SRC-2 Regulates Brain Endothelial and Neuronal Metabolism in a Mouse Model of Neurodegeneration

Cerebrovascular dysfunction and impaired brain energy metabolism are increasingly recognized as important contributors to neurodegenerative diseases, but their molecular regulators remain poorly understood. Here, we examined the roles of steroid receptor coactivator-2 (SRC-2/NCOA2) in the cerebrovascular and metabolic changes associated with neurodegeneration using ps19 mice as a model. In our study, we found a significant decrease in cortical SRC-2 expression in ps19 mice compared with wild-type (WT) controls, with no changes in SRC-1 and SRC-3 levels between the two groups. ps19 mice showed reduced cortical endothelial and blood–brain barrier-associated markers (CD31, occludin, claudin-5, total eNOS (endothelial nitric oxide synthase), and eNOS Ser1177) and increased eNOS Thr495 phosphorylation. HIF-1α, GLUT2, and GLUT4 were also reduced in ps19 mice, whereas GLUT1 and GLUT3 were unchanged between the groups. To examine the role of SRC-2, we used siRNA to reduce its expression in brain endothelial cells and primary neurons. In brain endothelial cells, SRC-2 knockdown reduced the expression of endothelial and BBB-associated markers, including CD31 and occludin, as well as GLUT3, while increasing inhibitory eNOS Thr495 phosphorylation and GLUT4 expression. In brain endothelial cells, SRC-2 knockdown significantly reduced the extracellular acidification rate (ECAR) and NAD+/NADH ratio. Knockdown of SRC-2 in primary neurons (from WT and ps19 mice) significantly reduced the oxygen consumption rate (OCR), while the NAD+/NADH ratio remained unchanged. These findings identify SRC-2 as a regulator of endothelial and neuronal metabolism and support further investigation of SRC-2-dependent pathways as potential therapeutic targets in neurodegenerative diseases.