Neve Rachael L, McPhie Donna L
Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA 02478, USA.
Biochim Biophys Acta. 2007 Apr;1772(4):430-7. doi: 10.1016/j.bbadis.2006.10.008. Epub 2006 Oct 18.
The classic neuropathological diagnostic markers for AD are amyloid plaques and neurofibrillary tangles, but their role in the etiology and progression of the disease remains incompletely defined. Research over the last decade has revealed that cell cycle abnormalities also represent a major neuropathological feature of AD. These abnormalities appear very early in the disease process, prior to the appearance of plaques and tangles; and it has been suggested that neuronal cell cycle regulatory failure may be a significant component of the pathogenesis of AD. The amyloid precursor protein (APP) is most commonly known as the source of the beta-amyloid (Abeta) peptides that accumulate in the brains of patients with AD. However, a large body of work supports the idea that APP is also a signaling receptor. Most recently, it has been shown that familial AD (FAD) mutations in APP or simple overexpression of wild type APP cause dysfunction of APP signaling, resulting in initiation of DNA synthesis in neurons and consequent apoptosis. In this article, we review the evidence that APP has the potential to activate aberrant neuronal cell cycle re-entry in AD, and we describe a signal transduction pathway that may mediate this abnormal activation of the cell cycle.
阿尔茨海默病（AD）经典的神经病理学诊断标志物是淀粉样斑块和神经原纤维缠结，但其在疾病病因和进展中的作用仍未完全明确。过去十年的研究表明，细胞周期异常也是AD的主要神经病理学特征。这些异常在疾病进程中出现得非常早，早于斑块和缠结的出现；有人提出，神经元细胞周期调节功能障碍可能是AD发病机制的重要组成部分。淀粉样前体蛋白（APP）最为人所知的是它是在AD患者大脑中积累的β淀粉样蛋白（Aβ）肽的来源。然而，大量研究支持APP也是一种信号受体这一观点。最近的研究表明，APP中的家族性AD（FAD）突变或野生型APP的简单过表达会导致APP信号功能障碍，从而引发神经元中的DNA合成并导致细胞凋亡。在本文中，我们回顾了APP有可能在AD中激活异常的神经元细胞周期重新进入的证据，并描述了一条可能介导细胞周期这种异常激活的信号转导途径。
