Abstract
Compared with APOE3, APOE4 is associated with greater age-related cognitive decline and higher risk of neurodegenerative disorders. Therefore, development of supplements that target APOE genotype-modulated processes could provide a great benefit for the aging population. Evidence suggests a link between APOE genotype and docosahexaenoic acid (DHA); however, clinical studies with current DHA supplements have produced negative results in dementia. The lack of beneficial effects with current DHA supplements may be related to limited bioavailability, as the optimal form of DHA for brain uptake is lysophosphatidylcholine (LPC)-DHA. We previously developed a method to enrich the LPC-DHA content of krill oil through lipase treatment (LT-krill oil), which resulted in fivefold higher enrichment in brain DHA levels in wild-type mice compared with untreated krill oil. Here, we evaluated the effect of a control diet, diet containing krill oil, or a diet containing LT-krill oil in APOE3- and APOE4-targeted replacement mice (APOE-TR mice; treated from 4 to 12 months of age). We found that DHA levels in the plasma and hippocampus are lower in APOE4-TR mice and that LT-krill oil increased DHA levels in the plasma and hippocampus of both APOE3- and APOE4-TR mice. In APOE4-TR mice, LT-krill oil treatment resulted in higher levels of the synaptic vesicle protein SV2A and improved performance on the novel object recognition test. In conclusion, our data demonstrate that LPC-DHA/EPA-enriched krill oil can increase brain DHA and improve memory-relevant behavior in mice that express APOE4. Therefore, long-term use of LT-krill oil supplements may on some level protect against age-related neurodegeneration.
Highlights
The human APOE genotype is linked to several adult-onset neurodegenerative disorders, as APOE4 is associated with greater age-related cognitive decline, poorer outcomes following brain trauma, and higher risk of developing Alzheimer’s disease (Liu et al, 2013; Mahley, 2016; Flowers and Rebeck, 2020) compared with APOE3
As APOE4 is associated with greater neuronal dysfunction during aging, docosahexaenoic acid (DHA) may be important for neuroprotection
It has been proposed that human APOE4 carriers are more vulnerable to global dietary DHA deficiencies than APOE3 and that diets enriched in DHA may be protective for APOE4 carriers (Nock et al, 2017; Yassine et al, 2017a; Chappus-McCendie et al, 2019; Patrick, 2019)
Summary
The human APOE genotype is linked to several adult-onset neurodegenerative disorders, as APOE4 is associated with greater age-related cognitive decline, poorer outcomes following brain trauma, and higher risk of developing Alzheimer’s disease (Liu et al, 2013; Mahley, 2016; Flowers and Rebeck, 2020) compared with APOE3. DHA is an essential fatty acid involved in multiple processes that maintain neuron function, and there are reports of altered DHA levels in Alzheimer’s disease patients (Cunnane et al, 2013; Lo Van et al, 2016). With APOE4, the combination of a greater DHA requirement to maintain neuronal function, and lower brain DHA enrichment from dietary sources, could collectively contribute to cognitive decline during aging. DHA supplements could provide some level of protection against cognitive decline in APOE4 carriers, yet clinical studies have produced negative results in Alzheimer’s disease patients (reviewed in Yassine et al, 2017a). The lack of activity for current supplements in APOE4 carriers may be related to limited DHA bioavailability (Vandal et al, 2014; Arellanes et al, 2020; Tomaszewski et al, 2020), supporting the need to identify other supplements that can enrich brain DHA
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