YAP Upregulation to Reduce Astrocyte Senescence in the Aging Brain
In recent years, researchers have noted that YAP upregulation suppresses cellular senescence in a number of different cell populations. While YAP upregulation appears to have other effects, for example on cell adhesion, relevant to cancer development, the fact that it suppresses cellular senescence means that it will likely show benefits in many different age-related conditions. That doesn't mean it is any better a choice than established senolytics that clear senescent cells, of course.
Emerging evidence has shown that senescent astrocytes are involved in initiating and promoting the progression of Alzheimer's disease (AD). Senescent astrocytes exhibit expression of senescence-associated secretory phenotype (SASP). It has been reported that the number of senescent astrocytes in the frontal cortex of AD patients is significantly higher than that of non-AD adults with similar ages. Accumulation of senescent astrocytes leads to massive secretion of SASP factors, reduces amyloid-β clearance, promotes aggregation of insoluble tau. Elimination of these senescent glial cells, including astrocytes, prevents the hyperphosphorylation of tau protein, neurofibrillary tangles, and cognitive hypofunction.
Yes-associated protein (YAP), as a co-activator and multi-functional protein, is a critical effector of the Hippo pathway, and has been shown to inhibit the senescence of various types of cells. Recently, we have found that YAP is down-regulated and inactivated in senescent astrocytes, not only in cultured senescent astrocytes, but also in hippocampal astrocytes of the aging mice and AD model mice, in a Hippo pathway-dependent manner, indicating a role of YAP in astrocytic senescence.
Cyclin-dependent kinase 6 (CDK6), as a downstream molecule of YAP, is decreased in YAP knockout astrocytes in vivo and in vitro, and over-expression of CDK6 partially rejuvenates YAP knockout astrocytes, indicating that YAP inhibits astrocytic senescence through the CDK6 signaling. Moreover, activation of YAP improves the cognitive decline of AD model mice. This evidence exhibits the positive potential of the YAP-CDK6 pathway in restraining astrocytic senescence in AD.