Female-specific neuroprotection against transient brain ischemia observed in mice devoid of prion protein is abolished by ectopic expression of prion protein-like protein.

This study was designed to examine the function of cellular prion protein and prion protein-like protein/Doppel, in transient ischemia-related neuronal death in the hippocampus. Two different lines of mice devoid of cellular prion protein, Zrch I Prnp0/0 and Ngsk Prnp0/0, were used. The former lacks cellular prion protein whereas the latter ectopically expresses prion protein-like protein/Doppel in the brain in the absence of cellular prion protein. Mice were subjected to 10 min-occlusion of the bilateral common carotid arteries with recovery for 14 days. Less than 10% of the pyramidal neurons in the CA1 subfield were degenerated in male and female wild-type mice. In contrast, more than half of the neurons were lost in male Zrch I Prnp0/0 and Ngsk Prnp0/0 mice. Such severe neuronal loss was also observed in female Ngsk Prnp0/0 mice. However, female Zrch I Prnp0/0 mice showed mild neuronal loss similar to wild-type mice. Flunarizine, a T- and L-type Ca2+-channel antagonist, significantly reduced the neuronal loss in female but not in male Ngsk Prnp0/0 mice. These results indicate that loss of cellular prion protein renders hippocampal neurons susceptible to ischemic insult specifically in male but not female mice and the ectopic expression of prion protein-like protein/Doppel aggravates the ischemic neuronal death in female prion protein-null mice probably via overloading of Ca2+-dependent signaling.