The pathogenic effects of senescent cells on their microenvironments and their role in human brain aging

PROJECT SUMMARY Senescent cells were hypothesized to contribute to development of Alzheimer’s Disease and Related Dementias (ADRD) by secreting inflammatory factors in their surrounding microenvironments. However, the exact role of senescent neurons in brain aging and effective ways to mitigate their contribution to ADRD development are unknown. To address this gap in knowledge, we need high-resolution spatial omics data, which covers hundreds of genes and potentially have the information on how a cell impacts its microenvironment. In this study, the Orr Lab generates spatial omics data from ADRD brains and the corresponding mouse models. The Zare Lab uses deep learning and other machine learning techniques to fully leverage the spatial aspects of these data. In the R21 phase, we identify molecular changes in the microenvironment of senescent neurons compared to healthy neurons. In Aim 1, we identify the general molecular markers of senescent neurons while Aim 2 is focused on their role specifically in neuronal death in brain aging and ADRD. The rationale for this study is the accumulating evidence by our team, and others, that demonstrate a mechanistic link between cellular senescence and ADRD. Specifically, a) in a seminal study, the Orr Lab identified senescent neurons in human Alzheimer’s disease that were mechanistically linked to neurodegeneration using tau transgenic mice, b) by analyzing transcriptome data of 140K single nuclei derived from 76 human brains with various levels of ADRD pathology, the Zare Lab identified cyclin- dependent kinase inhibitor 2D (CDKN2D/p19) as a marker for senescent neurons. Using p19 and other markers, we showed that senescent neurons have a significant overlap with neurofibrillary tangle (NFT) pathology in the human brain, and c) we have recently discovered that Fas receptor (CD95), which induces apoptosis, is overexpressed in the microenvironment of senescent neurons in ADRD brains compared to normal brains. The R33 phase has a mechanistic approach aiming at limiting negative effects of neural senescence on brain aging. In Aim 3, the Zare Lab uses deep models to simulate deregulation of a particular gene in senescent neurons to predict its effects on other genes in the microenvironment. In Aim 4, we use a similar approach to determine the most promising treatment that can possibly mitigate the negative effects of neural senescence. The Orr Lab determines their mechanistic role in pathogenesis using mouse models for ADRD. The expected outcomes of this study includes the discovery of negative senescence effects in brain aging and possible novel treatments for ADRD that mitigate these effects.