MGAT3 mRNA: A Biomarker for Prognosis and Therapy of Alzheimer's Disease by Vitamin D and Curcuminoids
Authors: Fiala, Milan | Mahanian, Michelle | Rosenthal, Mark | Mizwicki, Matthew T. | Tse, Eric | Cho, Tiffany | Sayre, James | Weitzman, Rachel | Porter, Verna
Article Type: Research Article
Abstract: Practical biomarkers of Alzheimer's disease (AD) prognosis are lacking. Correspondingly, no drugs are known to decrease disease progression, although vitamin D3 has positive effects on cognition in vivo and 1α, 25-dihydroxyvitamin D3 (1,25 D3) on amyloid-β 1-42 (Aβ) phagocytosis in vitro. We have examined in a pilot study a new biomarker in peripheral blood mononuclear cells, the transcription of mRNA of β-1,4-mannosyl-glycoprotein 4-β-N-acetylglucosaminyltransferase (MGAT3), the essential gene for Aβ phagocytosis. The transcription of MGAT3 stimulated by Aβ distinguishes macrophages into Type 0 (very low MGAT3 transcription), Type I (low MGAT3 transcription up regulated by bisdemethoxycurcumin), and Type II (high MGAT3 …transcription down regulated by bisdemethoxycurcumin). In this pilot study of 20 AD patients and 20 control subjects, 45% patients, but only 10% control subjects, were Type 0 (p-value = 0.009). Type 0 AD patients had worse 2-year prognosis regarding loss of independence than Type I and Type II patients (p-value = 0.013). Phagocytosis of Aβ in Type I and II patients was shown to be dependent on 1,25 D3 using a specific inhibitor of the 1,25 D3-VDR activated nuclear receptor transcription factor. In a Type II patient, recovery from cognitive dysfunction related to surgical anesthesia was preceded by an improvement in phagocytosis of Aβ. The results of this pilot study suggest that the MGAT3 Type biomarker may characterize subgroups of AD patients with different disease progression. In vitro results suggest that vitamin D3 supplementation might be beneficial in both Type I and II patients, whereas curcuminoids only in Type I. These results must be investigated in a large prospective study. Show more
Keywords: Alzheimer's disease, amyloid-β, MGAT3, surgical anesthesia, vitamin D3
DOI: 10.3233/JAD-2011-101950
Citation: Journal of Alzheimer's Disease, vol. 25, no. 1, pp. 135-144, 2011
Curcuminoids enhance amyloid-β uptake by macrophages of Alzheimer's disease patients
Authors: Zhang, Laura | Fiala, Milan | Cashman, John | Sayre, James | Espinosa, Araceli | Mahanian, Michelle | Zaghi, Justin | Badmaev, Vladimir | Graves, Michael C. | Bernard, George | Rosenthal, Mark
Article Type: Research Article
Abstract: Treatment of Alzheimer's disease (AD) is difficult due to ignorance of its pathogenesis. AD patients have defects in phagocytosis of amyloid-β (1-42) (Aβ) in vitro by the innate immune cells, monocyte/macrophages and in clearance of Aβ plaques [5]. The natural product curcuminoids enhanced brain clearance of Aβ in animal models. We, therefore, treated macrophages of six AD patients and 3 controls by curcuminoids in vitro and measured Aβ uptake using fluorescence and confocal microscopy. At baseline, the intensity of Aβ uptake by AD macrophages was significantly lower in comparison to control macrophages and involved surface binding but no intracellular uptake. …After treatment of macrophages with curcuminoids, Aβ uptake by macrophages of three of the six AD patients was significantly (P<0.001 to 0.081) increased. Confocal microscopy of AD macrophages responsive to curcuminoids showed surface binding in untreated macrophages but co-localization with phalloidin in an intracellular compartment after treatment. Immunomodulation of the innate immune system by curcuminoids might be a safe approach to immune clearance of amyloidosis in AD brain. Show more
Keywords: Alzheimer's disease, amyloid-β, phagocytosis, curcuminoids, immunomodulation
DOI: 10.3233/JAD-2006-10101
Citation: Journal of Alzheimer's Disease, vol. 10, no. 1, pp. 1-7, 2006
Omega-3 Fatty Acids Increase Amyloid-β Immunity, Energy, and Circadian Rhythm for Cognitive Protection of Alzheimer’s Disease Patients Beyond Cholinesterase Inhibitors
Authors: Fiala, Milan | Lau, Yik Chai Charles | Aghajani, Anthony | Bhargava, Sneha | Aminpour, Eli | Kaczor-Urbanowicz, Karolina Elżbieta | Mirzoyan, Hayk | Nichols, India | Ko, Meng-Wei | Morselli, Marco | Santana, Joslyn | Dang, Johnny | Sayre, James | Paul, Ketema | Pellegrini, Matteo
Article Type: Research Article
Abstract: 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-β (Aβ) 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, Aβ 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 vitro ω -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. Show more
Keywords: Amyloid-beta, bioenergy, cell signaling, cholinesterase inhibitor, glycolysis, ω-3 fatty acids, phagocytosis, tricarboxylic cycle
DOI: 10.3233/JAD-200252
Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 993-1002, 2020
Ineffective phagocytosis of amyloid-β by macrophages of Alzheimer's disease patients
Authors: Fiala, Milan | Lin, Justin | Ringman, John | Kermani-Arab, Vali | Tsao, George | Patel, Amish | Lossinsky, Albert S. | Graves, Michael C. | Gustavson, Andrew | Sayre, James | Sofroni, Emanuela | Suarez, Tatiana | Chiappelli, Francesco | Bernard, George
Article Type: Research Article
Abstract: The defective clearance of amyloid-β (Aβ) in the brain of Alzheimer's disease (AD) patients is unexplained. The immunohistochemical studies of the frontal lobe and hippocampus show perivascular and intraplaque infiltration by blood-borne macrophages containing intracellular Aβ but only inefficient clearance of Aβ deposits. Neurons and neuronal nuclei, respectively, express interleukin-1β and the chemokine RANTES, which could induce the inflammatory cell infiltration. To clarify the pathophysiology of Aβ clearance, we examined Aβ phagocytosis by monocytes and macrophages isolated from the blood of age-matched patients and controls. Control monocytes display excellent differentiation into macrophages and intracellular phagocytosis of Aβ followed by Aβ …degradation or export. AD monocytes show poor differentiation and only surface uptake of Aβ and suffer apoptosis. HLA DR and cyclooxygenase-2 are abnormally expressed on neutrophils and monocytes of AD patients. AD patients have higher levels of intracellular cytokines compared to controls. Thus Aβ clearance is not restricted to brain microglia and involves systemic innate immune responses. In AD, however, macrophage phagocytosis is defective, which may elicit compensatory response by the adaptive immune system. Show more
Keywords: macrophage/monocyte, amyloid-beta phagocytosis, macrophage apoptosis, innate immunity, inflammation and Alzheimer's disease
DOI: 10.3233/JAD-2005-7304
Citation: Journal of Alzheimer's Disease, vol. 7, no. 3, pp. 221-232, 2005
1α,25-Dihydroxyvitamin D 3 and Resolvin D1 Retune the Balance between Amyloid-β Phagocytosis and Inflammation in Alzheimer's Disease Patients
Authors: Mizwicki, Mathew T. | Liu, Guanghao | Fiala, Milan | Magpantay, Larry | Sayre, James | Siani, Avi | Mahanian, Michelle | Weitzman, Rachel | Hayden, Eric Y. | Rosenthal, Mark J. | Nemere, Ilka | Ringman, John | Teplow, David B.
Article Type: Research Article
Abstract: As immune defects in amyloid-β (Aβ) phagocytosis and degradation underlie Aβ deposition and inflammation in Alzheimer's disease (AD) brain, better understanding of the relation between Aβ phagocytosis and inflammation could lead to promising preventive strategies. We tested two immune modulators in peripheral blood mononuclear cells (PBMCs) of AD patients and controls: 1α,25(OH)2 -vitamin D3 (1,25D3) and resolvin D1 (RvD1). Both 1,25D3 and RvD1 improved phagocytosis of FAM-Aβ by AD macrophages and inhibited fibrillar Aβ-induced apoptosis. The action of 1,25D3 depended on the nuclear vitamin D and the protein disulfide isomerase A3 receptors, whereas RvD1 required the chemokine receptor, GPR32. The …activities of 1,25D3 and RvD1 commonly required intracellular calcium, MEK1/2, PKA, and PI3K signaling; however, the effect of RvD1 was more sensitive to pertussis toxin. In this case study, the AD patients: a) showed significant transcriptional up regulation of IL1RN, ITGB2, and NFκB; and b) revealed two distinct groups when compared to controls: group 1 decreased and group 2 increased transcription of TLRs, IL-1, IL1R1 and chemokines. In the PBMCs/macrophages of both groups, soluble Aβ (sAβ) increased the transcription/secretion of cytokines (e.g., IL1 and IL6) and chemokines (e.g., CCLs and CXCLs) and 1,25D3/RvD1 reversed most of the sAβ effects. However, they both further increased the expression of IL1 in the group 1, sβ-treated cells. We conclude that in vitro, 1,25D3 and RvD1 rebalance inflammation to promote Aβ phagocytosis, and suggest that low vitamin D3 and docosahexaenoic acid intake and/or poor anabolic production of 1,25D3/RvD1 in PBMCs could contribute to AD onset/pathology. Show more
Keywords: Alzheimer's disease, amyloid-β, 1α,25-dihydroxyvitamin D3, phagocytosis, resolvin D1
DOI: 10.3233/JAD-121735
Citation: Journal of Alzheimer's Disease, vol. 34, no. 1, pp. 155-170, 2013