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Department of Pharmacology and Experimental Neuroscience, Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE 68198-5880
Vaccination therapy of AD animal models and patients strongly suggests an active role of brain mononuclear phagocytes in immune-mediated clearance of amyloid-β peptides (Aβ) in brain. Although Aβ uptake by macrophages can be regulated by pro- and anti-inflammatory cytokines, their effects on macrophage-mediated Aβ degradation are poorly understood. To better understand this mechanism of degradation, we examined whether pro- and anti-inflammatory cytokines affect the degradation of Aβ using primary cultured human monocyte-derived macrophages (MDM) and microglia using pulse-chase analysis of fibrillar and oligomer 125I-Aβ40 and Aβ42. Initial uptake of fibrillar Aβ40 and Aβ42 was 40% and its degradation was saturated by 120 h in both MDM and microglia, compared with an initial uptake of oligomeric Aβ less than 0.5% and saturation of degradation within 24 h. IFN-
increased the intracellular retention of fibrillar Aβ40 and Aβ42 by inhibiting degradation, whereas IL-4, IL-10, and TGF-β1, but not IL-13 and IL-27, enhanced degradation. Fibrillar Aβ degradation in MDM is sensitive to lysosomal and insulin degrading enzyme inhibitors but insensitive to proteasomal and neprilysin inhibitors. IFN- and TNF-
directly reduced the expression of insulin degrading enzyme and chaperone molecules (heat shock protein 70 and heat shock cognate protein 70), which are involved in refolding of aggregated proteins. Coculture of MDM with activated, but not naive T cells, suppressed Aβ degradation in MDM, which was partially blocked by a combination of neutralizing Abs against proinflammatory cytokines. These data suggest that proinflammatory cytokines suppress Aβ degradation in MDM, whereas select anti-inflammatory and regulatory cytokines antagonize these effects.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Vada Kinman Alzheimer’s Research Awards (to T.I. and J.K.), NIH P01 NS043985 (to T.I.), and Nebraska Tobacco Settlement Biomedical Research Development Fund (to J.K.).
2 These two authors contributed equally to this work.
3 Current address: Department of Neuroscience, University of Virginia Health System, Charlottesville, VA 22908.
4 Address correspondence and reprint requests to Dr. Tsuneya Ikezu, Department of Pharmacology and Experimental Neuroscience, 985880 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198-5880. E-mail address: tikezu{at}unmc.edu
5 Abbreviations used in this paper: Aβ, β-amyloid peptide; AD, Alzheimer’s disease; APP, β-amyloid precursor protein; MDM, monocyte-derived macrophage; AFM, atomic force microscopy; IDE, insulin degrading enzyme; HSP70, heat shock protein 70; M6P-R, anti-mannose-6-phosphate receptor; AcLDL, acetylated low-density lipoprotein; HSC70, heat shock cognate protein 70.
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