Cellular senescence is a general stress response that is triggered by many stimuli, including telomere dysfunction, DNA damage, oxidative stress, aberrant oncogenic signaling and chronic inflammation. Senescent cells cease proliferation, undergo metabolic and transcriptional changes and secrete various pro-inflammatory molecules, collectively known as senescence-associated secretory phenotype (SASP). SASP mediates many of the pathophysiological effects of senescence with advancing age in many tissues. Recent data in the brain suggest that glial cells become senescent during neurodegeneration. This includes microglia, a resident CNS macrophage. Importantly, ablating all senescent glial cells, including microglia, astrocytes, and oligodendrocyte progenitor cells, is neuroprotective in mouse models of Alzheimer?s disease (AD)-related and tau-dependent neurodegeneration. However, it is unknown how senescence impacts microglial function and how senescent microglia then contribute to the disease process. A common feature among neurodegenerative diseases are reactive, pro-inflammatory microglia with dysfunctional phagocytic function, we will now test the hypothesis that senescence inhibits normal microglial phagocytic function and promotes a pro-inflammatory cell type, which accelerates AD-relevant neurodegeneration. We will test this hypothesis using a senescence regulator Smurf2 as a genetic tool. Using cell culture or mice with conditional overexpression of Smurf2, we have the unique capability to induce senescence specifically in microglia with high temporal resolution in vitro and in vivo. We also can express a ligase-dead Smurf2 as an elegant control for protein overexpression. Using these tools, we will investigate whether senescence in microglia affects their ability to phagocyte synapses and amyloid A? in Aim 1.
In Aim 2, we will assess how senescence affects microglial homeostasis and transition into a reactive, pro-inflammatory state.
In Aim 3, we will determine the impact of senescent microglia on neurodegenerative phenotypes in the APP/PS1 model of AD-relevant neurodegeneration and identify whether senolytic treatment to ablate senescent cells can attenuate or reverse neurodegeneration.
These aims are supported by our strong preliminary data that we can overexpress Smurf2 and induce senescence in microglia in vitro and in vivo . Further, in vitro senescent microglia exhibit reduced phagocytosis of cellular debris, reminiscent of what is observed in AD and engulfment of A?. Leveraging our unique genetic tool kit and our combined expertise in microglial biology (Schafer) and senescence mechanisms (Zhang), we are in a strong position to gain fundamental insight into how cellular senescence affects microglial function and, in turn, the neurodegenerative process. Long-term, we aim to identify novel, senescence-based therapeutic targets for AD and other related diseases where aging is a major risk factor.
Aging is the major risk factor for Alzheimer?s disease (AD) and ~50% of AD risk genes are expressed by microglia, resident immune cells of the central nervous system (CNS). This project will investigate how cellular senescence, which increases with age, affects microglia function and transition to an inflammatory cell type to affect neuroinflammation and neurodegeneration relevant to AD. The success of this project will uncover new mechanisms by which the aging brain influences AD pathogenesis and will likely uncover novel microglia-based mechanisms for therapeutic intervention.
