DHA may prevent age-related dementia

Abstract

The risk for dementia, a major contributor to incapacitation and institutionalization, rises rapidly as we age, doubling every 5 y after age 65. Tens of millions of new Alzheimer's disease (AD) and other dementia cases are projected as elderly populations increase around the world, creating a projected dementia epidemic for which most nations are not prepared. Thus, there is an urgent need for prevention approaches that are safe, effective, and affordable. This review addresses the potential of one promising candidate, the (n-3) fatty acid docosahexaenoic acid (DHA), which appears to slow pathogenesis of AD and possibly vascular dementia. DHA is pleiotropic, acting at multiple steps to reduce the production of the beta-amyloid peptide, widely believed to initiate AD. DHA moderates some of the kinases that hyperphosphorylate the tau-protein, a component of the neurofibrillary tangle. DHA may help suppress insulin/neurotrophic factor signaling deficits, neuroinflammation, and oxidative damage that contribute to synaptic loss and neuronal dysfunction in dementia. Finally, DHA increases brain levels of neuroprotective brain-derived neurotrophic factor and reduces the (n-6) fatty acid arachidonate and its prostaglandin metabolites that have been implicated in promoting AD. Clinical trials suggest that DHA or fish oil alone can slow early stages of progression, but these effects may be apolipoprotein E genotype specific, and larger trials with very early stages are required to prove efficacy. We advocate early intervention in a prodromal period with nutrigenomically defined subjects with an appropriately designed nutritional supplement, including DHA and antioxidants.

FIGURE 1

AD pathways targeted by DHA. AD is initiated by increased levels of Aβ-42 derived from APP, which traffics to a membrane compartment where secretase enzymes, including a complex dependent on presenilin 1 (PS1) generate Aβ. The chaperone LR11 traffics APP away from the secretases. DHA reduces Aβ production, reportedly by increasing LR11 and reducing PS1, leading to less Aβ and, thus, fewer toxic Aβ oligomers (AβO). DHA also increases levels of neuroprotectin D1 (NPD1) and neuroprotective brain-derived neurotrophic factor (BDNF). It improves signaling of BDNF, insulin, and other neurotrophic factors (NTF) through their receptors [NTF-R and insulin receptor (ins-R)], which autophosphorylate (P) at Tyr residues to couple to protective signaling via adaptor proteins, such as IRS. For example, IRS binds the p85 subunit of phosphatidylinositol 3-kinase (PI3K) to generate PIP3 lipid, which promotes binding and activation of downstream PDK and Akt kinases through their pleckstrin homology (PH) domains. DHA facilitates this activation by increasing phosphatidylserine (PS), which accelerates PH domain membrane binding. Activated Akt increases the Aβ protease, insulin degrading enzyme (IDE), inhibits the τ kinase GSK3β, and acts on multiple survival signals to promote neuron growth and survival. AβO acts on unidentified receptors (N-methyl-d-aspartate, integrin, and Prp), which signal through fyn to rac to cause toxicity via another τ kinase, JNK. JNK serves a priming kinase for GSK3β, also a τ kinase. Together, they phosphorylate and inactivate IRS, which leads not only to its rapid degradation and insulin/neurotrophic factor resistance, but also to accumulation of τ oligomers and tangles. In summary, DHA protects against these toxic pathways, reducing pJNK, ptau, and pIRS. DHA also reduces brain AA levels to limit AβO-induced increases AA via cytosolic phospholipase A2 (cPLA2) activation. Less AA means less downstream prostaglandin (PG), leukotriene (LT), and hydroxyeicosatetraenoic acid (HETE) products of COX and lipoxygenase (LOX). These AA products are implicated in inflammation and excitotoxicity, which, together with τ pathology and trophic signaling deficits, contribute to synaptic and cognitive deficits.