Role of immunosenescence in Alzheimer's disease

免疫衰老在阿尔茨海默病中的作用

• 批准号: 10286343
• 负责人: Laura Jane Niedernhofer
• 金额: $ 36.05万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10286343
• 关键词: Age-Years; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Aorta; Apoptosis; Automobile Driving; Brain; Brain Pathology; CDKN2A gene; Cardiovascular Diseases; Cell Differentiation process; Cells; Cellular Stress; Characteristics; Chronic; Chronic Disease; Chronic Kidney Failure; DNA Damage; DNA Repair Endonuclease; Data; Degenerative polyarthritis; Diabetes Mellitus; Disease; ERCC1 gene; Enzymes; Event; Fatty acid glycerol esters; Functional disorder; Genes; Health Care Costs; Hematopoietic; Holoenzymes; Homeostasis; Immune; Immune system; Immunological Models; Impairment; Intervertebral disc structure; Kidney; Lead; Liver; Lung; Measurement; Memory Loss; Mus; Muscular Atrophy; Mutant Strains Mice; Non-Insulin-Dependent Diabetes Mellitus; Organ; Pathology; Persons; Pharmacology; Phenotype; Plasma; Population; Proteinuria; Proteoglycan; Quality of life; Regenerative capacity; Role; Series; Serum; Signal Transduction; Solid; Structure of beta Cell of islet; Tissues; Transgenic Mice; Wild Type Mouse; age related; aged; burden of illness; cell type; clinically relevant; experimental study; functional loss; immune function; immunosenescence; improved; mouse model; novel; podocyte; premature; promoter; recombinase-mediated cassette exchange; repaired; resilience; senescence; therapeutic target

ABSTRACT The world’s population is rapidly aging. Seventy percent of persons over 65 years of age have two or more chronic diseases1. This includes Alzheimer’s disease (AD) and related dementias, cardiovascular disease, osteoarthritis and diabetes, all of which negatively impact quality of life and resilience. Identifying fundamental cell autonomous and non-autonomous mechanisms driving aging and age-related diseases such as AD and devising strategies to therapeutically target them is imperative to alleviate tremendous disease burden and healthcare costs. It is generally accepted that damaged or stressed cells activate a variety of signaling cascades that regulate cell fate decisions, including senescence and apoptosis. These cell autonomous events can lead to impaired tissue homeostasis via loss of functional, terminally-differentiated cells or via loss of regenerative capacity. For example, senescence increases in different cell types in the brains of mouse models of AD and reduction in this senescent cell burden either genetically or pharmacologically improves pathology. There is also strong evidence for cell non-autonomous mechanisms of aging, including data from experiments implementing heterochronic parabiosis2-7, plasma transfer7 and measurement of the senescence-associated secretory phenotype (SASP) produced by senescent cells8-11. To ask if “aging” of one organ or cell type is sufficient to drive aging in other tissues, we created a series of mice with tissue-specific “aging”. Ercc1, a gene that encodes one subunit of the DNA repair endonuclease ERCC1-XPF, was deleted in 7 organs or cell types using Cre-lox technology. Loss of Ercc1 expression destabilizes the holoenzyme ERCC1-XPF in vivo12. As a consequence, spontaneous, endogenous DNA damage accumulates more rapidly in tissues of mutant mice compared to wild- type (WT) mice able to repair the damage13. For example, deletion of Ercc1 in pancreatic ß cells results in a type II diabetes-like condition with evidence of senescence and SASP in fat and liver whereas deletion in podocytes develop chronic kidney disease. Interestingly, deletion of Ercc1 in the hematopoietic compartment using the Vav (HS21/45) promoter to drive Cre expression14 potently drove senescence and loss of tissue homeostasis in the immune compartment, but also in multiple solid organs including the brain. Vav-Cre+/-;Ercc1-/fl mice have premature senescence of immune cells and many characteristics of immunosenescence typical of aged mice and humans15, including impaired immune function. This was accompanied by increased expression of senescence markers p16Ink4a, p21Cip1 and senescence-associated secretory phenotype (SASP) factors in multiple tissues including brain, liver, kidney, lung, GI and aorta. The “aged” immune system was sufficient to damage and impair function of solid organs as evidenced by increased liver enzymes in the serum, proteinuria, loss of repair of damaged muscle and loss of intervertebral disc proteoglycan. Here we will examine the hypothesis that immune aging contributes to driving senescence, SASP, brain pathology, and loss of memory in the MAPT and APP transgenic mouse models of AD.

抽象的 世界人口正在迅速老龄化。 70% 65 岁以上的人有两个或以上 慢性病1.这包括阿尔茨海默病 (AD) 和相关痴呆症、心血管疾病、 骨关节炎和糖尿病，所有这些都会对生活质量和恢复能力产生负面影响。识别基本面 细胞自主和非自主机制驱动衰老和与年龄相关的疾病，如 AD 和 制定针对它们的治疗策略对于减轻巨大的疾病负担和 医疗费用。人们普遍认为，受损或应激的细胞会激活多种信号级联反应 调节细胞命运决定，包括衰老和细胞凋亡。这些细胞自主事件可以导致 通过功能性、终末分化细胞的丧失或再生能力的丧失，导致组织稳态受损 容量。例如，AD 和 AD 小鼠模型大脑中不同细胞类型的衰老增加 从遗传或药理学角度减少这种衰老细胞负担可以改善病理学。还有 细胞非自主衰老机制的有力证据，包括来自实施的实验的数据 异时性联体共生2-7、血浆转移7和衰老相关分泌的测量 衰老细胞产生的表型（SASP）8-11。询问一种器官或细胞类型的“衰老”是否足以 为了驱动其他组织的衰老，我们创造了一系列具有组织特异性“衰老”的小鼠。 Ercc1，编码基因 使用 Cre-lox 在 7 种器官或细胞类型中删除了 DNA 修复核酸内切酶 ERCC1-XPF 的一个亚基 技术。 Ercc1 表达的缺失会破坏体内全酶 ERCC1-XPF 的稳定性12。结果， 与野生小鼠相比，突变小鼠组织中自发的内源性 DNA 损伤积累得更快 型（WT）小鼠能够修复损伤13。例如，删除胰腺β细胞中的Ercc1会产生一种类型 II 型糖尿病样病症，有脂肪和肝脏衰老和 SASP 的证据，而足细胞缺失 发展为慢性肾脏疾病。有趣的是，使用以下方法删除造血室中的 Ercc1 Vav (HS21/45) 启动子驱动 Cre 表达14，有效驱动衰老和组织稳态丧失 免疫区室，而且还存在于包括大脑在内的多个实体器官中。 Vav-Cre+/-;Ercc1-/fl 小鼠有 免疫细胞的过早衰老以及老年小鼠典型的免疫衰老的许多特征 和人类15，包括免疫功能受损。这伴随着表达增加 衰老标记物 p16Ink4a、p21Cip1 和衰老相关分泌表型 (SASP) 因子 多种组织，包括脑、肝、肾、肺、胃肠道和主动脉。 “老化”的免疫系统足以 实体器官的损伤和功能损害，表现为血清中肝酶增加、蛋白尿、 受损肌肉修复能力丧失和椎间盘蛋白多糖丧失。在这里我们将检查 假设免疫老化会导致衰老、SASP、脑病理学和记忆丧失 AD 的 MAPT 和 APP 转基因小鼠模型。