Selective vulnerability of cell types in brain aging and Alzheimer's disease

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Project Summary Major hallmarks of aging and neurodegeneration include cognitive decline, altered body composition, dysregulation of circadian rhythms, and changes in neuroendocrine systems. The hypothalamus is the brain region that harbors a diversity of neuronal subtypes that coordinate these important functions. Yet, the extent to which changes in the hypothalamus underlie functional decline in normal aging and neurodegeneration is not well understood. Intriguingly, interventions targeting the hypothalamus can significantly extend lifespan in mice, with a discrepancy in females versus males. Moreover, alterations in sleep and body weight can occur prior to the onset of neurodegeneration, for example in Alzheimer’s Disease (AD). One challenge in understanding the aging process is that it is highly heterogeneous, meaning that different cell-types age differently. For example, in brain aging, within individuals, the immune cells (microglia) age very differently from neurons. Moreover, across individuals, women are more susceptible to age-associated neurodegenerative diseases such as Alzheimer’s disease (AD) than men. However, the selective vulnerability of different cell-types in the brain in aging and AD, and the cell-type specific mechanism underlying female bias in brain aging are largely unknown. For the F99 phase of this proposal, in Dr. Webb’s laboratory at Brown University, I will build on my foundational work in which I defined the cell-type transcriptional changes that occur in the aging female mouse hypothalamus. I will perform machine learning analysis to identify signatures of cell vulnerability and resilience with age and extend this work to a model of neurodegeneration (AD mouse models and human post-mortem tissue). Understanding the selective vulnerability in aging and AD can help develop precise interventions to specifically target the vulnerable neurons to slow down brain aging and promote health span. For the K00 phase of this proposal, I will seek to understand the epigenetic mechanisms regulating sex-differences in brain aging. My previous analysis found increased expression of Xist, the master regulator for silencing one of the two chrX in females in eutherian mammals, in aging and AD brain. Given that chrX is enriched for neural and immune genes and the known loss of heterochromatin in aging, I hypothesize that Xist is required for maintaining chrX silencing to protect neurons in brain aging. I will test this hypothesis by epigenetically activating or silencing Xist in induced neurons derived from aged fibroblasts to determine the impact on neuronal aging, and in vivo to reveal the cell-type specific response to the chrX-specific perturbation. This work will contribute to the understanding of the heterogeneity, especially cell-type specific and sex-specific vulnerability, in normal brain aging and AD. Further, it will lead to the discovery of novel biomarkers to assess age and AD status at single cell resolution, which will contribute to the development of cell-type specific interventions. To successfully complete these goals, I will gain extensive training from a team of experts in computational biology, biology of aging, neurodegeneration, and neuroscience.