Docosahexaenoic acid and the aging brain - PubMed (original) (raw)

FIGURE 1

DHA, NPD1, and β_APP-derived A_β peptide signaling circuits in homeostatic aging and in AD. DHA and NPD1 act as PLA2- and 15-LOX-mediated neuroprotectants in the β_APP-sAPP_α_-A_β peptide signaling pathway. Free DHA is liberated from membrane-bound stores via the action of a highly regulated membrane-associated PLA2 that may be subsequently converted into a potent neurotrophic NPD1 through an enzyme-mediated lipoxygenation via 15-LOX-1 or 15-LOX-like activities. NPD1 has been shown to convey multiple neuroprotective effects including induction of antiapoptotic Bcl-2 proteins, inhibition in the expression of proapoptotic Bcl-2 proteins, and suppression of inflammatory gene expression. Various ROS are more abundant in AD than in control brain, suggesting a possible role for oxidation-related decrease in protein function in processes such as depletion of the cellular redox balance, loss of specific protein function, interference with the cell cycle, and abnormal clearance of proteins and neurodegeneration leading ultimately to neuronal death. Nonenzymatic oxidation of free DHA results in the formation of neuroprostanes, a class of peroxidized lipids that further support oxidative stress, neuronal dysfunction, and apoptosis. Nonenzymatic reactions may be quenched by specific antioxidants and free radical scavengers, indicating that the redox state of brain cells has bearing on neurotrophic or oxidative-neurotoxic pathways for DHA. Enriched within neuronal plasma and endoplasmic membranes, the integral β_APP gives rise to sAPP_α via an _α_-secretase/ADAM (a disintegrin and metalloprotease) 10-mediated pathway that is nonamyloidogenic and neurotrophic and whose synthesis is supported by free DHA and NPD1 (upper pathways). The _β_APP membrane-integral sorting receptor sortilin-1 (SORL1), when proximal to _β_APP, has direct effects on _β_APP trafficking, and decreased abundance of SORL1, or _β_APP-SORL1 dissociation, is coupled to activation of the amyloidogenic pathway from β_APP and the increased generation and secretion of A_β peptides (lower pathways) (–49). SORL-1 further interacts with the type E apolipoprotein (ApoE), a major biolipid and cholesterol transporter in the brain, and the interaction of β_APP and ApoE within cholesterol-enriched lipid raft membrane domains, especially in the absence of SORL-1, gives rise to an increased generation of A_β peptides via stimulation of β_-amyloid cleavage enzyme (BACE) and presenilin 1 (PS1). The tandem actions of BACE and PS1 are sometimes referred to as the β_-γ_-secretase signaling pathway, an integral component of the amyloid cascade hypothesis, and known to contribute to A_β peptide accumulation, neuropathology, and neurodegeneration. A_β peptides bind directly to ApoE and cholesterol, and both A_β peptides and _β_APP oxidize ApoE-cholesterol to form the proapoptotic neurotoxic oxysterol 7_β_-hydroxycholesterol (7_β_-HC) or 24S hydroxycholesterol (24S-HC) via the action of CYP46A1 (–50). 24S-HC, highly enriched in the human CNS, is membrane permeable and is associated with amyloidogenesis and AD pathology (49). The actions of DHA or NPD1 on CYP46A1 and oxidation of cholesterol to 7_β_-HC or 24S-HC are not well understood. Current and emerging pharmaceutical strategies aim at the modulation of secretase activities through the actions of SALA to favor the more neurotrophic _β_APP-cleavage signaling pathways (upper pathways) over the neurotoxic, amyloidogenic BACE-PS1 _β_-γ_-secretase pathways (lower pathways; 50). The therapeutic use of statins, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, that lower serum cholesterol has also been shown to reduce A_β peptide abundance in in vitro models of AD using human brain cell primary cultures and in some clinical trials, and large phase III studies are currently in progress (–50). The interactions of DHA and NPD1 with SALA drugs or statins are not well understood; however, early clinical trials using DHA and antioxidants together as enhancers of cognition in aged patients showed synergistic beneficial effects (23,49,50).