Omega-3 Docosahexaenoic Acid Is a Mediator of Fate-Decision of Adult Neural Stem Cells

Abstract

The mammalian brain is enriched with lipids that serve as energy catalyzers or secondary messengers of essential signaling pathways. Docosahexaenoic acid (DHA) is an omega-3 fatty acid synthesized de novo at low levels in humans, an endogenous supply from its precursors, and is mainly incorporated from nutrition, an exogeneous supply. Decreased levels of DHA have been reported in the brains of patients with neurodegenerative diseases. Preventing this decrease or supplementing the brain with DHA has been considered as a therapy for the DHA brain deficiency that could be linked with neuronal death or neurodegeneration. The mammalian brain has, however, a mechanism of compensation for loss of neurons in the brain: neurogenesis, the birth of neurons from neural stem cells. In adulthood, neurogenesis is still present, although at a slower rate and with low efficiency, where most of the newly born neurons die. Neural stem/progenitor cells (NSPCs) have been shown to require lipids for proper metabolism for proliferation maintenance and neurogenesis induction. Recent studies have focused on the effects of these essential lipids on the neurobiology of NSPCs. This review aimed to introduce the possible use of DHA to impact NSPC fate-decision as a therapy for neurodegenerative diseases.

Keywords: adult neurogenesis; docosahexaenoic acid; neural stem cell; neuroprotection; omega-3 fatty acids.

Figure 1

Representation of the major metabolic pathway changes of glycolysis, oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), lipogenesis, and reactive oxygen species (ROS) generation and defense in neural stem/progenitor cells (NSPCs) during cell-fate decision. Illustrated for NSPC metabolism from quiescent cells to immature neuron differentiation in the adult subgranular zone (SGZ) and the developing forebrain. From Knobloch et al. [86].

Figure 2

Docosahexaenoic acid (DHA) uptake through the blood–brain barrier (BBB) and metabolism in brain cells. Transfer from plasma to endothelial cells is possible through passive diffusion and active transport of non-esterified DHA (NE-DHA) or lysophospholipid containing DHA (LysoPL), including LysoPC–DHA. Active transport involves lipoproteins and Mfsd2a. Inside endothelial cells, NE-DHA and DHA cleaved from LysoPL–DHA are bound to fatty acid binding proteins (FABP) to cross the intercellular space to reach brain cells. DHA then participates in cell metabolism for energy production of CoA and production of signaling mediators, specialized pro-resolving mediators (SPM), producing beta-oxidation. For further details, refer to original figure from Lacombe et al. [129].