Age is the most significant risk factor for late-onset Alzheimer’s disease (AD). Aging is also a multifaceted biological process driven by numerous interconnected factors. Among these factors is the accumulation of senescent cells throughout the body. Senescent cells stop dividing and functioning normally, but rather than dying off and being cleared away, these lingering cells accumulate and release harmful substances that can damage nearby cells and disrupt normal bodily systems.
Even neurons—which don’t divide in adulthood—can become senescent in response to stress and damage. In the context of AD, the accumulation of senescent neurons is particularly concerning, as their inflammatory secretions may directly accelerate neurodegeneration and cognitive decline.
One key marker of neuronal senescence in AD patients is a protein called p16INK4a. This protein is involved in the later stages of a cell’s transition into senescence, and cells positive for p16INK4a accumulate with age. Drs. Kanekiyo and Ren have shown that clearing cells expressing p16INK4a counteracts the cognitive deficits seen in a tau mouse model. In comparison, increasing p16INK4a levels in cells of the blood-brain barrier leads to cognitive impairment. Drs. Kanekiyo and Ren believe that the induction of senescence in key neurons is a major contributor to AD. They hypothesize that p16INK4a expression triggers neuronal senescence and worsens neurodegeneration, neuroinflammation, and amyloid and tau pathologies in AD.
They will test this hypothesis with two primary aims. In the first, they determine the impact of p16INK4a on neurons by artificially expressing p16INK4a in cultured neurons and brain organoids. This way, they can assess changes in neuroinflammation, synaptic function, and mitochondrial efficiency, all of which they expect to be affected by the induction of senescence. The second aim focuses on using a new mouse model the team has developed that selectively expresses p16INK4a in neurons. This allows them to examine the impact of p16INK4a in a functioning mouse brain and assess changes in cognitive functions. By using both models, Drs. Kanekiyo and Ren aim to build a comprehensive picture of how p16INK4a and senescence in neurons contribute to AD.
This project examines the role of neuronal senescence in AD. This could open the door to novel therapeutic targets in AD, focusing on reversing senescent characteristics or clearing senescent cells.
