Abstract
Amyloid β (Aβ) skews microglia to M1 phenotype and induces inflammation and neurodegeneration. On the other hand, another type of microglia, M2, shows anti-inflammatory and neurotrophic effects. We previously clarified that HDAC3 inhibition induced predominance of M2 microglia and axonal growth, and recovered locomotor function in spinal cord injured mice. Therefore, this study aimed to clarify that HDAC3 inhibition skewed to M2 microglia and restored memory function in Alzheimer's disease model mice. An HDAC3 inhibitor, RGFP966 was intraperitoneally administered to 5XFAD mice, a transgenic model of Alzheimer's disease. RGFP966 improved novel object recognition memory in 5XFAD mice. When microglia in the brain of 5XFAD mice were eliminated by intracerebroventricular administration of clophosome, the effect of RGFP966 was diminished. In cultured microglia, RGFP966 treatment skewed to M2 microglia when treated 24 h after Aβ addition. Conditioned medium was collected from RGFP966-treated microglia, which recovered Aβ-induced collapse of axonal growth cones. These results suggest that HDAC3 inhibition increased predominance of M2 microglia, recovered axonal degeneration, and ameliorated memory deficit in 5XFAD mice.
