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. Author manuscript; available in PMC: 2009 Mar 11.
Published in final edited form as: Biol Chem. 2008 Aug;389(8):993–1006. doi: 10.1515/BC.2008.124

Figure 4. In vivo administration of CA074Me or E64d improves memory and reduces brain plaque in transgenic mice expressing human APP containing the wild-type β-secretase site.

Figure 4

a. Inhibitors of cathepsin B improve memory deficit in the London APP mouse model of AD. The CA074Me and E64d inhibitors of cathepsin B were administered (icv) to the London APP mice that express human APP with the wild-type β-secretase site and a mutation near the γ-secretase site. The constant icv administration into the brain utilized Alzet minipumps for 28 days. Mice were then evaluated for the status of memory by the Morris water maze test; the latency period measures the time required for the animal to swim to a submerged platform after training to learn of the platform location, with shorter times reflecting improved memory. The mean latency times and percent standard errors (% SEM) are shown for the control (vehicle treated), CA074Me-treated, and E64d-treated London APP animals. The statistical significance between the means for the London APP animals of each treated group and the control is indicated (*** p < 0.0001, student’s t-test). The mean latency period for untreated wild-type, strain-matched, non-transgenic mice is shown as a dashed line. Thus, the CA074Me and E64d treatments significantly shortened the latency period by 42% and 53%, respectively, relative to the London APP controls and restored about 68% and 86%, respectively, of the memory of wild-type non-transgenic mice.

b. Inhibitors of cathepsin B reduce amyloid plaque load in the London APP mice. Reduction of total amyloid plaque load occured in brains after treatment of London APP mice with CA074Me or E64d inhibitors. After treatment with these inhibitors (as described in previous paragraph), amyloid plaques in brain were revealed by anti-Aβ immunohistochemistry of brain sections. Quantitation of relative amyloid plaque load in the entire brain section was achieved by computer image analyses, expressed as percent of the tissue area. The relative amyloid loads are displayed as the mean (% tissue area) and SEM. Statistical significance between each inhibitor-treated group and control is indicated (*** p < 0.0001, student’s t-test). Inhibitor treatments reduce the plaque load by about 45%.