The dietary fatty acids α-linolenic acid (ALA) and linoleic acid (LA) selectively inhibit microglial nitric oxide production

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder without a known cure or effective treatment. Research has identified several modifiable risk factors and suggested preventative measures to reduce the risk of developing AD, including alterations in diet. Polyunsaturated fatty acids (PUFAs) have been shown to regulate inflammatory responses in the central nervous system (CNS), the main site of inflammation in AD. In the CNS, microglia are immune cells responsible for the maintenance of homeostasis. However, in AD, microglia can become adversely activated, causing them to release increased levels of cytotoxins and inflammatory mediators, including nitric oxide (NO) and monocyte-chemoattractant protein (MCP)-1. We assessed the effects of two PUFAs, α-linolenic acid (ALA) and linoleic acid (LA), on select microglial immune functions, since the effects of these dietary fatty acids on neuroimmune responses are not well characterized. In BV-2 mouse microglia activated with lipopolysaccharide (LPS), exposure to LA reduced NO secretion and inducible nitric oxide synthase (iNOS) levels, whereas exposure to ALA reduced NO without a corresponding reduction of iNOS. Neither ALA nor LA altered MCP-1 levels or cytotoxins released by THP-1 human microglia-like cells stimulated with a combination of LPS and interferon (IFN)-γ. Specific receptor antagonists were used to demonstrate that the inhibitory effect of LA on NO secretion did not depend on the free fatty acid receptor (FFAR) 1 or FFAR4. Furthermore, gas chromatography with a flame ionization detector (GC-FID) revealed that exposure to LA or ALA did not alter the fatty acid composition of BV-2 microglia. Our data indicate that regulation of select microglial immune functions by ALA and LA could be one of the mechanisms underlying the observed link between certain dietary patterns and AD, such as reduced risk of cognitive decline and dementia associated with the Mediterranean diet.