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Authors: Fiala, Milan | Cribbs, David H. | Rosenthal, Mark | Bernard, George

Article Type: Research Article

Abstract: Innate immunity provides the first line of defense by recognizing pathogen-associated microbial patterns and inducing key co-stimulatory molecules and cytokines, which activate the mechanisms of the adaptive immune response. Innate immune cells perform phagocytosis, which can clear pathogens and tissue waste products but may also contribute to tissue injury due to harmful side effects of inflammation. Genetic studies of APOE4, cytokine polymorphisms and overexpression of inflammatory genes suggest that chronic inflammation may have adverse effects in patients with sporadic Alzheimer's disease. However, a vaccine against amyloid-β induced beneficial clearance of amyloid-β deposits, possibly through Fc receptor-mediated stimulation of microglial and …macrophage uptake. A reconciliation of these two pathogenetic mechanisms is crucial to future progress in immune diagnosis and effective therapy. This may be possible by extending our recent observations suggesting that phagocytosis of amyloid-β by macrophages is excellent in normal subjects but is deficient in most AD patients. Thus increased proinflammatory cytokine levels and activated microglia and macrophages in patients may be compensatory for defective clearance of amyloid-β. Consequently, therapeutic interventions that increase phagocytosis of amyloid-β might decrease brain inflammation as well as reduce inflammation-induced neurodegeneration. Finally, peripheral blood leukocytes are a superior model system for investigation of innate immune dysfunction in Alzheimer's disease. Show more

Keywords: Amyloid-β, inflammation, innate immunity

DOI: 10.3233/JAD-2007-11406

Citation: Journal of Alzheimer's Disease, vol. 11, no. 4, pp. 457-463, 2007

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

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

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