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P2‐326: Towards a comprehensive analysis of the role of inflammatory mediators on Alzheimer's like pathology in pre‐clinical mouse models
Author(s) -
Chakrabarty Paramita,
CeballosDiaz Carolina,
Beccard Amanda,
Cruz Pedro,
Dickson Dennis,
Das Pritam,
Golde Todd
Publication year - 2011
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.2011.05.1202
Subject(s) - inflammation , neuropathology , neurodegeneration , innate immune system , proinflammatory cytokine , context (archaeology) , immunology , biology , microglia , tumor necrosis factor alpha , interleukin , alzheimer's disease , neuroscience , immune system , cytokine , medicine , pathology , disease , paleontology
Background: Beta-secretase, BACE1 is a membrane-bound aspartyl protease that cleaves amyloid precursor protein (APP) to produce beta-amyloid protein (Abeta). Reticulon (RTN) proteins such as RTN3 have been identified as membrane proteins that interact with BACE1 and inhibit its Abeta-generating activity. It has not yet been clarified whether RTN3 can regulate Abeta production in vivo. We investigated this issue by using transgenic mice expressing APP with Swedish and London mutations (APP-SL Tg mice) and those expressing RTN3 (RTN3 Tg mice). Methods: APP-SL Tg mice and RTN3 Tg mice were generated on the same genetic background (C57BL/6). These heterozygous mice were crossed to generate double Tg mice expressing APP and RTN3 (A-R Tg mice). At the age of w15 months, immunohistochemical and biochemical analyses of single APP Tg mice and double A-R Tg mice were performed to evaluate the extent of Abeta accumulation in specific brain regions such as the hippocampus and the cerebral cortex. Results: Western blot analysis showed that expression levels of RTN3 protein in the cerebral cortex of RTN3 Tg mice were w1.4-fold higher than those in non-transgenic controls. Immunohistochemical analysis demonstrated that Abeta plaque load was decreased by w50% in the hippocampus and the cerebral cortex of A-R Tg mice, compared to APP-SL Tg mice. The levels of guanidine-soluble Abeta in these brain regions of A-R Tg mice, estimated by sandwich ELISA, were also relatively lower than those in APP-SL Tg mice. Conclusions: These findings indicate that even a small increase of RTN3 expression exerts an inhibitory effect on Abeta accumulation in our Alzheimer’s disease (AD) model mice and imply that induction of RTN3 may be an effective approach for the treatment of AD.