Gender difference in valproic acid-induced neuroprotective effects on APP/PS1 double transgenic mice modeling Alzheimer＇s disease

Alzheimer＇s disease （AD） is a neurodegenerative disorder that causes progressive memory and cog- nitive impairment with gender difference in specific cognitive ability domains, pathology, and risk of AD. Since valproic acid （VPA） is a widely used mood stabilizer and an antiepileptic drug, which exhi- bits multiple neuroprotective activities on AD, this study intended to investigate the gender differ- ence in the effect of VPA on APP/PS1 double transgenic mice modeling AD. Behavioral experiments showed that VPA reduced the autonomous behaviors, improved learning and memory, and exhib- ited gender differences in AD mice compared with the control mice. The decrease in senile plaque, amyloid β （Aβ） 40, and Aβ42 caused by VPA in the male AD mice was more notable than that in the female AD mice. Meanwhile, VPA protected brain cells from dying notably in the male AD mice but only slightly in the female AD mice, and VPA treatment thickened the postsynaptic density and markedly increased the number and density of presynaptic vesicles in both male and female AD mice. However, the effects of rescuing early synaptic structural and functional deficits by VPA were more obvious in the male mice. Overall, these results supported the hypothesis that gender differ- ence significantly influences AD and indicated that VPA may be a promising remedy for AD if basic biological differences and gender specificity were prudently taken into account.