The role of autophagy in the neurovascular unit for the physiological response to stress.

PROJECT SUMMARY Macroautophagy (MA) is a cellular response to stress whose dysfunction is implicated in several neurodegenerative diseases. Our limited understanding about how MA is used by distinct CNS cell types has hindered our ability to fully understand the implications of its dysfunction for CNS diseases. A fundamental and well-defined physiologic stress linked to MA is acute nutrient starvation. In vertebrates, starvation-induced activation of MA in peripheral organs such as liver, heart and muscle is essential for maintaining amino acid and glucose blood levels. However, prolonged MA results in loss of organ mass, ultimately leading to breakdown and irreparable damage of these vital organs. It has long been appreciated that under conditions of prolonged starvation, peripheral organs are sacrificed to maintain brain function; however, the mechanisms remain poorly understood. In contrast to most cells in the body, neurons receive nutrients indirectly from the blood through a tightly coordinated signalling with endothelial cells (ECs), pericytes and astrocytes that collective form the neurovascular unit (NVU). Given the critical role that these cells play in forming the blood- brain barrier (BBB), that tightly regulates the influx of nutrients into the brain, they are likely to be highly sensitive to the nutrient status of the periphery, and play a key role in prioritizing the brain during starvation. In this proposal, we will test the hypothesis that MA is upregulated in astrocytes upon starvation and plays a central role in triggering an essential, positive-feedback loop with brain ECs to maintain neuronal function during physiologic starvation. In Aim 1, we will characterize the metabolic function of mice lacking MA in discrete CNS cell types. In Aim 2 we will establish the autophagic response to starvation in astrocytes and how this influences ECs. Upon successful completion of the proposed studies, we will gain new understanding into the molecular and cell-specific response of MA in NVU cells of the CNS before and during starvation, and how they coordinate their efforts to ensure that neuronal function is maintained. In addition to gaining insight into this important and critical physiologic response, these studies will provide conceptual and methodological advances regarding how discrete cell types of the CNS use MA during conditions of stress and disease.