Omega-3 fatty acids: potential role in the management of early Alzheimer's disease

Abstract

Omega-3 fatty acids are essential for brain growth and development. They play an important role throughout life, as critical modulators of neuronal function and regulation of oxidative stress mechanisms, in brain health and disease. Docosahexanoic acid (DHA), the major omega-3 fatty acid found in neurons, has taken on a central role as a target for therapeutic intervention in Alzheimer's disease (AD). A plethora of in vitro, animal model, and human data, gathered over the past decade, highlight the important role DHA may play in the development of a variety of neurological and psychiatric disorders, including AD. Cross sectional and prospective cohort data have demonstrated that reduced dietary intake or low brain levels of DHA are associated with accelerated cognitive decline or the development of incipient dementia, including AD. Several clinical trials investigating the effects of omega-3 fatty acid supplementation in AD have been completed and all failed to demonstrate its efficacy in the treatment of AD. However, these trials produced intriguing data suggesting that the beneficial effects of omega-3 fatty acid supplementation may depend on the stage of disease, other dietary mediators, and apolipoprotein E status.

Keywords: Alzheimer’s disease; clinical studies; omega-3 fatty acids; oxidative stress; treatment.

Figure 1

Polyunsaturated fatty acids increase membrane fluidity and facilitate incorporation of essential membrane bound proteins required for synapse and lipid raft formation A) Saturated fatty acids and cholesterol pack tightly to form a more rigid and less fluid lipid bilayer. B) Double-bond formation in polyunsaturated fatty acids creates a “bend” in the fatty acid tail that prevents the tight packing of saturated fatty acids and cholesterol leading to increased membrane fluidity and incorporation of integral synaptic proteins.

Figure 2

Phospholipase A₂ lipoxygenase forms neuroprotectin D1 (NPD1) from membrane bound DHA. Downstream effects of NPD1 include a) down regulation of pro-apoptotic signaling pathways, b) upregulation of the bcl-2 family of anti-apoptotic proteins, c) inhibition of cyclooxygenase mediated production of inflammatory eicosanoids.

Figure 3

Omega-3 PUFAs influence amyloidogenic processing through several distinct and interrelated mechanisms: a) facilitation of the interaction of α-secretase with APP to produce non-toxic fragments and prevent the formation of Aβ, b) shielding the essential recognition sequence and intramembrane cleavage site for γ-secretase, c) serving as a local sink for free radicals that reduce the enzymatic augmentation of γ-secretase activity that can be induced by free radical damage to the protein complex important for the regulation of normal γ-secretase function, and d) directly inhibiting fibrillation and formation of toxic oligomeric species of A β.