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

2005; Elsevier BV; Volume: 136; Issue: 1 Linguagem: Inglês

10.1016/j.neuroscience.2005.06.095

1873-7544

Yasuko Sakurai‐Yamashita, Suehiro Sakaguchi, Daisuke Yoshikawa, Naonobu Okimura, Yuichi Masuda, Shigeru Katamine, Masami Niwa,

Alzheimer's disease research and treatments

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.