Takeda Shuko, Sato Naoyuki, Rakugi Hiromi, Morishita Ryuichi
Department of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
Mol Biosyst. 2011 Jun;7(6):1822-7. doi: 10.1039/c0mb00302f. Epub 2011 Mar 24.
The incidence of Alzheimer disease (AD) and diabetes mellitus (DM) is increasing at an alarming rate and has become a major public health concern worldwide. Recent epidemiological studies have provided direct evidence that DM is a strong risk factor for AD; this finding is now attracting attention. However, the underlying mechanisms for this association remain largely unknown. Previous in vitro and in vivo studies reported that diabetic conditions could cause an increase in the beta-amyloid peptide (Aβ) levels, which exhibits neurotoxic properties and plays a causative role in AD. However, unexpectedly, recent clinicopathological studies have shown no evidence that the pathological hallmarks of AD, including amyloid plaque, were increased in the brains of diabetic patients, suggesting that DM could affect the pathogenesis of AD through mechanisms other than modulation of Aβ metabolism. One possible mechanism is the alteration in brain insulin signaling. It has been shown that insulin signaling is involved in a variety of neuronal functions, and that it also plays a significant role in the pathophysiology of AD. Thus, the modification of neuronal insulin signaling by diabetic conditions may contribute to AD progression. Another possible mechanism is cerebrovascular alteration, a common pathological change observed in both diseases. Accumulating evidence has suggested the importance of Aβ-induced cerebrovascular dysfunction in AD, and indicated that pathological interactions between the receptor for advanced glycation end products (RAGE) and Aβ peptides may play a role in this dysfunction. Our study has provided a further understanding of the potential underlying mechanisms linking DM and AD by establishing novel mouse models showing pathological manifestations of both diseases. The current review summarizes the results from recent studies on the pathological relationship between DM and AD while focusing on brain insulin signaling and cerebrovascular alteration. It also discusses the therapeutic potential of these findings and future treatment strategies for AD.
阿尔茨海默病（AD）和糖尿病（DM）的发病率正以惊人的速度上升，已成为全球主要的公共卫生问题。最近的流行病学研究提供了直接证据，表明DM是AD的一个强有力的风险因素；这一发现目前正引起关注。然而，这种关联的潜在机制在很大程度上仍然未知。以往的体外和体内研究报告称，糖尿病状态可导致β-淀粉样肽（Aβ）水平升高，Aβ具有神经毒性特性，并在AD中起致病作用。然而，出乎意料的是，最近的临床病理学研究表明，没有证据显示糖尿病患者大脑中AD的病理特征（包括淀粉样斑块）有所增加，这表明DM可能通过调节Aβ代谢以外的机制影响AD的发病机制。一种可能的机制是脑胰岛素信号的改变。已表明胰岛素信号参与多种神经元功能，并且在AD的病理生理学中也起重要作用。因此，糖尿病状态对神经元胰岛素信号的改变可能有助于AD的进展。另一种可能的机制是脑血管改变，这是两种疾病中都观察到的常见病理变化。越来越多的证据表明Aβ诱导的脑血管功能障碍在AD中的重要性，并表明晚期糖基化终产物受体（RAGE）与Aβ肽之间的病理相互作用可能在这种功能障碍中起作用。我们的研究通过建立显示两种疾病病理表现的新型小鼠模型，进一步了解了将DM和AD联系起来的潜在机制。本综述总结了最近关于DM与AD病理关系的研究结果，同时重点关注脑胰岛素信号和脑血管改变。它还讨论了这些发现的治疗潜力以及AD的未来治疗策略。
