumes NAD, increases during aging and mice lacking CD38 are protected from age-related NAD decline. CD38 levels increase in the brain during disease progression in a double transgenic mouse model of AD (APP and presenilin-1). Remarkably, deleting CD38 in the APP.PS AD mouse model decreased amyloid- ß plaques and improved spatial learning, compared to wild-type mice. Our own new observations indicate that supernatants from senescent cells (SASP) activate CD38 expression in macrophages. These findings suggest a direct and causal link between senescence, the SASP and aging-associated decreases in cognitive function during AD via changes in NAD levels. Our working hypothesis is that senescent cells in the brain induce NAD decrease by inducing the expression of CD38 via their senescence-associated secretory phenotype (SASP). We propose: Aim 1. To determine the NAD metabolome of neurons, astrocytes, and microglia in mouse models of AD, in senescent cell cultures and in AD patient tissue samples. Using flow cytometry, single-cell transcriptomics (with Core D), proteomic/metabolomics analysis (with Core C), and IHC/IF immunostaining, we will measure NAD levels and protein expression levels of metabolic enzymes that regulate NAD metabolism in neurons, astrocytes, and microglia after induction of senescence in culture and in mouse models of AD and AD patient brain tissues. Aim 2: To determine the effect of cellular senescence and SASPs on NAD metabolism, proliferation, using co-cultured microglia, astrocytes and neurons. With Core B and Projects 1 and 3, we will use single- cell transcriptomics (Core D) and proteomic/metabolomics (Core C) analysis to determine the effect of extracellular SASP factors on neuron, astrocyte, and microglia NAD levels, expression of NAD hydrolases and NAD biosynthetic pathways, proliferation, and other phenotypical markers. Aim 3: To determine the effect of whole body and tissue-specific knockdown of the NAD hydrolase CD38 in neurons, astrocytes, and microglia in AD disease progression in mice. We will use a newly developed tissue-specific CD38 knockout mouse line to test the role of CD38 in each main cell type of the brain in AD mouse model backgrounds.

项目摘要 衰老和阿尔茨海默氏病（AD）和相关痴呆症伴随着全身性和 细胞代谢。最近发表的几个结果支持了变化NAD代谢游戏的模型 在AD中的作用以及通过NAD助推器恢复NAD水平的作用，可以防止疾病进展。这 酶CD38消耗NAD，在衰老期间增加，而缺乏CD38的小鼠免受与年龄有关的保护 NAD下降。双转基因小鼠模型中疾病进展过程中大脑的CD38水平增加 AD（App和Presenilin-1）的广告。值得注意的是，在App.ps AD小鼠模型中删除CD38降低了淀粉样蛋白 与野生型小鼠相比，β斑块和改进的空间学习。我们自己的新观察表明 来自感觉细胞（SASP）的上清液激活巨噬细胞中的CD38表达。这些发现表明 感应，SASP和与衰老相关的认知功能下降之间的直接和因果关系 在AD期间通过NAD级别的变化。我们的工作假设是，大脑中的感觉细胞会诱导NAD 通过通过其感应相关的秘书表型（SASP）诱导CD38的表达来减少。我们 提议： 目标1。确定AD小鼠模型中神经元，星形胶质细胞和小胶质细胞的NAD代谢组， 在感觉细胞培养物和AD患者组织样品中。使用流式细胞仪，单细胞转录组学 （使用核心D），蛋白质组学/代谢组学分析（使用核心C），IHC/如果免疫染色，我们将测量 调节神经元中NAD代谢的代谢酶的NAD水平和蛋白质表达水平， 培养和AD和AD患者小鼠模型中诱导培养物和小鼠模型中诱导感应后的星形胶质细胞和小胶质细胞 脑组织。 目标2：确定细胞感应和SASP对NAD代谢，增殖的影响， 使用共培养的小胶质细胞，星形胶质细胞和神经元。使用核心B和项目1和3，我们将使用单一 细胞转录组学（核心D）和蛋白质组学/代谢组学（核心C）分析，以确定 神经元，星形胶质细胞和小胶质细胞水平的细胞外SASP因子，NAD水解酶和 NAD生物合成途径，增殖和其他表型标记。 目标3：确定NAD水解酶CD38的全身和组织特异性敲低的影响 在小鼠AD疾病进展的神经元，星形胶质细胞和小胶质细胞中。我们将使用新开发的 组织特异性的CD38基因敲除小鼠系，以测试CD38在AD中每种主要细胞类型中的作用 鼠标模型背景。