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P3‐368: Stabilization of mitochondrial function, the probable effects of SWe on mitochondrial dysfunction mimicked Alzheimer models
Author(s) -
Zhang Ruyi,
Li Lin
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.2010.05.1910
Subject(s) - mitochondrion , cytochrome c , apoptosis , microbiology and biotechnology , cytochrome c oxidase , sodium azide , membrane potential , mitochondrial apoptosis induced channel , apoptosis inducing factor , caspase 9 , chemistry , programmed cell death , biology , caspase 3 , caspase , biochemistry
transmembrane receptor (CSF-1R) kinase inhibitors, PLX647 and PLX3397, were formulated as drug chows using standard AIN17 chow. 8-week-old C57/b6 mice were injected with LPS (0.5 mpk i.p) every other day for 1 week to drive CNS inflammation. Groups of mice were treated simultaneously with either control diet, or diet supplemented with either PLX647 or PLX3397 at doses of 100 or 200 mpk. After one week of LPS+treatment, CNS inflammation was assessed. Results: We found robust reductions in TNFa and IL1b with treatments, and highly significant reductions in IBA1-positive microglia and number, showing that CSF-1R inhibitors were able to cross the blood brain barrier, and to effectively prevent microglial activation and proliferation. PLX647 at 60 mpk was then administered to 3xTg-AD mice with severely developed pathology (26 month-old) for 3 weeks and their brains analyzed. No significant changes in Ab or tau levels were detected, but highly significant and reproducible reductions were seen in IBA1 levels with treatment; PLX3397, is currently in phase I clinical safety testing and may represent an effective way to reduce AD-related neuroinflammation. Conclusions: Here we show that orally active, selective small molecule inhibitors of the CSF-1R kinase are able to robustly diminish microglia activation and numbers in the CNS. These data are encouraging of further testing of inhibitors of CSF-1R to reduce brain inflammation for AD and other diseases with neuroinflammatory components.