Abstract TMP29: Elevated Levels Of Palmitic Acid Mediate Early Disruption Of Endothelial Barrier Integrity And Promote Behavioral Dysfunction Relevance To Vascular Cognitive Impairment And Dementia (VCID)

Abstract

Increased consumption of a high-fat diet (HFD) is believed to increase the risk for the development and progression of VCID, but the underlying mechanisms of how HFD leads to cognitive impairment are unclear, partly due to the use of different HFD models in preclinical studies. Palmitic acid (PA), the most common form of saturated fatty acid, found in the human cerebrospinal fluid in obesity, promotes disruption of BBB integrity. We hypothesized that a PA-rich diet mediates early disruption of blood brain barrier (BBB) integrity which leads to progressive neurovascular pathologies and cognitive impairment in VCID. Methods: Experimental design for in vivo studies is depicted in Fig 1. In vitro studies included assessment of endothelial integrity by trans-endothelial electrical resistance (TEER) and FITC measurements, cell viability, and expression levels of tight junction proteins and cell stress markers (Hsp70, Occludin1, Claudin 5, and Carnitine Palmitoyl transferase 1A -CTP1A) in male BMVECs cultured in normal and high PA conditions. Results (Table): Animals that were on the PA-rich diet exhibited risk-taking behavior. BMVECs showed significantly increased permeability of FITC-dextran and decreased TEER measurements. While Hsp70 and CTP1A increased with PA treatment, tight junction protein levels did not change. Conclusion: A special PA-rich diet mediates an anxiety-like behavior as early as 8 weeks without any metabolic effects. Assessments at 22 and 24W will determine whether behavioral dysfunction worsens and progresses to cognitive deficits. In vitro results suggest that initiation of the stress response may be the underlying mechanism of early BBB impairment. Modulation of the endothelial stress response may prevent/attenuate the development/progression of cognitive deficits induced by a PA-rich diet.