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P1‐096: IRAK‐4 KINASE INHIBITION REDUCES PRO‐INFLAMMATORY CYTOKINE SECRETION BUT HAS NO EFFECT ON THE UPTAKE OF AMYLOID BETA BY HUMAN GLIAL CELLS
Author(s) -
Vies Saskia M.,
Haastert Elise S.,
Mulder Sandra,
Nielsen Henrietta M.,
Veerhuis Rob,
Ruijtenbeek Rob,
Rozemuller Annemieke J.M.,
Hilhorst Riet,
Hoozemans Jeroen J.M.
Publication year - 2014
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2014.05.332
Subject(s) - microglia , cytokine , kinase , pathogenesis , biology , receptor , alzheimer's disease , secretion , protein kinase a , microbiology and biotechnology , inflammation , immunology , medicine , pathology , endocrinology , biochemistry , disease
which function in innate immunity also suggests that innate immunity may have a significant role in AD. Given that gliosis occurs at least decades earlier than the first appearance of clinical symptoms in AD, it is conceivable that glial dysfunction and mis-activation of the innate immune system drives AD type neurodegeneration.However, very few studies have directly addressed how inflammation per se drives Ab or tau pathology.To characterize the role of innate immunefactors on amyloid b (Ab) plaque and tau pathology, we overexpressed several mouse cytokines, chemokine receptors and soluble innate immune receptors in Amyloid precursor protein (APP) expressingTgCRND8 mice or tau transgenic mice. Methods: Using adeno associated virus (AAV2/1) mediated gene delivery in neonatal mice brain, we effectively demonstrate that this technique allows us to achieve high levels of transgene expression while 1) bypassing the need to create bigenic mice to test hypotheses in a rapid cost-effective manner, 2) testing different mediators on a uniform genetic background and 3) modeling cell non autonomous signaling in vivo. Results: We show that in TgCRND8 mice brain, expression of 1) inflammatory cytokines reduce Ab plaques; 2) anti-inflammatory cytokines exacerbate Ab pathology; and 3) modulating the innate immune receptors using soluble Toll-like receptors (sTLR4 and sTLR5) decrease Ab pathology. On the other hand, over-expression of inflammatory cytokines increase soluble phosphorylated tau while differentially affecting insoluble tau levels in tau transgenic mice. Conclusions: Understanding how innate immune activation states regulate tau and Abpathology could reveal novel therapeutic approaches for AD, including re-purposing current forms of immune therapy already tested in the clinic. Our ongoing studies show that manipulating innate immunity can be a double edged sword, and that development of any innate immune therapy for AD will need to be finely tuned and extensively validated in order to be truly effective. We demonstrate that though engagement of the innate immune system early on during disease pathogenesis may be beneficial in restricting the development of Ab plaques, this may potentially exacerbate tau pathology and negatively affect proteostasis. Therefore, our study strongly argues for a cautious re-examination of unwarranted side-effects of immune based therapies and calls for exploring the therapeutic potential of decoy receptors in preclinical mouse models ofAD as a means of restricting AD pathology while simultaneously minimizing bystander toxicity.