Abstract: Objective To study the effects of intrahippocampal injection of cellular prion protein (PrPC) antibody on cognitive deficits of APPswe/PSEN1dE9 transgenic mice. Methods Eight-month-old male APPswe/PSEN1dE9 transgenic mice were subjected to bilateral intrahippocampal injection of a single dose (2 μL) of anti-PrPC monoclonal antibody (EP1802Y) or PBS, with wild-type C57Bl/6J mice serving as the control group. After two months, the mice were tested for cognitive behaviors using open filed (OF) test, Morris water maze (MWM) test, fear conditioning (FC) test, and novel object recognition (NOR) test, and immunohistochemistry was used to examine the changes in hippocampal expression of Aβ1-42. Results The EP1802Ytreated and PBS-treated mice showed no significantly differences in the performance in OF test in terms of central activity time or total distance of activity (P>0.05), nor in NOR test in terms of novel object recognition index (P>0.05). In MWM test, the EP1802Y-treated and PBS-treated mice showed significantly reduced crossings of the hidden platform as compared with the wild-type mice (P<0.05), but EP1802Y-treated mice had a significantly shorter swimming distance to find the platform than PBS-treated mice (P<0.05). No significant differences were found in the results of FC test among the 3 groups. Immunohistochemistry revealed a significantly reduced expression of Aβ1-42 in the hippocampus of EP1802Y-treated mice. Conclusion Intrahippocampal injection of PrPC antibody can improve cognitive deficits of APPswe/PSEN1dE9 transgenic mice, which sheds light on a novel therapeutic approach for Alzheimer’s disease that targets PrPC to lower the toxicity of Aβ oligomer.