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

Abstract

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 Aβ1–42 phagocytosis 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 Aβ1–42 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) ε3/ε3 and ApoE ε3/ε4 groups was 26.0 and macrophage Aβ1–42 phagocytosis 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. Aβ1–42 phagocytosis 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.

Effects of n-3 fatty acid treatment on monocyte phenotypes in humans with hypertriglyceridemia

“…In addition, besides the greater reductions in TG levels, the DPA content of MAT9001 may also help improve monocyte phenotypes given the potential direct anti-inflammatory effects of DPA (50). While our current study focused on effects of n-3 PUFAs on circulating monocyte phenotypes, previous studies showed that n-3 PUFAs may promote macrophage polarization from M1-like proinflammatory to M2-like phenotypes (51–53), which may also provide benefit on the prevention and treatment of ASCVD.…”

Recent developments in solid lipid nanoparticle and surface-modified solid lipid nanoparticle delivery systems for oral delivery of phyto-bioactive compounds in various chronic diseases

“…Recently, resveratrol has gained more interest to treat AD due to its greater neuroprotective effect, and many studies confirmed that resveratrol treatment significantly improved the cognition and biochemical parameters. [114][115][116][117][118][119][120][121][122][123] Recently, resveratrol-loaded SLN was studied for its bioavailability and brain delivery. Resveratrol was efficiently delivered to the brain and exhibited its potential bioactivity.…”

Modulation of innate immunity of patients with Alzheimer's disease by omega‐3 fatty acids

“…Translation of these results to patients with MCI is not straightforward because the inflammatory activation of peripheral blood mononuclear cells is heterogeneous: down‐regulated in a subgroup of “noninflammatory” patients and up‐regulated in a subgroup of “inflammatory” patients (47, 48). The macrophage phenotype of patients with MCI is also heterogeneous and either highly proinflammatory M1 or very low inflammatory M2 (49). Thus, ω‐3 therapy should lead to an intermediate proresolution M1‐M2 phenotype, as shown in a pilot study (49).…”

“…The macrophage phenotype of patients with MCI is also heterogeneous and either highly proinflammatory M1 or very low inflammatory M2 (49). Thus, ω‐3 therapy should lead to an intermediate proresolution M1‐M2 phenotype, as shown in a pilot study (49).…”

“…Immune approaches in animal models, such as chemokine receptor CCR2 antagonists, purinergic receptor P2Y6 antagonists, or a CX 3 CR1 agonist (31), target single genes in CNS myeloid cells and do not consider the heterogeneity of inflammation or immune exhaustion with deregulation of many genes and pathways in amyotrophic lateral sclerosis (50, 51) and AD (49). Remarkably, lipid mediators from ω‐3 regulate the activation of a multitude of genes and pathways that are related to inflammation and resolution in vitro and in vivo (52) and provide a different approach to AD therapy by multitargeting.…”