Alzheimer’s disease (AD) is one of the most devastating and costly age-related conditions, affecting more than 30 million people worldwide. In the brains of people with Alzheimer’s, two abnormal proteins, amyloid and tau, build up and interfere with how neurons communicate. However, scientists are discovering that the story is more complex than protein buildup alone. Amyloid plaques and tau tangles interact with normal aging processes that make the brain more vulnerable over time. One of these processes is cellular senescence. Senescent cells are older or stressed cells that stop dividing but don’t die. Instead, they release a mix of inflammatory molecules, called the senescence-associated secretory phenotype (SASP), which can damage nearby healthy cells. In the brain, an accumulation of these “zombie-like” cells contributes to chronic inflammation. Microglia and astrocytes, the brain’s immune and support cells, are especially likely to become senescent, which may further drive the inflammation and cell loss seen in Alzheimer’s.
Dr. Darren Baker’s laboratory has been at the forefront of investigating how cellular senescence contributes to the death of brain cells. His previous work demonstrated that removing senescent cells in tauopathy mice (PS19) significantly reduced tau-dependent cell death and cognitive decline. His team also found that microglia can undergo senescent-like changes that are closely associated with the buildup of amyloid plaques and tau tangles. Further, they found that blocking the expression of p16, a protein that regulates senescence, can protect against disease progression. In new and surprising findings, the Baker lab has identified a sex-specific role for another senescence regulator, p21, in driving AD pathology. In female PS19 mice, deleting p21 markedly reduced neurofibrillary tangle formation, neuroinflammation, and behavioral deficits. Conversely, forcing microglia to overexpress p21 triggered reactive changes even in otherwise healthy brains. The Baker lab hypothesizes that p21 actively drives microglial senescence and neurodegeneration in a sex-dependent manner, contributing to the higher incidence and severity of AD in women.
They will investigate this hypothesis using two complementary aims. In aim 1, the team will define the sex-specific properties of senescent microglia by either deleting p21 expression or overexpressing it in tau (PS19) and amyloid (5XFAD) mice. These studies will clarify how p21-dependent senescence influences disease onset and progression in both male and female mice. The researchers will test learning and memory using a series of behavioral assessments and analyze brain tissue with RNA sequencing and immunofluorescence to detect molecular and cellular changes. They will also isolate microglia for single-cell RNA sequencing to identify shifts in inflammatory gene expression and microglial subtypes associated with disease progression. In aim 2, they will determine how hormones influence these processes by altering estrogen levels and examining the resulting molecular and pathological changes. As in aim 1, they will conduct behavioral tests before tissue collection and perform the same molecular and cellular analyses to compare outcomes across hormone conditions.
Together, these studies will reveal how sex and cellular senescence intersect to shape AD pathology. By defining the mechanisms through which p21 regulates microglial senescence, this work could identify new biomarkers and therapeutic targets for preventing or slowing AD, particularly in women.
