Increased intermediate M1-M2 macrophage polarization and improved cognition in mild cognitive impairment patients on ω-3 supplementation

Monocyte/macrophages of patients with mild cognitive impairment (MCI) and Alzheimer disease (AD) are defective in phagocytosis and degradation amyloid beta(1-42) (A beta(1-42)), but are improved by omega-3 fatty acids (omega-3s). The hypothesis of this study was that active A beta(1-42) phagocytosis by macrophages prevents brain amyloidosis and thus maintains cognition. We studied the effects of self-supplementation with a drink withv-3s, antioxidants, and resveratrol on Mini-Mental State Examination (MMSE) scores, macrophage M1M2 phenotype [the ratio of inflammatory cluster of differentiation (CD) 54+CD80 and proresolution markers CD163+CD206], and A beta(1-42) phagocytosis in patients initially diagnosed as having MCI or subjective cognitive impairment (SCI). At baseline, the median MMSE score in patients in both the apolipoprotein E (ApoE) epsilon 3/epsilon 3 and ApoE epsilon 3/epsilon 4 groups was 26.0 and macrophage Ab1-42 phagocytosis was defective. The MMSE rate of change increased in the ApoE epsilon 3/epsilon 3 group a median 2.2 points per year (P=0.015 compared to 0) but did not change in the ApoE epsilon 3/epsilon 4 group(P = 0.014 between groups). In the ApoE epsilon 3/epsilon 3 group, all patients remained cognitively stable or improved; in the ApoE epsilon 3/epsilon 4 group, 1 recovered from dementia, but 3 lapsed into dementia. The macrophage phenotype polarized in patients bearing ApoE epsilon 3/epsilon 3 to an intermediate (green zone) M1-M2 type at the rate of 0.226 U/yr, whereas in patients bearing ApoE epsilon 3/epsilon 4, polarization was negative (P=0.08 between groups). The baseline M1M2 type in the extreme M1(red zone) or M2 (white zone) was unfavorable for cognitive outcome. A beta(1-42) phagocytosis increased in both ApoE groups (P= 0.03 in each groups). In vitro, the lipidic mediator resolv in D1(RvD1) down regulated the M1 type in patients with ApoE epsilon 3/epsilon 3 but in some patients with epsilon 3/epsilon 4, paradoxically up-regulated the M1 type. Antioxidant/omega-3/resveratrol supplementation was associated with favorable immune and cognitive responses in ApoE epsilon 3/epsilon 3 and individual patients bearing ApoE epsilon 3/epsilon 4, and brings into personalized clinical practice the immune benefits expected from omega-3 mediators called resolvins. The validity of this study is limited by its small size and uncontrolled design.-Famenini, S., Rigali, E. A., Olivera-Perez, H. M., Dang, J., Chang, M T., Halder, R., Rao, R. V., Pellegrini, M., Porter, V., Bredesen, D., Fiala, M. Increased intermediate M1-M2 macrophage polarization and improved cognition in mild cognitive impairment patients on v-3 supplementation.