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. 2021 Jun 22;26(11):6394–6410. doi: 10.1038/s41380-021-01166-2

Fig. 2. BACE1 inhibitors markedly reduce learning behaviors and long-term potentiation.

Fig. 2

A Fear conditioning tests were conducted in 6-month-old WT (BACE1+/+) mice treated with Lanabecestat (AZD3293) at 0.5 mg/kg or Verubecestat at 3 mg/kg. A significant reduction in freezing time in both contextual and cue phases in BACE1-inhibited mice (N = 10 in each group, ***P < 0.01, Student’s t test). B LTP was recorded on horizontal hippocampal slices from these treated mice. At 30 min post stimulation, the potentiation was 105.6 ± 0.6137% from slices treated with Lanabecestat, 113.1 ± 1.353% from slices treated with Verubecestat, lower than WT controls (BACE1+/+, 245.9 ± 0.9864%; N = 7–8, ***P < 0.001, ns meaning no significance, Student’s t test). The typical traces are shown in correlated colors. C In comparison to BACE1-null mice, WT results were removed so that fEPSP was in a narrowed range. LTP reduction by Lanabecestat or Verubecestat treatment was worse than BACE1 deficiency. D Lower dose of Lanabecestat (0.25 mg/kg) showed significantly less reduction on LTP compared to the higher dose (0.5 mg/kg), suggesting a dose dependent reduction in LTP by this compound. N = 7–8, ***P < 0.001, and ns meaning no significance, Student’s t test. E Total hippocampal lysates from mice treated with BACE1 inhibitors were examined by western analysis with the indicated antibodies. F Bar graphs showing a significant reduction in levels of synaptophysion in BACE1-null or inhibitors treated mice (N = 3 independent experiments; *P < 0.05; Student’s t test). Reduction of mGluR1 in BACE1-null mice was visible, but not significant (P = 0.65).