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.

摘要 世界人口正在迅速老龄化。70%的65岁以上的人有两个或两个以上的 慢性疾病1.这包括阿尔茨海默病（AD）和相关痴呆、心血管疾病、 骨关节炎和糖尿病，所有这些都对生活质量和恢复力产生负面影响。确定基本 细胞自主和非自主机制驱动衰老和年龄相关疾病，如AD和 制定针对这些疾病的治疗策略对于减轻巨大的疾病负担至关重要， 医疗费用。人们普遍认为，受损或应激细胞激活多种信号级联反应 调节细胞命运的决定，包括衰老和凋亡。这些细胞自主活动可以导致 通过功能性终末分化细胞的丧失或通过再生性细胞的丧失， 容量例如，在AD小鼠模型的脑中不同细胞类型的衰老增加， 这种衰老细胞负荷的减少在遗传上或遗传学上改善了病理学。还有 细胞非自主衰老机制的有力证据，包括实验数据， 异时性副作用2 -7、血浆转移7和衰老相关分泌的测量 表型（SASP）由衰老细胞产生8 -11。问一个器官或细胞类型的“老化”是否足以 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。Ercc 1是一种编码 DNA修复内切酶ERCC 1-XPF的一个亚基在7种器官或细胞类型中被Cre-lox缺失 技术. Ercc 1表达的丧失使体内全酶ERCC 1-XPF不稳定12。因此，在这方面， 与野生型小鼠相比，自发的内源性DNA损伤在突变型小鼠的组织中积累得更快， 型（WT）小鼠能够修复损伤13.例如，在胰腺癌细胞中Ercc 1的缺失导致一种类型的 II糖尿病样疾病，脂肪和肝脏中有衰老和SASP的证据，而足细胞中有缺失 患上慢性肾病。有趣的是，使用免疫组织化学方法在造血区室中缺失Ercc 1， Vav（HS 21/45）启动子驱动Cre表达14，有效地驱动衰老和组织稳态的丧失。 免疫区室，但也在多个实体器官，包括大脑。Vav-Cre+/-; Ercc 1-/fl小鼠具有 免疫细胞的过早衰老和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。这伴随着表达的增加， 衰老标记物p16 Ink 4a、p21 Cip 1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 如血清中肝酶增加，蛋白尿， 受损肌肉的修复丧失和椎间盘蛋白聚糖的丧失。在这里，我们将检查 假设免疫老化有助于驱动衰老，SASP，脑病理学和记忆丧失， AD的MAPT和APP转基因小鼠模型。