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PO1-1-51

DJ-1-binding compound ameliorates spatial learning and memory impairment in a mouse model of Alzheimer's disease

[Speaker] Yoshihisa Kitamura:1
[Co-author] Masanori Hijioka:1
1:College of Pharmaceutical Sciences, Ritsumeikan University, Japan

Background: DJ-1 is identified as the causative gene of familial Parkinson's Diseases (PD). In our previous study, we found some small molecular weight compounds that can bind to C106 site of DJ-1 protein by virtual screening. Especially, UCP0054278/compound B (comp-B) that binds to SO2H-oxidized C106 region of DJ-1 protein prevented the oxidative stress-induced degeneration of dopaminergic neurons in rat model of PD. Here we show the therapeutic effects of comp-B against memory impairment in a mouse model of Alzheimer's disease (AD).
Methods: Male APP/PS1 mice (12-month-old) were received daily intraperitoneal administration with comp-B (1 or 3 mg/kg/per day) for 56 days. Morris water maze (MWM) test were performed at 12, 13 and 14 months. One day after the final drug treatment, mice were decapitated and brains were removed. A cerebral hemisphere was performed histochemical analysis with anti-amyloid β (Aβ) antibody and another cerebral hemisphere was used in ELISA and Western blot for detection of Aβ and synaptic markers.
Results: APP/PS1 mice needed longer time to reach the platform in the acquisition trials of MWM compared with WT littermates. Administration of Comp-B (1 or 3 mg/kg) to APP/PS1 mice reduced the time to reach the platform but not significant. In the probe test of MWM, APP/PS1 mice showed shorter time spent in the target quadrant compared with WT littermates. Whereas, administration of Comp-B (3 mg/kg) to APP/PS1 mice significantly increased the time spent in the target quadrant. Histochemical analysis with Aβ antibody revealed that comp-B reduced Aβ deposition in hippocampus. Furthermore, amount of Aβ42 contents in insoluble fraction of brain homogenate of APP/PS1 mice were decreased by comp-B administration. Amount of DJ-1 and synaptic markers such as synaptophysin and drebrin in membrane fraction was increased by comp-B administration.
Conclusion: We found that comp-B resolved the cognitive deficits, reduced insoluble Aβ42 levels, and prevented the degeneration of synaptic functions in this study. These results suggest that targeting of C106 region of DJ-1 protein can be a novel therapeutic approach to ameliorate cognitive impairment of Aβ patients.

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