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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos 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

项目摘要

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.

项目概要衰老和阿尔茨海默病 (AD) 以及相关的痴呆症伴随着全身和神经系统的显着变化。最近发表的几项结果支持 NAD 代谢变化所起的作用的模型。在 AD 中发挥作用，并且通过 NAD 增强剂恢复 NAD 水平可防止疾病进展。 CD38 酶会消耗 NAD，并在衰老过程中增加，缺乏 CD38 的小鼠可以免受年龄相关的影响在双转基因小鼠模型中，疾病进展期间大脑中 NAD 水平下降。值得注意的是，删除 APP.PS AD 小鼠模型中的 CD38 会减少淀粉样蛋白。与野生型小鼠相比，β 斑块和空间学习能力得到改善。这些发现表明，衰老细胞 (SASP) 的上清液可激活巨噬细胞中的 CD38 表达。衰老、SASP 和与衰老相关的认知功能下降之间存在直接的因果关系 AD 期间，NAD 水平发生变化，我们的假设是大脑中的衰老细胞会诱发 NAD。通过其衰老相关的分泌表型（SASP）诱导 CD38 的表达来减少。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，使用流式细胞术、单细胞转录组学在衰老细胞培养物和 AD 患者组织样本中进行检测。（使用 Core D）、蛋白质组学/代谢组学分析（使用 Core C）和 IHC/IF 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， AD 和 AD 患者的培养物和小鼠模型中诱导衰老后的星形胶质细胞和小胶质细胞脑组织。目标 2：确定细胞衰老和 SASP 对 NAD 代谢、增殖、使用共培养的小胶质细胞、星形胶质细胞和神经元，对于核心 B 和项目 1 和 3，我们将使用单细胞。细胞转录组学（核心 D）和蛋白质组学/代谢组学（核心 C）分析以确定细胞外 SASP 因子对神经元、星形胶质细胞和小胶质细胞 NAD 水平、NAD 水解酶表达和 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效果我们将使用一种新开发的药物来治疗小鼠 AD 疾病进展中的神经元、星形胶质细胞和小胶质细胞。组织特异性 CD38 敲除小鼠系，用于测试 CD38 在 AD 大脑每种主要细胞类型中的作用鼠标模型背景。