Abstract
DHA (docosahexaenoic acid) is perhaps the most pleiotropic molecule in nerve cell biology. This long-chain highly unsaturated fatty acid has evolved to accomplish essential functions ranging from structural components allowing fast events in nerve cell membrane physiology to regulation of neurogenesis and synaptic function. Strikingly, the plethora of DHA effects has to take place within the hostile pro-oxidant environment of the brain parenchyma, which might suggest a molecular suicide. In order to circumvent this paradox, different molecular strategies have evolved during the evolution of brain cells to preserve DHA and to minimize the deleterious effects of its oxidation. In this context, DHA has emerged as a member of the “indirect antioxidants” family, the redox effects of which are not due to direct redox interactions with reactive species, but to modulation of gene expression within thioredoxin and glutathione antioxidant systems and related pathways. Weakening or deregulation of these self-protecting defenses orchestrated by DHA is associated with normal aging but also, more worryingly, with the development of neurodegenerative diseases. In the present review, we elaborate on the essential functions of DHA in the brain, including its role as indirect antioxidant, the selenium connection for proper antioxidant function and their changes during normal aging and in Alzheimer’s disease.
Highlights
The brain is one of the richest organs in lipids, just after adipose tissue
docosahexaenoic acid (DHA) is a pleiotropic molecule that modulates the physicochemical properties and architecture of neuronal plasma membrane, but beyond structural functions, DHA is involved in multiple facets of neuronal biology, from regulation of synaptic function to neuroprotection and modulation of gene expression
In the pro-oxidant environment of brain parenchyma, DHA is highly susceptible to oxidation, but the brain neurochemistry has evolved to provide exceptional protection against LCPUFA peroxidation
Summary
The brain is one of the richest organs in lipids, just after adipose tissue. In nerve cells, lipids represent approximately 60–70% of total brain constituents. Most PUFAs in the brain contain 18 or more carbon atoms and are named long-chain PUFAs or LCPUFAs, of which the most abundant are arachidonic acid (AA, 20:4n-6) and docosahexaenoic acid (DHA, 22:6n3) Because of their elevated number of unsaturations, they are referred to a highly unsaturated fatty acids (HUFAs), and this property has an enormous impact on their cellular biology. Particular attention has been given to cholesterol-enriched ordered domains, which are ordinarily enriched in saturated sphingolipids and specific scaffold proteins, named lipid rafts, which serve as signaling platforms [6,10,16] Both domains are compositionally and organizationally opposite and contain different subsets of integral proteins, which give them different physiological roles in nerve cells [11,12,14,17]. We review and discuss the diversity of physiological effects demonstrated for DHA, its novel role as an indirect antioxidant, its changes with aging, and the relation between its dyshomeostasis and neurodegenerative diseases, in Alzheimer’s disease
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