APP and Cognitive impairment: To explore the effective time window of E2 treatment for alleviating AD-associated cognitive impairment and the hippocampal mechanisms, we used female transgenic mice carrying mutant human APPswe and PS1dE9 genes (APP/PS1 mice), in which the production of Aβ appears at approximately 4–5 months of age and dramatically accelerates during 6–8 months of age (Garcia-Alloza et al., 2006).