The role of ATP13A5 ATPase in determining blood-brain pericyte functions

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Abstract The blood-brain barrier (BBB) provides a physical barrier limiting the entrance of circulating pathogens and environmental toxins, immune cells and body’s metabolic waste products into the central nervous system (CNS); it also supplies the brain with critical energy metabolites such as glucose and lactate, essential amino acids, fatty acids and vitamins, and regulatory molecules and growth hormones via selective transport systems. The BBB also helps clear brain’s own metabolic wastes including excess of neurotransmitters and proteinaceous molecules such as Alzheimer’s amyloid-β species (Aβ), providing neurons with a tightly controlled microenvironment. The lessons we learned from the failures of drug development for the neurodegenerative diseases have led us to revisit the BBB in recent years, not only for its contribution to CNS diseases such as Alzheimer’s disease and related dementia (ADRD), but also to circumvent this formidable barrier for drug delivery. The answers may remain in the biological mechanisms that make the BBB fundamentally different from other parts of the vascular system. Therefore, the major goal of the current proposal is to determine the genetic marker(s) that separates the BBB from non-BBB vascular system, and delineate a molecular mechanism that potentially drives the specialization and maintenance of the BBB in animal models. Brain endothelial cells are known to form a more tightly sealed barrier through tight junctions and eliminating transcytosis. They are also in close interactions with astrocytes and perivascular mural cells, resulting in specialized perivascular structures such as the basement membrane, pericyte coverage and astrocytic endfeet. It has been known for nearly a century that vascular cells are heterogeneous even within the brain, and several brain regions are not protected by the BBB, particular the circumventricular organs (CVOs). However, no good marker or genetic tool is available for us to reliably identify and separate the BBB and non-BBB vascular system. Using single cell transcriptomics and data mining, we have identified markers and generated new transgenic tools for separating BBB and non-BBB vascular cells. Therefore, we propose to further determine the heterogeneity of brain endothelial cells and pericytes. As our preliminary data indicate that Atp13a5 is unique to brain pericytes and essential for BBB integrity, we hypothesize that Atp13a5 is acquired by brain pericytes during BBB specialization, and required for pericyte’s role in fortifying the BBB, particularly in aging and Alzheimer’s disease. We plan to determine its biological functions in vitro at molecular and cellular levels, and in vivo using a knockout model. We hope that the new marker and tools will help us to achieve a better understanding of brain vascular biology and heterogeneity in the context of BBB functions, as well as their contributions to CNS disorders, e.g., ADRD.