Role of immunosenescence in Alzheimer's disease

摘要

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.