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 β1-42(Aβ1-42), but are improved by ω-3 fatty acids (ω-3s). The hypothesis of this study was that active Aβ1-42phagocytosis by macrophages prevents brain amyloidosis and thus maintains cognition. We studied the effects of self-supplementation with a drink with ω-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 Aβ1-42phagocytosis 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) ε3/ε3 and ApoE ε3/ε4 groups was 26.0 and macrophage Aβ1-42phagocytosis was defective. The MMSE rate of change increased in the ApoE ε3/ε3 group a median 2.2 points per year (P = 0.015 compared to 0) but did not change in the ApoE ε3/ε4 group (P = 0.014 between groups). In the ApoE ε3/ε3 group, all patients remained cognitively stable or improved; in the ApoE ε3/ε4 group, 1 recovered from dementia, but 3 lapsed into dementia. The macrophage phenotype polarized in patients bearing ApoE ε3/ε3 to an intermediate (green zone) M1-M2 type at the rate of 0.226 U/yr, whereas in patients bearing ApoE ε3/ε4, 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. Aβ1-42phagocytosis increased in both ApoE groups (P = 0.03 in each groups). In vitro, the lipidic mediator resolvin D1 (RvD1) down regulated the M1 type in patients with ApoE ε3/ε3 but in some patients with ε3/ε4, paradoxically up-regulated the M1 type. Antioxidant/ω-3/resveratrol supplementation was associated with favorable immune and cognitive responses in ApoE ε3/ε3 and individual patients bearing ApoE ε3/ε4, and brings into personalized clinical practice the immune benefits expected from ω-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 ω-3 supplementation.
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, California, USA.
Sam
S
Famenini
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, California, USA.
Elizabeth A
EA
Rigali
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, California, USA.
Henry M
HM
Olivera-Perez
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, California, USA.
Johnny
J
Dang
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, California, USA.
Michael To
MT
Chang
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, California, USA.
Ramesh
R
Halder
Buck Institute for Research on Aging, Novato, California, USA; and.
Rammohan V
RV
Rao
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, California, USA.
Matteo
M
Pellegrini
Department of Neurology, University of California School of Medicine, Los Angeles, California; and.|Easton Laboratories for Neurodegenerative Disease, University of California School of Medicine, Los Angeles, California, USA.
Verna
V
Porter
Buck Institute for Research on Aging, Novato, California, USA; and.|Department of Neurology, University of California School of Medicine, Los Angeles, California; and.|Easton Laboratories for Neurodegenerative Disease, University of California School of Medicine, Los Angeles, California, USA.
Dale
D
Bredesen
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, California, USA; mfiala@ucla.edu.
Milan
M
Fiala
D000368:Aged; D000369:Aged, 80 and over; D001057:Apolipoproteins E / Q000097:blood / Q000145:classification / Q000378:metabolism; D003071:Cognition / Q000187:drug effects*; D003072:Cognition Disorders / Q000188:drug therapy*; D019587:Dietary Supplements; D015525:Fatty Acids, Omega-3 / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008875:Middle Aged
D001057:Apolipoproteins E; D015525:Fatty Acids, Omega-3
ApoE genotype; amyloid-β phagocytosis; inflammation; resolvin D1; ω-3 fatty acids
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