Microvascular endothelial lipid metabolism as a target for age-related vascular cognitive impairment

PROJECT SUMMARY/ABSTRACT Lipids constitute ~50% of the brain’s dry weight, yet very little is known about how brain lipid metabolism is regulated in both physiological and pathological states. Lipid droplets (LDs) are lipid-storing organelles that play a significant role in regulating cellular lipid metabolism. Dysregulated lipid homeostasis, resulting in excessive accumulation of LDs in brain cells, has been implicated in neuroinflammation associated with aging and other neurodegenerative diseases. While most studies have focused on lipotoxicity in glial cells, our single-cell RNA-sequencing (scRNA-seq) analysis reveals that brain endothelial cells are equally vulnerable to age-related LD accumulation. Endothelial cells accumulating LDs in the aged brain displayed a transcriptomic signature associated with reduced LD turnover, increased neuroinflammation, and impaired blood-brain barrier (BBB) function. However, the mechanisms by which age-related lipid dysregulation in brain vascular cells, specifically endothelial cells, contribute to cognitive impairment remain poorly understood. In this novel pilot study, we build on our exciting preliminary data and propose that decreased lipid turnover induces microvascular endothelial dysfunction, which impairs cerebral blood flow responses, promotes BBB disruption, and triggers neuroinflammation, ultimately leading to cognitive decline in aging. To test this hypothesis, we will knock down the critical triglyceride hydrolytic enzyme, adipose triglyceride lipase (ATGL), specifically in brain endothelial cells using the recently developed AAV serotype BI30. We will utilize this model to evaluate how LD accumulation in endothelial cells drives microvascular aging and cognitive impairment. In Aim 1, we will assess the effects of LD accumulation on endothelial structure and function. In Aim 2, we will evaluate how endothelial LD accumulation impacts endothelial bioenergetics and cognitive function in aging. The successful completion of these studies will pave the way for novel therapeutic strategies targeting endothelial lipid metabolism to delay or prevent cognitive decline associated with aging and neurodegenerative diseases.