5XFAD, 5XFAD^Pparα-null, and 5XFAD^{Pparα-ΔHippo} mice (n = 6/group; 6–7 months old) were orally treated with Hex (5 mg/kg body weight) or vehicle (0.1% methyl cellulose) for 30 days. Age-matched non-Tg (NTG) mice without any treatment (n = 6) were used as controls. Following treatment, AMPA- (A) and NMDA-dependent (B) calcium currents were measured in the hippocampal slices of NTG, vehicle-fed or Hex-fed 5XFAD mice, vehicle-fed or Hex-fed 5XFAD^Pparα-null mice, and vehicle-fed or Hex-fed 5XFAD^{Pparα-ΔHippo} mice. Arrow indicates the application of AMPA and NMDA into the assay. Results represent 3 independent experiments. Following Hex treatment, hippocampus-dependent spatial behavior of mice across all groups was also analyzed using Barnes maze (BM). (C) Representative track plots summarizing the overall activity of mice on the apparatus recorded with a Noldus camera and visualized by Ethovision XT software. (D) Latency and (E) number of errors made by NTG, vehicle-fed or Hex-fed 5XFAD mice, vehicle-fed or Hex-fed 5XFAD^Pparα-null mice, and vehicle-fed or Hex-fed 5XFAD^{Pparα-ΔHippo} mice. Results are shown as mean ± SEM. One-way ANOVA [BM latency: F_(6,35) = 23.28, P < 0.0001 and BM errors: F_(6,35) = 16.002, P < 0.001], followed by Bonferroni’s multiple comparisons test, was used to assess the significance of the mean; ***P < 0.001 vs. vehicle-fed 5XFAD, ^nsP > 0.05 vs. vehicle-fed 5XFAD. Context-dependent hippocampal behavior was analyzed by T-maze test. (F) Number of positive turns and (G) number of errors of NTG, control and Hex-treated 5XFAD, 5XFAD^Pparα-null and 5XFAD^{Pparα-ΔHippo} mice on an appetitive T maze conditioning task were manually recorded. Results are shown as mean ± SEM. One-way ANOVA [TM positive turns: F_(6,35) = 5.361, P = 0.0005 and TM errors: F_(6,35) = 5.361, P = 0.0005], followed by Bonferroni’s multiple comparisons test, was used to assess the significance of the mean, *P < 0.05 vs. vehicle-fed 5XFAD, **P < 0.01 vs. vehicle-fed 5XFAD, ^nsP > 0.05 vs. vehicle-fed 5XFAD.