title: Fatty Acid-Binding Protein 5 at the Blood-Brain Barrier Regulates Endogenous Brain Docosahexaenoic Acid Levels and Cognitive Function.
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 measuring14C-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.
  
  
  
  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.
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Yijun
authors.identifier: 0000-0002-1442-3333
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Jennifer L
authors.identifier: 0000-0002-2785-6875
authors.initials: JL
authors.lastname: Short
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Kwok H C
authors.identifier: 0000-0002-4650-2220
authors.initials: KH
authors.lastname: Choy
authors.affiliation: Australian Centre for Research on Separation Science, School of Chemistry, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Annie X
authors.initials: AX
authors.lastname: Zeng
authors.affiliation: Australian Centre for Research on Separation Science, School of Chemistry, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Marriott
authors.affiliation: Department of Organ Anatomy, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Owada
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia, and.
authors.forename: Martin J
authors.identifier: 0000-0002-9230-7506
authors.initials: MJ
authors.lastname: Scanlon
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.|ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Christopher J H
authors.identifier: 0000-0003-3474-7551
authors.initials: CJ
authors.lastname: Porter
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia, joseph.nicolazzo@monash.edu.
authors.forename: Joseph A
authors.identifier: 0000-0002-0983-7152
authors.initials: JA
authors.lastname: Nicolazzo
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000502:physiology*; D003071:Cognition / Q000502:physiology*; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D056344:Executive Function / Q000502:physiology*; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000378:metabolism*
chemical_list: C082667:Fabp5 protein, mouse; D050556:Fatty Acid-Binding Proteins; D009363:Neoplasm Proteins; D004281:Docosahexaenoic Acids
keywords: blood–brain barrier; brain microvascular endothelial cell; cognitive function; docosahexaenoic acid; fatty acid-binding protein