Target Senescence Mechanisms to Restore Brain Lymphatic Drainage in Preclinical Models of Alzheimer’s Disease

Aging is the most significant risk factor for AD. As cells age, they degrade and become senescent, often requiring them to either repair themselves to an extent or be removed and replaced to prevent harm to nearby cells. However, the processes responsible for the removal of degraded cells also becomes impaired with aging, leading to the accumulation of dysfunctional senescent cells, as they are called. These senescent cells have been linked to AD and other diseases of aging previously, but Dr. Da Mesquita has identified a novel mechanism by which they may be contributing to AD. He has found that senescent cells can impair efficient removal of cellular waste from the brain through the meningeal lymphatic vascular system. As a result of this disruption, Dr. Da Mesquita believes the brain accumulates more of the waste and senescent cells it should be removing, driving inflammation and dysfunction of other cells, and perpetuating a spiral of worsened clearance, inflammation, and neuronal dysfunction.

This project seeks to investigate this feedforward loop in three ways. Firstly, Dr. Da Mesquita intends to identify the specific senescent cell types and molecular players contributing to the breakdown in the meningeal lymphatic drainage system associated with aging. Second, he will test how a therapy that removes senescent cells improves the ability of the brain to effectively clear waste. Finally, his team will investigate if uncoupling senescence and impaired lymphatic drainage can meaningfully correct harmful inflammation, neurodegeneration, and cognitive decline. These experiments collectively seek to identify the key connecting points between aging and the brain’s capacity to remove waste to find new therapeutic windows to combat AD.