Wednesday, April 2, 2025
4/2/2025
Probing the heterogeneity of brain pericytes using new genetic tools - Abstract Pericytes are vascular mural cells embedded in the basement membrane and extending their processes along the walls of blood microvessels; they play key roles in vascular development and the maintenance of microvascular functions. In the last decade, our knowledge about pericytes and their functions in CNS diseases has grown tremendously, and brain pericytes are increasingly accepted as a guardian of mammalian blood-brain barrier, as well as an important player in neurological disorders and neurodegenerative diseases, such as Alzheimer’s disease. However, the lack of specific marker or genetic tools for brain pericytes has become a major hurdle to key questions such as brain pericyte’s heterogeneity, specialization during embryonic development and plasticity in aging and diseases. Many genetic models have been developed in the past based on classic genetic markers such as Pdgfrb, Cspg4 and Rgs5, but none of them are truly specific to brain pericytes. To address this gap in brain pericyte specific tools, we compiled 8 transcriptomic datasets and identified that Atp13a5 is perhaps a better marker for brain pericytes in mice. After generating a transgenic reporter and CreER model, we confirmed that Atp13a5 is specific to brain pericytes, as the reporter is not expressed in peripheral organs. Surprisingly, we also found that in the brain, Atp13a5 reporter only marks BBB-pericytes, as it is not found in the brain regions that are outside of the BBB, including the pineal gland, pituitary gland and choroid plexus, which are also known as the circumventricular organs. Therefore, based on this new Atp13a5 marker, we are now able to clearly separate BBB pericytes from the non-BBB pericytes. The finding of Atp13a5-based brain pericyte heterogeneity now allows us to define and study BBB pericytes more accurately in aging and disease conditions, as well as probe the fundamental difference between BBB pericytes with non-BBB ones at anatomical and histological levels. Since pericyte degeneration, injury and loss are commonly found in age-related neurodegenerative disorders, here we propose to anatomically map pericyte’s heterogeneity in brain, and further determine the heterogeneity throughout aging and AD (Aim 1). In addition, we also found Atp13a5-expressing BBB pericytes are highly vulnerable to hypoxic condition and amyloid toxicity, and plan to conduct CRISPR genome-wide screenings to discover new molecular regulators that can potentially overriding the pericyte loss in aging and AD (Aim 2). We hope that the new marker and tools will help us to achieve a better understanding of brain pericyte biology and heterogeneity in the context of BBB functions, as well as their contributions to CNS disorders. The data to be gathered from this study will open a door to a new level of research to understand pericyte biology, functions, diversity, and contributions to aging and related CNS diseases, such as Alzheimer’s disease, as well as provide new insights for potential applications of gene therapy targeting brain pericytes in CNS disorders.
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