DHA Selectively Protects SAMP-8-Associated Cognitive Deficits Through Inhibition of JNK

Abstract

A potential role of marine n-3 polyunsaturated fatty acids (ω-3 PUFAs) has been suggested in memory, learning, and cognitive processes. Therefore, ω-3 PUFAs might be a promising treatment option, albeit controversial, for Alzheimer's disease (AD). Among the different mechanisms that have been proposed as responsible for the beneficial effects of ω-3 PUFAs, inhibition of JNK stands as a particularly interesting candidate. In the present work, it has been studied whether the administration of two different PUFAs (docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)) and a DHA-derived specialized pro-resolving lipid mediator (MaR1) is able to reverse cognitive deficits in the senescence-accelerated mouse prone 8 (SAMP8) mouse model of sporadic AD. The novel object recognition test (NORT) test showed that recognition memory was significantly impaired in SAMP8 mice, as shown by a significantly decreased discrimination index that was reversed by MaR1 and DHA. In the retention phase of the Morris water maze (MWM) task, SAMP8 mice showed memory deficit that only DHA treatment was able to reverse. pJNK levels were significantly increased in the hippocampus of SAMP8 mice compared to SAMR1 mice, and only DHA treatment was able to significantly reverse these increased pJNK levels. Similar results were found when measuring c-Jun, the main JNK substrate. Consequently to the increases in tau phosphorylation after increased pJNK, it was checked that tau phosphorylation (PHF-1) was increased in SAMP mice, and this effect was reversed after DHA treatment. Altogether, DHA could represent a new approach for the treatment of AD through JNK inhibition.

Intranasal Administration of Nanovectorized Docosahexaenoic Acid (DHA) Improves Cognitive Function in Two Complementary Mouse Models of Alzheimer’s Disease

“…The inhibition of JNK stands as an important mechanism responsible for the beneficial effects of ω-3 PUFAs. In a recent study by Vela et al, DHA was shown to inhibit cognitive deficits in a mouse model of AD through this mechanism [76] and several polyphenols, including CUR, were also shown to be potent JNK inhibitors [77,78]. In the present study, a significant increase of JNK2 phosphorylation was observed in J20 mice, which was abolished in CURDHA-ME-treated animals (Figure 6C).…”

Associations of erythrocyte omega-3 fatty acids with cognition, brain imaging and biomarkers in the Alzheimer’s disease neuroimaging initiative: cross-sectional and longitudinal retrospective analyses

“…To our knowledge, only one study investigated the association between serum DHA levels and Aβ positron-emission tomography (PET) imaging, and reported an inverse correlation with brain Aβ load (8). Although even less is known, DHA could also additionally contribute to the inhibition of tau phosphorylation (9). Finally, the beneficial effects of ω-3 PUFA on cognition have been most often seen in cognitively healthy individuals or individuals with mild cognitive impairment (MCI) (10).…”

Alzheimer’s Disease and Specialized Pro-Resolving Lipid Mediators: Do MaR1, RvD1, and NPD1 Show Promise for Prevention and Treatment?

“…Furthermore, a prospective human study showed that the intake of DHA, the precursor of MaR1, significantly reduced the incidence of AD [125,126]. On the other hand, there are reports that while DHA treatment improved memory impairment in mice, MaR1 treatment did not [127,128]. Considering that ω-3 PUFAs were effective only in addressing MCI and not advanced AD [103][104][105], it is necessary to elucidate the mechanism by which DHA is metabolized into MaR1 and the biochemical relationship between MaR1 and its receptor.…”