Chronic hyperglycemia induced via the heterozygous knockout of Pdx1 worsens neuropathological lesion in an Alzheimer mouse model.
Chronic hyperglycemia induced via the heterozygous knockout of Pdx1 worsens neuropathological lesion in an Alzheimer mouse model.
复制标题
通过 Pdx1 杂合敲除诱导的慢性高血糖会加重阿尔茨海默小鼠模型中的神经病理病变。
DOI：
10.1038/srep29396
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发表时间：
2016-07-12
影响因子：
4.6
通讯作者：
Wang ZY
中科院分区：
文献类型：
--
作者：
Guo C;Zhang S;Li JY;Ding C;Yang ZH;Chai R;Wang X;Wang ZY
大量证据表明，糖代谢异常通过糖代谢产物与阿尔茨海默病（AD）和糖尿病（DM）相关。然而，由于缺乏合适的动物模型，慢性高血糖是否会导致体内AD的病理改变仍有待证实。在这里，我们将糖尿病小鼠（Pdx 1 +/−小鼠）与阿尔茨海默病小鼠（APP/PS1转基因小鼠）杂交，以产生Pdx 1 +/−/APP/PS1。我们确定了tau磷酸化的强烈增加、突触棘蛋白的丢失、淀粉样蛋白-β（Aβ）沉积和斑块形成与增加的小胶质细胞和星形胶质细胞活化增殖相关，这导致记忆和认知缺陷加剧。更重要的是，我们还观察到AD进展过程中葡萄糖不耐受增加伴Pdx 1减少、晚期糖基化终产物（AGEs）形成和AGEs受体（AGEs）信号通路激活;这些变化被认为有助于Aβ前体蛋白的加工，导致Aβ生成增加和Aβ降解减少。蛋白质糖化、氧化应激增加和高血糖引起的炎症反应是AD病理生理学的主要机制。这些结果表明了这些疾病之间的病理关系，并提供了新的见解，表明血糖控制可能有利于降低AD在糖尿病患者中的发病率和延缓AD的进展。
Compelling evidence has indicated that dysregulated glucose metabolism links Alzheimer’s disease (AD) and diabetes mellitus (DM) via glucose metabolic products. Nevertheless, because of the lack of appropriate animal models, whether chronic hyperglycemia worsens AD pathologies in vivo remains to be confirmed. Here, we crossed diabetic mice (Pdx1+/− mice) with Alzheimer mice (APP/PS1 transgenic mice) to generate Pdx1+/−/APP/PS1. We identified robust increases in tau phosphorylation, the loss of the synaptic spine protein, amyloid-β (Aβ) deposition and plaque formation associated with increased microglial and astrocyte activation proliferation, which lead to exacerbated memory and cognition deficits. More importantly, we also observed increased glucose intolerance accompanied by Pdx1 reduction, the formation of advanced glycation end-products (AGEs), and the activation of the receptor for AGEs (RAGE) signaling pathways during AD progression; these changes are thought to contribute to the processing of Aβ precursor proteins and result in increased Aβ generation and decreased Aβ degradation. Protein glycation, increased oxidative stress and inflammation via hyperglycemia are the primary mechanisms involved in the pathophysiology of AD. These results indicate the pathological relationship between these diseases and provide novel insights suggesting that glycemic control may be beneficial for decreasing the incidence of AD in diabetic patients and delaying AD progression.