Role of docosahexaenoic acid in the modulation of glial cells in Alzheimer's disease

Abstract

Docosahexaenoic acid (DHA) is an omega-3 (ω-3) long-chain polyunsaturated fatty acid (LCPUFA) relevant for brain function. It has largely been explored as a potential candidate to treat Alzheimer's disease (AD). Clinical evidence favors a role for DHA in the improvement of cognition in very early stages of the AD. In response to stress or damage, DHA generates oxygenated derivatives called docosanoids that can activate the peroxisome proliferator-activated receptor γ (PPARγ). In conjunction with activated retinoid X receptors (RXR), PPARγ modulates inflammation, cell survival, and lipid metabolism. As an early event in AD, inflammation is associated with an excess of amyloid β peptide (Aβ) that contributes to neural insult. Glial cells are recognized to be actively involved during AD, and their dysfunction is associated with the early appearance of this pathology. These cells give support to neurons, remove amyloid β peptides from the brain, and modulate inflammation. Since DHA can modulate glial cell activity, the present work reviews the evidence about this modulation as well as the effect of docosanoids on neuroinflammation and in some AD models. The evidence supports PPARγ as a preferred target for gene modulation. The effective use of DHA and/or its derivatives in a subgroup of people at risk of developing AD is discussed.

Keywords: Alzheimer’s disease (AD); Amyloid β peptide (Aβ); Docosahexaenoic acid (DHA); Glial cells; Neuroinflammation; Neuroprotectin D1 (NPD1); Resolvin D1 (RvD1).

Fig. 1

DHA modulation of gene transcription through the action of RXR/PPARγ transcription factors heterodimers. DHA is cut from PLs in cellular membranes by the action of iPLA₂. DHA is oxygenated by the action of LOX, or alternatively by the action of COX2. The products of DHA oxygenation are docosanoids, such as NPD1 and RvD1. DHA is a ligand for RXR and NPD1 for PPARγ. Activation of RXR and PPARγ leads to the formation of RXR/PPARγ, which binds to a PPAR response element, in the promoter region of target genes [38], thus modulating inflammation, lipid metabolism, and cellular differentiation. DHA docosahexaenoic acid, PL phospholipids, iPLA ₂ independent phospholipase A₂, LOX lipoxygenases, COX2 cyclooxygenase 2, NPD1 neuroprotectin D1, RvD1 resolvin D1, RXR retinoid X receptor, PPARγ peroxisome proliferator-activated receptors gamma, RXR/PPARγ heterodimers of nuclear transcription factors RXR and PPARγ. Activation is indicated by black arrows and modulation by the black gaped arrow

Fig. 2

Participation of glial cells in AD. 1 Aβ is secreted by the action of BACE1 and γ-secretase, thus forming aggregates of Aβ (oligomers, insoluble fibrillary aggregates and plaques), 2 microglia (M2- like phenotype) and astrocytes capture and degrade Aβ peptides, 3 Aβ aggregates can activate or harm microglia and astrocytes, promoting the production of pro-inflammatory cytokines and mediators, 4 dysfunction of microglia and astrocytes allows Aβ deposition, increasing cellular damage and inflammation, BACE1 β site cleavage enzyme 1, Aβ amyloid β peptide, M1 pro-inflammatory microglia, M2 anti-inflammatory microglia, green arrows anti-inflammatory and clearing action, red arrows pro-inflammatory actions, black arrows interaction

Fig. 3

DHA and docosanoids modulate the activation of microglia. DHA and/or docosanoids activate RXR/PPARγ heterodimers that promote transcription of anti-inflammatory cytokines and acquisition of M2 anti-inflammatory profile [–78]. IL-1 interleukin 1, IL1RN interleukin 1 receptor antagonist, ITGB2 integrin B 2 protein, IL-4 interleukin 4, IL-6 interleukin 6, NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells, Aβ amyloid β peptide, DHA docosahexaenoic acid, NPD1 neuroprotectin D1, RvD1 resolvin D1, RXR/PPARγ heterodimers of nuclear transcription factors RXR and PPARγ, M1 pro-inflammatory microglia, M2 anti-inflammatory microglia, green arrows anti-inflammatory and clearance action