Guillot-Sestier MV, Doty KR, Gate D, Rodriguez J Jr, Leung BP, Rezai-Zadeh K, Town T. Il10 deficiency rebalances innate immunity to mitigate Alzheimer-like pathology. Neuron. 2015 Feb 4;85(3):534-48. Epub 2015 Jan 22 PubMed.

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  1. There is considerable confusion over the roles of neuroinflammation in animal models of Alzheimer’s disease and other neurodegenerative disorders. The complementary studies of Chakrabarty et al. and Guillot-Sestier et al. have shed new light, but not necessarily enhanced understanding, of the roles of IL-10 in AD pathogenesis. The anti-inflammatory cytokine IL-10 was generally thought to have salutary effects in mouse models of AD, based on a modest literature. The two new studies have provided compelling evidence that IL-10 acts to exacerbate amyloid pathology and impair behavior. Thus, we have fundamentally misunderstood the in vivo actions of this cytokine. Clearly, this is not the only immune effector whose actions in the brain have not conformed to their established roles in the periphery. These compelling and provocative studies serve to highlight the turmoil in understanding the complex actions of immunity in the normal and diseased brain. The field as a whole is undergoing a resurgence in interest owing to new genetic linkages of immune genes to various neurodegenerative diseases. However, as the current work highlights, loss- and gain-of-function interventions have yielded unpredicted and not readily interpretable outcomes. And our notions of pro- and anti-inflammatory actions, based largely on studies in peripheral macrophages, have proven to be false.

    Both papers report IL-10 regulation of ApoE expression in the brain, which was not previously appreciated. Similarly, they postulate that phagocytosis is suppressed by IL-10. The linkage between these two observations was explored by Guillot-Sestier et al. who found IL-10- and ApoE-isoform-dependent microglial phagocytosis, and the basis of this latter effect is unexplained. Chakrabarty et al. report an ApoE-stimulated uptake of Aβ (and it is unclear whether this was murine or human ApoE), using an unusual experimental design. While the new data strongly suggests that ApoE may participate in Aβ uptake by microglia, I think the jury is still out, and this point requires additional investigation.

    View all comments by Gary Landreth

  2. This is nice intricate work in a model system on the importance of inflammation in clearing amyloid-β (Aβ), as shown indirectly through improvement of clearance by blockade of IL-10. The role of inflammatory activation of macrophages/microglia and phagocytosis of Aβ has been investigated in patients with AD and controls for years (Fiala et al., 2001, 2002, 2007, 2009, 2015). The effect of the blockade of IL-10 is another piece of evidence that inflammation can be both detrimental and beneficial. However, inflammation in animal models has low correlation with human inflammation (Seok et al., 2013). The patients with AD and mild cognitive impairment are very heterogeneous, either “inflammatory” with a high level of inflammation, or “non-inflammatory” with a low level of inflammation. Any single approach is not going to fit all, and modulation of cytokines over long periods has unknown consequences. It is clear from our studies that phagocytosis of Aβ is defective in all AD and MCI patients (unless supplemented with omega-3); whereas it is excellent in some cognitively normal persons into very old age. Thus physiological mechanisms exist which balance inflammation and phagocytosis. Omega-3 fatty acid-derived specialized proresolving mediators (resolvins, protectins and maresins) both terminate inflammation and perform resolution (Serhan and Petasis, 2011). Extensive studies of omega-3 fatty acids are ongoing in various disorders. Our recent study shows that omega-3 fatty acid supplementation in MCI patients with a daily drink, Smartfish, increases phagocytosis of Aβ and resolvin D1 in macrophages (Fiala et al., 2015). Omega-3 supplementation is a practical approach for improving amyloid-beta immunity in MCI patients, which seems to also stabilize the cognition (Freund-Levi et al., 2006).

    References:

    Fiala M, Liu QN, Reddy S, Graves MC. Macrophages infiltrate the brain and express COX-2 and iNOS in Alzheimer's disease and AIDS. Alzheimer's Rep. 2001;4(1):1-7.

    Fiala M, Liu QN, Sayre J, Pop V, Brahmandam V, Graves MC, Vinters HV. Cyclooxygenase-2-positive macrophages infiltrate the Alzheimer's disease brain and damage the blood-brain barrier. Eur J Clin Invest. 2002 May;32(5):360-71. PubMed.

    Fiala M, Liu PT, Espinosa-Jeffrey A, Rosenthal MJ, Bernard G, Ringman JM, Sayre J, Zhang L, Zaghi J, Dejbakhsh S, Chiang B, Hui J, Mahanian M, Baghaee A, Hong P, Cashman J. Innate immunity and transcription of MGAT-III and Toll-like receptors in Alzheimer's disease patients are improved by bisdemethoxycurcumin. Proc Natl Acad Sci U S A. 2007 Jul 31;104(31):12849-54. PubMed.

    Avagyan H, Goldenson B, Tse E, Masoumi A, Porter V, Wiedau-Pazos M, Sayre J, Ong R, Mahanian M, Koo P, Bae S, Micic M, Liu PT, Rosenthal MJ, Fiala M. Immune blood biomarkers of Alzheimer disease patients. J Neuroimmunol. 2009 May 29;210(1-2):67-72. PubMed.

    Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, Richards DR, McDonald-Smith GP, Gao H, Hennessy L, Finnerty CC, López CM, Honari S, Moore EE, Minei JP, Cuschieri J, Bankey PE, Johnson JL, Sperry J, Nathens AB, Billiar TR, West MA, Jeschke MG, Klein MB, Gamelli RL, Gibran NS, Brownstein BH, Miller-Graziano C, Calvano SE, Mason PH, Cobb JP, Rahme LG, Lowry SF, Maier RV, Moldawer LL, Herndon DN, Davis RW, Xiao W, Tompkins RG, Inflammation and Host Response to Injury, Large Scale Collaborative Research Program. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):3507-12. Epub 2013 Feb 11 PubMed.

    Serhan CN, Petasis NA. Resolvins and protectins in inflammation resolution. Chem Rev. 2011 Oct 12;111(10):5922-43. Epub 2011 Jul 18 PubMed.

    Fiala M, Halder RC, Sagong B, Ross O, Sayre J, Porter V, Bredesen DE. ω-3 Supplementation increases amyloid-β phagocytosis and resolvin D1 in patients with minor cognitive impairment. FASEB J. 2015 Jul;29(7):2681-9. Epub 2015 Mar 24 PubMed.

    Freund-Levi Y, Eriksdotter-Jönhagen M, Cederholm T, Basun H, Faxén-Irving G, Garlind A, Vedin I, Vessby B, Wahlund LO, Palmblad J. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch Neurol. 2006 Oct;63(10):1402-8. PubMed.

    View all comments by Milan Fiala

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