Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, California, USA.
Biol Psychiatry. 2012 Mar 1;71(5):403-9. doi: 10.1016/j.biopsych.2011.08.016. Epub 2011 Sep 25.
Down syndrome (DS) is the most common cause of cognitive dysfunction in children. Additionally, most adults with DS will eventually show both clinical and neuropathologic hallmarks of Alzheimer's disease (AD). The hippocampal formation constitutes the primary target for degeneration in both AD and DS. Over the past few years, we have studied the molecular mechanisms behind degeneration of this region and its major inputs in mouse models of DS. Our investigation has suggested that the loss of hippocampal inputs, particularly cholinergic and noradrenergic terminals, leads to de-afferentation of this region in the Ts65Dn mouse model of DS. Interestingly, we were able to link the overexpression of amyloid precursor protein (App) gene to degeneration of cholinergic and noradrenergic neurons in DS mouse models. We examined the underlying mechanisms of degeneration of multiple systems with extensive projections to the hippocampus in DS and its mouse models and the role of App overexpression in neurodegeneration. Understanding mechanisms behind hippocampal dysfunction has helped us to test several therapeutic strategies successfully in mouse models of DS. Here we review these strategies and mechanisms and discuss ways to translate our findings into possible interventions in humans.
唐氏综合征（DS）是儿童认知功能障碍最常见的原因。此外，大多数唐氏综合征患者最终都会表现出阿尔茨海默病（AD）的临床和神经病理学特征。海马结构是 AD 和 DS 中退化的主要靶标。在过去的几年里，我们研究了 DS 小鼠模型中海马区及其主要传入区退化的分子机制。我们的研究表明，海马传入神经，特别是胆碱能和去甲肾上腺素能末梢的丧失，导致 Ts65Dn 小鼠模型中海马区的去传入。有趣的是，我们能够将淀粉样前体蛋白（App）基因的过表达与 DS 小鼠模型中胆碱能和去甲肾上腺素能神经元的退化联系起来。我们研究了 DS 及其小鼠模型中多个系统向海马区广泛投射的退化的潜在机制，以及 App 过表达在神经退行性变中的作用。了解海马功能障碍的机制有助于我们在 DS 小鼠模型中成功测试几种治疗策略。在这里，我们回顾这些策略和机制，并讨论将我们的发现转化为人类可能干预的方法。
