Fatty Acid-Binding Protein 5 at the Blood-Brain Barrier Regulates Endogenous Brain Docosahexaenoic Acid Levels and Cognitive Function

Yijun Pan; Jennifer L Short; Kwok H C Choy; Annie X Zeng; Philip J Marriott; Yuji Owada; Martin J Scanlon; Christopher J H Porter; Joseph A Nicolazzo

doi:10.1523/JNEUROSCI.1583-16.2016

Fatty Acid-Binding Protein 5 at the Blood-Brain Barrier Regulates Endogenous Brain Docosahexaenoic Acid Levels and Cognitive Function

J Neurosci. 2016 Nov 16;36(46):11755-11767. doi: 10.1523/JNEUROSCI.1583-16.2016.

Authors

Yijun Pan¹, Jennifer L Short², Kwok H C Choy², Annie X Zeng³, Philip J Marriott³, Yuji Owada⁴, Martin J Scanlon⁵, Christopher J H Porter^{1

6}, Joseph A Nicolazzo⁷

Affiliations

¹ Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
² Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
³ Australian Centre for Research on Separation Science, School of Chemistry, Monash University, Clayton, Victoria 3800, Australia.
⁴ Department of Organ Anatomy, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
⁵ Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia, and.
⁶ ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
⁷ Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia, joseph.nicolazzo@monash.edu.

Abstract

Fatty acid-binding protein 5 (FABP5) at the blood-brain barrier contributes to the brain uptake of docosahexaenoic acid (DHA), a blood-derived polyunsaturated fatty acid essential for maintenance of cognitive function. Given the importance of DHA in cognition, the aim of this study was to investigate whether deletion of FABP5 results in cognitive dysfunction and whether this is associated with reduced brain endothelial cell uptake of exogenous DHA and subsequent attenuation in the brain levels of endogenous DHA. Cognitive function was assessed in male and female FABP5^+/+ and FABP5^-/- mice using a battery of memory paradigms. FABP5^-/- mice exhibited impaired working memory and short-term memory, and these cognitive deficits were associated with a 14.7 ± 5.7% reduction in endogenous brain DHA levels. The role of FABP5 in the blood-brain barrier transport of DHA was assessed by measuring ¹⁴C-DHA uptake into brain endothelial cells and capillaries isolated from FABP5^+/+ and FABP5^-/- mice. In line with a crucial role of FABP5 in the brain uptake of DHA, ¹⁴C-DHA uptake into brain endothelial cells and brain capillaries of FABP5^-/- mice was reduced by 48.4 ± 14.5% and 14.0 ± 4.2%, respectively, relative to those of FABP5^+/+ mice. These results strongly support the hypothesis that FABP5 is essential for maintaining brain endothelial cell uptake of DHA, and that cognitive deficits observed in FABP5^-/- mice are associated with reduced CNS access of DHA.

Significance statement: Genetic deletion of fatty acid-binding protein 5 (FABP5) in mice reduces uptake of exogenous docosahexaenoic acid (DHA) into brain endothelial cells and brain capillaries and reduces brain parenchymal levels of endogenous DHA. Therefore, FABP5 in the brain endothelial cell is a crucial contributor to the brain levels of DHA. Critically, lowered brain DHA levels in FABP5^-/- mice occurred in tandem with cognitive deficits in a battery of memory paradigms. This study provides evidence of a critical role for FABP5 in the maintenance of cognitive function via regulating the brain uptake of DHA, and suggests that upregulation of FABP5 in neurodegenerative diseases, where brain DHA levels are possibly diminished (e.g., Alzheimer's disease), may provide a novel therapeutic approach for restoring cognitive function.

Keywords: blood–brain barrier; brain microvascular endothelial cell; cognitive function; docosahexaenoic acid; fatty acid-binding protein.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blood-Brain Barrier / metabolism*
Brain / physiology*
Cognition / physiology*
Docosahexaenoic Acids / metabolism*
Executive Function / physiology*
Fatty Acid-Binding Proteins / metabolism*
Female
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Neoplasm Proteins / metabolism*

Substances

Fabp5 protein, mouse
Fatty Acid-Binding Proteins
Neoplasm Proteins
Docosahexaenoic Acids