Université de Toulouse (UPS) Centre de Recherches sur la Cognition Animale, Toulouse, France ; Centre National de la Recherche Scientifique (CNRS) Centre de Recherches sur la Cognition Animale, Toulouse, France.
PLoS One. 2013 Sep 27;8(9):e76497. doi: 10.1371/journal.pone.0076497. eCollection 2013.
At advanced stages of Alzheimer's disease, cognitive dysfunction is accompanied by severe alterations of hippocampal circuits that may largely underlie memory impairments. However, it is likely that anatomical remodeling in the hippocampus may start long before any cognitive alteration is detected. Using the well-described Tg2576 mouse model of Alzheimer's disease that develops progressive age-dependent amyloidosis and cognitive deficits, we examined whether specific stages of the disease were associated with the expression of anatomical markers of hippocampal dysfunction. We found that these mice develop a complex pattern of changes in their dentate gyrus with aging. Those include aberrant expression of neuropeptide Y and reduced levels of calbindin, reflecting a profound remodeling of inhibitory and excitatory circuits in the dentate gyrus. Preceding these changes, we identified severe alterations of adult hippocampal neurogenesis in Tg2576 mice. We gathered converging data in Tg2576 mice at young age, indicating impaired maturation of new neurons that may compromise their functional integration into hippocampal circuits. Thus, disruption of adult hippocampal neurogenesis occurred before network remodeling in this mouse model and therefore may account as an early event in the etiology of Alzheimer's pathology. Ultimately, both events may constitute key components of hippocampal dysfunction and associated cognitive deficits occurring in Alzheimer's disease.
在阿尔茨海默病的晚期，认知功能障碍伴随着海马回路的严重改变，这可能是记忆障碍的主要原因。然而，海马的解剖重塑可能早在任何认知改变被发现之前就已经开始了。我们使用了一种描述明确的阿尔茨海默病 Tg2576 小鼠模型，该模型会发生进行性的年龄依赖性淀粉样变性和认知缺陷，研究了疾病的特定阶段是否与海马功能障碍的解剖标志物的表达有关。我们发现这些小鼠在衰老过程中会出现齿状回的复杂变化模式。这些变化包括神经肽 Y 的异常表达和钙结合蛋白水平的降低，反映了齿状回抑制和兴奋回路的深刻重塑。在这些变化之前，我们在 Tg2576 小鼠中发现了成年海马神经发生的严重改变。我们在年轻的 Tg2576 小鼠中收集了趋同的数据，表明新神经元的成熟受损，这可能会损害它们在海马回路中的功能整合。因此，在这个小鼠模型中，成年海马神经发生的破坏发生在网络重塑之前，因此可能是阿尔茨海默病病理病因的早期事件。最终，这两个事件都可能是阿尔茨海默病中海马功能障碍和相关认知缺陷的关键组成部分。
