YAP prevents premature senescence of astrocytes and cognitive decline of Alzheimer's disease through regulating CDK6 signaling

Abstract

Senescent astrocytes accumulate with aging and contribute to brain dysfunction and diseases such as Alzheimer's disease (AD), however, the mechanisms underlying the senescence of astrocytes during aging remain unclear. In the present study, we found that Yes‐associated Protein (YAP) was downregulated and inactivated in hippocampal astrocytes of aging mice and AD model mice, as well as in D‐galactose and paraquat‐induced senescent astrocytes, in a Hippo pathway‐dependent manner. Conditional knockout of YAP in astrocytes significantly promoted premature senescence of astrocytes, including reduction of cell proliferation, hypertrophic morphology, increase in senescence‐associated β‐galactosidase activity, and upregulation of several senescence‐associated genes such as p16, p53 and NF‐κB, and downregulation of Lamin B1. Further exploration of the underlying mechanism revealed that the expression of cyclin‐dependent kinase 6 (CDK6) was decreased in YAP knockout astrocytes in vivo and in vitro, and ectopic overexpression of CDK6 partially rescued YAP knockout‐induced senescence of astrocytes. Finally, activation of YAP signaling by XMU‐MP‐1 (an inhibitor of Hippo kinase MST1/2) partially rescued the senescence of astrocytes and improved the cognitive function of AD model mice and aging mice. Taken together, our studies identified unrecognized functions of YAP‐CDK6 pathway in preventing astrocytic senescence in vitro and in vivo, which may provide further insights and new targets for delaying brain aging and aging‐related neurodegenerative diseases such as AD.

YAP: a novel target for Alzheimer's disease

“…Selectively knockout YAP in astrocytes promotes premature senescence of astrocytes, which further confirmed the senescence-inhibiting effects of YAP in astrocytes [ 6 ]. Cyclin-dependent kinase 6 (CDK6), as a downstream molecule of YAP, is decreased in YAP -/- astrocytes in vivo and in vitro , and over-expression of CDK6 partially rejuvenates YAP -/- astrocytes, indicating that YAP inhibits astrocytic senescence through the CDK6 signaling [ 6 ]. Moreover, activation of YAP by XMU-MP-1 (an inhibitor of Hippo kinase MST1/2) improves the cognitive decline of AD model mice [ 6 ].…”

“…YAP is down-regulated in D-galactose-induced senescent glioblastoma cells, and over-expression of YAP partially reverses the senescence of glioblastoma cells, indicating a role of YAP in cellular senescence [ 5 ]. 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 [ 6 ]. Selectively knockout YAP in astrocytes promotes premature senescence of astrocytes, which further confirmed the senescence-inhibiting effects of YAP in astrocytes [ 6 ].…”

“…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 [ 6 ]. Selectively knockout YAP in astrocytes promotes premature senescence of astrocytes, which further confirmed the senescence-inhibiting effects of YAP in astrocytes [ 6 ]. Cyclin-dependent kinase 6 (CDK6), as a downstream molecule of YAP, is decreased in YAP -/- astrocytes in vivo and in vitro , and over-expression of CDK6 partially rejuvenates YAP -/- astrocytes, indicating that YAP inhibits astrocytic senescence through the CDK6 signaling [ 6 ].…”

Hyperglycemia Promotes Endothelial Cell Senescence through AQR/PLAU Signaling Axis

“…YAP upregulates the expression of PLAU [ 39 ], and YAP promotes senescence in both endothelial cells and smooth muscle cells [ 40 ], suggesting that PLAU may serve as a downstream molecule, contributing to YAP-induced vascular cell senescence. However, in another study on glioma cells, glioblastoma cells, and astrocytes, it was shown that YAP prevents senescence induced by several factors [ 41 , 42 ], and in cancer cells, PLAU accelerates proliferation [ 39 , 43 , 44 , 45 ]. These indicate that the involvement of PLAU in cellular senescence is conditional and likely cell-type dependent.…”

The Multifaceted Neurotoxicity of Astrocytes in Ageing and Age-Related Neurodegenerative Diseases: A Translational Perspective

“…It prevented gliosis, decreased NFTs deposition and degeneration of neurons, and helped to preserve cognitive functions. Xu et al (2021) reported downregulation of the Yes-associated protein (YAP) paralleled with a decrease of lamin B1 in hippocampal astrocytes during normal ageing and in APP/PS1 mice. The downregulation of YAP was also shown in D-galactose and paraquat-induced senescent astrocytes.…”