Investigating the Role of Tau Protein in Neuronal Senescence


Advanced age is the greatest risk factor for developing Alzheimer’s disease and related dementias. Disease processes begin decades prior to noticeable symptoms. Our work focuses on how brain cells change throughout the lifespan to identify early disease processes. This strategy led to the discovery of an abnormal type of brain cell that displayed characteristics of damaged, aged cells called senescent. The senescent cells were closely connected with memory loss and disease, and removing them improved brain function in Alzheimer’s disease mouse models. Senescent cells accumulate in many tissues during aging and contribute to disease and dysfunction. In Alzheimer’s disease brain tissue, we found that the senescent cells are neurons, the brain cells important for making, storing, and retrieving memories. Many of the senescent neurons contain large deposits of tau protein. All neurons normally contain tau protein; however, the accumulation of abnormal tau proteins causes various brain diseases. Tau aggregates called neurofibrillary tangles closely correlate with dementia and neuron death. Similar to senescent cells, neurons with neurofibrillary tangles display signs of damage and stress, but they do not die. Their survival comes with a tradeoff. They become toxic to surrounding healthy cells. We have found senescent neurons rely on tau to execute this toxic stress response. The objective of this project is to better understand how tau proteins guide neurons to become senescent and what type of damage initiates neurons to become senescent. This is important because senescent cells contribute to disease and dysfunction. A better understanding of how, why, and when neurons become senescent may lead to drug therapies that interrupt the toxic process. Moreover, some of these therapies may be most useful in midlife when risk factors are evident, but neurons are still healthy. This approach may reduce the risk of developing Alzheimer’s disease in later life.

Funding to Date



Studies of Tau, Translational


Miranda Orr, Ph.D.