Nasal Rifampicin Improves Cognition in a Mouse Model of Dementia with Lewy Bodies by Reducing α-Synuclein Oligomers.

ABSTRACT

α-Synuclein oligomers are thought to play an important role in the pathogenesis of dementia with Lewy bodies (DLB). There is no effective cure for DLB at present. Previously, we demonstrated that in APP- and tau-transgenic mice, oral or intranasal rifampicin reduced brain Aß and tau oligomers and improved mouse cognition. In the present study, we expanded our research to DLB. Rifampicin was intranasally administered to 6-month-old A53T-mutant α-synuclein-transgenic mice at 0.1 mg/day for 1 month. The mice displayed memory impairment but no motor deficit at this age, indicating a suitable model of DLB. α-Synuclein pathologies were examined by the immunohistochemical/biochemical analyses of brain tissues. Cognitive function was evaluated by the Morris water maze test. Intranasal rifampicin significantly reduced the levels of [pSer129] α-synuclein in the hippocampus and α-synuclein oligomers in the visual cortex and hippocampus. The level of the presynaptic marker synaptophysin in the hippocampus was recovered to the level in non-transgenic littermates. In the Morris water maze, a significant improvement in spatial reference memory was observed in rifampicin-treated mice. Taken together with our previous findings, these results suggest that intranasal rifampicin is a promising remedy for the prevention of neurodegenerative dementia, including Alzheimer's disease, frontotemporal dementia, and DLB.