Neurite outgrowth stimulation by n-3 and n-6 PUFAs of phospholipids in apoE-containing lipoproteins secreted from glial cells

Mitsuhiro Nakato,Michinori Matsuo,Nozomu Kono,Makoto Arita,Hiroyuki Arai,Jun Ogawa,Noriyuki Kioka,Kazumitsu Ueda

doi:10.1194/jlr.m058164

Abstract

PUFAs, which account for 25-30% of the total fatty acids in the human brain, are important for normal brain development and cognitive function. However, it remains unclear how PUFAs are delivered to neurons and exert their effects. In this study, we demonstrated that n-3 and n-6 PUFAs added to the medium are incorporated into membrane phospholipids of primary glial cells from rat cortices, and then secreted as the fatty acid moiety of phospholipids in apoE-containing lipoproteins (LpEs). Tandem mass spectrometry analysis further showed that LpEs secreted from glial cells contain a variety of metabolites of PUFAs produced in glial cells by elongation and unsaturation. LpEs are absorbed by endocytosis into neurons via LDL receptor-related protein 1. LpE-containing n-3 and n-6 PUFAs exhibit a strong effect on neurite outgrowth of hippocampal neurons by increasing the number of branches. This study sheds light on the novel role of LpEs in the central nervous system and also a novel pathway in which PUFAs act on neurons.

Highlights

PUFAs, which account for 25–30% of the total fatty acids in the human brain, are important for normal brain development and cognitive function
We demonstrate that the fatty acid composition in apoEcontaining lipoprotein (LpE) is modified by n-3 and n-6 PUFAs provided to glial cells, and that n-3 and n-6 PUFAs in LpEs are incorporated by LDL receptor-related protein 1 (LRP1)-mediated endocytosis and enhance neurite outgrowth of hippocampal neurons
PUFAs, which account for 25–30% of the total fatty acids in human brain, are important for normal brain development and cognitive function [1, 5]

Summary

Introduction

PUFAs, which account for 25–30% of the total fatty acids in the human brain, are important for normal brain development and cognitive function It remains unclear how PUFAs are delivered to neurons and exert their effects. The addition of DHA in free fatty acid form to neurons increases neurite outgrowth, which is critical for synaptic formation in developing and adult brain [6,7,8]. It remains unclear whether DHA is primarily delivered to neurons in vivo in the unesterified free form or the phospholipid-esterified form.

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