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O5‐05‐05: REPURPOSING THE KCA3.1 INHIBITOR SENICAPOC AS A MICROGLIA‐TARGETED THERAPEUTIC CANDIDATE FOR ALZHEIMER'S DISEASE
Author(s) -
Jin Lee-Way,
Di Lucente Jacopo,
Nguyen Hai Minh,
Singh Vikrant,
Chavez Monique,
Wulff Heike,
Maezawa Izumi
Publication year - 2018
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.2018.06.3023
Subject(s) - microglia , hippocampal formation , long term potentiation , neuroscience , dementia , medicine , neuroinflammation , pharmacology , inflammation , biology , receptor , pathology , disease
Background:Alzheimer’s disease (AD), the most common neurodegenerative disorder, is pathologically characterized by the presence of senile plaques (composed of amyloid beta) and neurofibrillary tangles in the brain. At present, there is no curative treatment available for AD. In our study, we explored the effect of a FDA approved drug for lipid-lowering, an agonist of the Peroxisome Proliferatoractivated Receptor a (PPARa), Gemfibrozil, on amyloid plaque pathology, neuroinflammation and memory in 5X Familial Alzheimer’s Disease (5XFAD) mouse model. Methods: Six months old 5XFAD mice (male and female; n1⁄46/group) were treated with Gem (7.5mg/kg/day) or vehicle via oral gavage daily for one month. To confirm the role of PPARa, transgenic 5XFAD mice null for PPARa were treated with Gem or Vehicle (n1⁄45). After one month, behavioral tests (Barnes maze, T maze, Open field) were performed, following which mice were perfused and brains were used for biochemical analysis. Results: We observed that Gem treatment remarkably reduced the level of amyloid beta (Ab) in the hippocampal homogenates compared to the transgenic untreated control (Tg) and vehicle groups. Moreover, double-labeling of hippocampal sections with Thioflavin S and Ab specific monoclonal antibody 6E10 revealed a marked decrease in the Thio-S positive area fraction and plaque count in the hippocampus of Gem treated mice, but not in the vehicle mice. Diaminobenzidine staining using 6E10 showed a similar pattern of results. Importantly, Gem treatment also showed reduced neuroinflammation including astrogliosis and microgliosis (indicated by GFAP and IBA1 respectively), decreased level of iNOS and apoptosis. Finally, Gem treated mice performed better than Vehicle treated mice in Barnes maze and T maze indicating that Gem significantly enhanced the memory in 5XFAD mice. However, Gem treatment was not able to enhance the memory in 5XFAD/PPARa-/mice, further confirming that activation of PPARa by Gem is the underlying mechanism. Conclusions:Our study demonstrates that Gemfibrozil, a FDA approved drug, can attenuate amyloid plaque pathology, reduce inflammation and enhance memory in 5XFAD model of AD. Acknowledgement: The study was supported by NIH (AG050431) and Alzheimer’s Association (ZEN-17-438829).