Role of immunosenescence in Alzheimer's disease

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 慢性病1。这包括阿尔茨海默病(AD)和相关的痴呆症、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。确定基本原则 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 制定针对他们的治疗策略是缓解巨大疾病负担和 医疗保健成本。人们普遍认为，受损或应激的细胞会激活各种信号级联反应。 调节细胞命运的决定，包括衰老和凋亡。这些细胞自主事件可以导致 通过丧失功能的终末分化细胞或通过失去再生能力而损害组织内稳态 容量。例如，AD和AD模型小鼠大脑中不同类型细胞的衰老增加 减少这种衰老的细胞负担，无论是从遗传上还是从药物上都可以改善病理学。还有就是 细胞衰老的非自主机制的有力证据，包括来自实施 异慢性寄生虫2-7、血浆转移7和衰老相关分泌的测定 衰老细胞产生的表型(SASP)8-11。问一个器官或细胞类型的“老化”是否足以 为了在其他组织中驱动衰老，我们创造了一系列具有组织特异性“衰老”的小鼠。ERCC1，一种编码 使用Cre-lox在7个器官或细胞类型中缺失了DNA修复内切酶ERCC1-XPF的一个亚基 技术ERCC1表达缺失会破坏活体12中全酶ERCC1-XPF的稳定性。因此， 自发的内源性DNA损伤在突变小鼠的组织中积累得比野生小鼠更快. 能够修复损伤的(WT)型小鼠13。例如，胰腺细胞中ERCC1的缺失会导致一种类型 II糖尿病样状态，脂肪和肝脏中有衰老和SASP的证据，而足细胞中有缺失 患上慢性肾脏疾病。有趣的是，ERCC1在造血室中的缺失 Vav(HS21/45)启动子驱动Cre表达14有效地促进衰老和组织动态平衡的丧失 免疫隔间，但也在包括大脑在内的多个固体器官中。Vav-Cre/-；ERCC1-/f1小鼠 免疫细胞早衰与老年小鼠免疫衰老的许多特征 和人类，包括免疫功能受损。伴随而来的是基因表达的增加 衰老标志物p16INK4a、p21Cip1与衰老相关分泌表型因子 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 实质器官的损害和功能受损，表现为血清中肝酶升高，蛋白尿， 丧失受损肌肉的修复能力和椎间盘蛋白多糖的丧失。在这里，我们将研究 免疫老化导致衰老、SASP、脑病理和记忆丧失的假说 MAPT和APP转基因AD小鼠模型的建立。

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.