Omega‐3 fatty acids increase OXPHOS energy for immune therapy of Alzheimer disease patients

Abstract

Sporadic late-onset Alzheimer disease (LOAD) preceded by mild cognitive impairment (MCI) is the most common type of dementia. Long-term studies of immunity to pathogenic amyloid-β (Aβ) in LOAD are lacking. Innate immunity of LOAD patients is malfunctioning in phagocytosis and degradation of Aβ and LOAD patients' macrophage transcriptome and metabolome are deregulated. We previously showed omega-3 fatty acid (ω-3)-mediated repair of unfolded protein response and here we show much broader transcriptomic effects. ω-3 treatment in vitro and ω-3 supplementation by the drink Smartfish (SMF) in vivo increased the transcripts of the genes and pathways of immunity, glycolysis, tricarboxylic acid cycle, OX-PHOS, nicotinamide dinucleotide (NAD +) synthesis, and reversed the defects in Aβ phagocytosis. In both peripheral blood mononuclear cells (PBMC) and macrophages, ω-3 increased ATP-linked oxygen consumption rate (OCR) and ω-3 with carnitine was superior to ω-3. ω-3 treatment in vitro and supplementation by the ω-3 drink SMF in vivo rescued macrophage phagocytosis when glycolysis or glycosylation were blocked. ω-3 provide flexible energy for immune clearance of the brain throughout the diurnal cycle, even in hypo-or hyper-glycemia. In certain LOAD patients, ω-3 may delay progression to dementia.

The Immunometabolic Roles of Various Fatty Acids in Macrophages and Lymphocytes

“…Adolescents with obesity who received 1.2 g/day of omega-3 FAs for the same period of intervention had elevated serum omega-3 FA concentrations together with lower inflammatory markers [58]. Apart from the control of macrophage metabolism and function by FAs, Lau et al [59] reported that monocytederived macrophages from patients with Alzheimer's disease treated with omega-3 FAs had increased ATP synthesis through oxidative phosphorylation [59], suggesting a move to a less inflammatory phenotype.…”

The Role of M1- and M2-Type Macrophages in Neurological and Infectious Diseases

“…In an uncontrolled study of mild cognitive impairment (MCI) patients supplemented by the omega-3 fatty acid drink Smartfish, macrophage phenotype changed from either a highly inflammatory M1 or a very low non-inflammatory M2 to the desired pro-resolution M1/M2 (Table 1) [2]. Importantly, in this study, PUFA supplementation improved the cognitive status of MCI/AD patients for 4-17 months and protected against dementia for 4.5 years in certain patients [13]. In vivo supplementation and in vitro stimulation by the Smartfish drink stimulated the pro-resolution M1/M2 macrophage type with increased phagocytosis and energy [14].…”

“…RNA-seq analysis of single blood cell types in PUFA-supplemented MCI patients showed up-regulation of the transcripts for glycolysis, tricarboxylic acid cycle, OX-PHOS, nicotinamide dinucleotide (NAD + ) synthesis in monocytes, neutrophils, regulatory T cells, memory CD4 and CD8 T cells, and NK cells, but the most consistent effects across the whole spectrum were in monocytes/macrophages (MM). Importantly, the supplementation showed that PUFA provide energy for immune clearance of the brain throughout the diurnal cycle and even in hypo-or hyper-glycemia [13]. Both hypo-and hyper-glycemic glucose concentrations in the medium of macrophages in vitro inhibit Aβ phagocytosis, but phagocytosis is restored in presence of PUFA in the medium.…”

Mitochondrial Dysfunction in Advanced Liver Disease: Emerging Concepts

“…This study demonstrated the role for omega-3 PUFAs in the mitochondrial membrane reorganization while ameliorating mitochondrial function and ADP sensitivity ( Herbst et al, 2014 ). Importantly, dietary omega-3 PUFA enrichment favored ATP-linked OCR in both peripheral mononuclear cells and macrophages ( Lau et al, 2020 ).…”