Abstract：
Women have a two-fold increased risk of developing Alzheimer\'s disease (AD) than men, yet the underlying mechanisms of this sex-specific vulnerability remain unknown. Here, we aimed at determining in the 5XFAD mouse model whether deficits in prefrontal-dependent cognitive functions, which are impacted in the preclinical stages of AD, appear earlier in females, and whether these cognitive deficits are associated with alterations in the activity of prefrontal parvalbumin (PV)-neurons that regulate prefrontal circuits activity. We observed that 3.5-month-old 5XFAD females, but not males, display impairments in spatial short-term recognition memory, a function that relies on the integrity of the prefrontal cortex. Hippocampal-dependent cognitive functions were intact in both sexes. We then observed that 5XFAD females have more prefrontal PV neurons expressing the marker of chronic activity FosB; this was inversely correlated with prefrontal-dependent cognitive performances. Our findings show for the first time sex-specific, early deregulation of prefrontal PV neurons activity, which is associated with early appearance of prefrontal-dependent cognitive functions in 5XFAD females providing a potential novel mechanism to the increased risk to AD in females.
摘要：
女性患阿尔茨海默病（AD）的风险比男性增加两倍，然而,这种性别特异性脆弱性的潜在机制仍然未知.这里,我们的目的是在5XFAD小鼠模型中确定前额叶依赖性认知功能是否存在缺陷，在AD的临床前阶段受到影响，更早出现在女性身上，以及这些认知缺陷是否与调节前额叶回路活动的前额叶小清蛋白（PV）神经元活动的改变有关。我们观察到3.5个月大的5XFAD女性，但不是男性，空间短期识别记忆中的显示障碍，这种功能依赖于前额叶皮层的完整性。两性海马依赖性认知功能完整。然后，我们观察到5XFAD雌性有更多的前额叶PV神经元表达慢性活动标记FosB；这与前额叶依赖性认知表现成反比。我们的发现首次显示了性别特异性，前额叶PV神经元活动的早期失调，这与5XFAD女性前额叶依赖性认知功能的早期出现有关，为女性AD风险增加提供了潜在的新机制。
