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P3‐417: Antisense directed at the Abeta region of APP reverses the differences in the phosphatidylinositol signaling pathway seen in aged, senescence accelerated mice
Author(s) -
Morley John E.,
Kumar Vijaya B.,
Armbrecht Harvey J.,
Siddique Akbar,
Green Michael,
Banks William A.,
Farr Susan A.
Publication year - 2010
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.2010.05.1960
Subject(s) - signal transduction , gene , biology , phosphatidylinositol , gene expression , hippocampal formation , microbiology and biotechnology , genetics , endocrinology
peripheral mononuclear phagocytes promotes brain trafficking and infiltration of these cells in AD model mice. Methods: We have developed a peripheral mononuclear phagocyte model system using thioglycollate-elicited peritoneal macrophages. This system relies on Ab pulse-chase assays and in-gel kinase analyses to evaluate the relative contribution(s) of transforming growth factor-b (TGF-b)-Smad 2/3 and bone morphogenic protein (BMP)Smad 1/5/8 signaling pathways to macrophage Ab uptake. Results: We show that blood-born professional phagocytes demonstrate the capacity to engulf cerebral b-amyloid deposits without inducing deleterious bystander inflammation. Interestingly, following inhibition of classical TGF-b-Smad 2/3 signaling, peripheral macrophages show concomitant hyper-activation of alternative BMP-Smad 1/5/8 signaling and increased uptake and clearance of Ab. We also show that direct stimulation with either BMP-2 or BMP-4 results in elevated Smad 1/5/8 signaling and PAK2 phosphorylation. This shift in favor of BMP-Smad signaling seems to initiate cytoskeletal remodeling required for enhanced Ab uptake and clearance in this scenario. Conclusions: Taken together, our results suggest that shifting from TGF-b-Smad 2/3 to BMP-Smad 1/5/8 signaling is essential for efficient macrophage Ab phagocytosis. Pharmacologic strategies targeting these pathways in peripheral mononuclear phagocytes would, in principle, have significant potential for treatment of AD.