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-ß (Aß) in LOAD are lacking. Innate immunity of LOAD patients is malfunctioning in phagocytosis and degradation of Aß 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 Aß 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.
Subject(s)
Alzheimer Disease/drug therapy , Dietary Supplements , Fatty Acids, Omega-3/administration & dosage , Immunity, Innate/drug effects , Leukocytes, Mononuclear/drug effects , Neurodegenerative Diseases/drug therapy , Oxidative Phosphorylation , Adult , Aged , Aged, 80 and over , Alzheimer Disease/genetics , Alzheimer Disease/immunology , Female , Humans , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Macrophages/drug effects , Macrophages/immunology , Macrophages/metabolism , Male , Middle Aged , Neurodegenerative Diseases/genetics , Neurodegenerative Diseases/immunology , Phagocytosis , Transcriptome/drug effectsABSTRACT
BACKGROUND: The cholinesterase inhibitor therapeutics (CI) approved for use in Alzheimer's disease (AD) are palliative for a limited time. OBJECTIVE: To examine the outcome of AD patients with add-on therapy of the omega-3 fatty acid drink Smartfish. METHODS: We performed a prospective study using Mini-Mental State Examination, amyloid-ß (Aß) phagocytosis blood assay, and RNA-seq of peripheral blood mononuclear cells in 28 neurodegenerative patients who had failed their therapies, including 8 subjective cognitive impairment (SCI), 8 mild cognitive impairment (MCI), 2 AD dementia, 1 frontotemporal dementia (FTD), 2 vascular cognitive impairment, and 3 dementia with Lewy bodies (DLB) patients. RESULTS: MCI, FTD, and DLB patients patients volunteered for the addition of a ω-3 fatty acid drink Smartfish protected by anti-oxidants to failing CI therapy. On this therapy, all MCI patients improved in the first year energy transcripts, Aß phagocytosis, cognition, and activities of daily living; in the long term, they remained in MCI status two to 4.5 years. All FTD and DLB patients rapidly progressed to dementia. On in vivo or in vitroω-3 treatments, peripheral blood mononuclear cells of MCI patients upregulated energy enzymes for glycolysis and citric acid cycle, as well as the anti-inflammatory circadian genes CLOCK and ARNTL2. CONCLUSION: Add-on ω-3 therapy to CI may delay dementia in certain patients who had failed single CI therapy.
