Ganesh Anish, Choudhury Wajih, Coutellier Laurence
Department of Psychology, The Ohio State University, Columbus, OH, USA.
Department of Psychology, The Ohio State University, Columbus, OH, USA; Department of Neuroscience, The Ohio State University, Columbus, OH, USA.
Brain Res. 2024 Oct 15;1841:149122. doi: 10.1016/j.brainres.2024.149122. Epub 2024 Jul 14.
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.
女性患阿尔茨海默病（AD）的风险是男性的两倍，但这种性别特异性易感性的潜在机制尚不清楚。在此，我们旨在确定在5XFAD小鼠模型中，在AD临床前阶段受到影响的前额叶依赖认知功能缺陷是否在雌性中更早出现，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白蛋白（PV）神经元活动改变有关。我们观察到，3.5个月大的5XFAD雌性小鼠而非雄性小鼠，在空间短期识别记忆方面存在损伤，这一功能依赖于前额叶皮层的完整性。两性中依赖海马体的认知功能均保持完好。然后我们观察到，5XFAD雌性小鼠有更多表达慢性活动标志物FosB的前额叶PV神经元；这与前额叶依赖的认知表现呈负相关。我们的研究结果首次表明，前额叶PV神经元活动存在性别特异性的早期失调，这与5XFAD雌性小鼠前额叶依赖认知功能的早期出现有关，为女性AD风险增加提供了一种潜在的新机制。
