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 世界的人口正在迅速衰老。 65岁以上的人中有70％有两个或更多 慢性疾病1。这包括阿尔茨海默氏病（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韧性产生负面影响。确定基本 细胞自主和非自主机制驱动衰老和与年龄有关的疾病，例如AD和 制定策略以热为目标是减轻伯恩和 医疗保健费用。普遍认为，受损或压力的细胞激活各种信号级联 调节细胞脂肪的决策，包括感应和凋亡。这些细胞自主事件可以领导 通过丧失功能性，终末分化的细胞或通过再生而损害组织稳态的组织体内稳态。 容量。例如，在AD和 这种感觉细胞负担一般或药物的减少可改善病理。也有 有力证据证明细胞非自主衰老机制，包括实施实验的数据 杂化核副作用2-7，等离子体转移7和与感应相关分泌的测量 Senscent细胞产生的表型（SASP）8-11。询问一种器官或细胞类型的“老化”是否足以 在其他时候，我们创建了一系列具有组织特异性“衰老”的小鼠。 ERCC1，一种编码的基因 使用CRE-LOX在7个器官或细胞类型中删除DNA修复核酸内切酶ERCC1-XPF的一个亚基 技术。 ERCC1表达的损失破坏了vivo12中的Holeenzyme ERCC1-XPF。结果， 与野生小鼠的组织相比 类型（wt）小鼠可以修复损伤13。例如，胰腺ß细胞中ERCC1的删除导致一种类型 II类糖尿病状态，具有脂肪和肝脏中的感受和SASP的证据，而足细胞缺失 发展慢性肾脏疾病。有趣的是，使用造血室中ERCC1的删除 VAV（HS21/45）启动子以驱动CRE表达14可能会引起组织稳态的感受和损失 免疫区室，但在包括大脑在内的多个固体器官中。 VAV-CRE +/-; ERCC1-/FL小鼠具有 免疫细胞的过早感应和典型的年龄小鼠免疫衰老的许多特征 和人类15，包括免疫功能受损。这是通过增加表达来实现的 传感标记物P16INK4A，P21CIP1和相关的秘书表型（SASP）因子 多次包括大脑，肝脏，肾脏，肺，GI和主动脉。 “老化”免疫系统足以 固体器官的损害和损害功能，这是血清中肝酶增加的蛋白尿中升高的损害和损害功能 肌肉受损的修复损失和椎间盘蛋白聚糖的丧失。在这里，我们将检查 免疫衰老有助于驱动感受，SASP，脑病理学和记忆力丧失的假设 AD的MAPT和APP转基因小鼠模型。