Fig. 3

NMZ treated 3xTg mice show improvements in LTP, behavior, synaptic biomarkers, and Aβ pathology. LTP was measured in the CA1 region of hippocampal sections from 16 month male 3 × Tg mice (n = 9-12) or in littermate controls treated with NMZ (50 μM) and ODQ (10 μM) 30 min prior to TBS and continued throughout. Fifty min after LTP induction, NMZ showed restoration of LTP deficits to WT levels, while ODQ completely blocked this activity (a). Analysis of theta bursts showed an increase by NMZ during induction of long-term potentiation (b). Data show mean ± S.E.M. normalized to baseline. Male and female 3xTg mice (n = 8–12) treated for 10 weeks with NMZ (1 mg/kg, i.p. + 20 mg/kg/day p.o) showed reversal of memory deficits to levels observed in WT mice in the STPA task 24 h after training (c). NMZ treatment resulted in an elevation of biomarkers associated with synaptic and neuronal plasticity (pCREB and BDNF) in whole brain homogenates measured by ELISA however not changing the total amount of total CREB measured by western blot (d and e). NMZ treatment attenuated insoluble and oligomeric Aβ (f) and total tau (g), both markers of AD hallmark pathology, in whole brain homogenates. Data show mean ± S.E.M. compared to vehicle control. Statistical significance is indicated by *p < 0.05, **p < 0.01, ***p < 0.001 and were analyzed by unpaired student’s t-test. NMZ treatment showed a decrease in Aβ staining in the CA1 region of the hippocampus in treated animals but a negligible effect on the cortex. Representative images are shown with thioflavin-S (magnification 4×) staining and 6E10 antibody in the hippocampus (magnification 4×) and subiculum (magnification 10×) (h). AT8 immunohistochemistry in hippocampus and cortex (magnification 6× and 20×) showed a decrease in phosphorylated tau in the NMZ treated compared to the vehicle (i)