Rensink Annemieke A M, Gellekink Henkjan, Otte-Höller Irene, ten Donkelaar Hans J, de Waal Robert M W, Verbeek Marcel M, Kremer Berry
Department of Pathology, University Medical Center Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
Acta Neuropathol. 2002 Nov;104(5):525-33. doi: 10.1007/s00401-002-0585-x. Epub 2002 Jul 20.
Amyloid-beta (Abeta) deposition in cerebral blood vessel walls is one of the key features of Alzheimer's disease (AD). Abeta(1-40) carrying the "Dutch" mutation (DAbeta(1-40)) induces rapid degeneration of cultured human brain pericytes (HBP). To study the mechanisms of this Abeta-induced toxicity, a comparative cDNA expression array was performed to detect differential gene expression of Abeta-treated versus untreated HBP. Messenger RNA expression of leukemia inhibitory factor (LIF) and insulin-like growth factor binding protein 3 (IGFBP-3) was increased in DAbeta(1-40)-treated HBP, whereas early growth response factor-1 (Egr-1) expression was decreased. Corresponding protein expression was investigated in AD and control brains. In all AD cases examined, LIF expression was observed in senile plaques and cerebral amyloid angiopathy, whereas IGFBP-3 expression in these lesions was only observed in a subset of cases. LIF and IGFBP-3 were also expressed in neurofibrillary tangles, as well as in neurons in AD and control brains. Egr-1 was predominantly expressed in astrocytes. Given its known involvement in both neuronal and immune responses to injury, the cytokine LIF may be a mediator of the inflammatory reaction seen in AD. IGFBP-3 is known to inhibit cell proliferation and induce apoptosis and may therefore contribute to neuronal degeneration in AD.
淀粉样β蛋白（Aβ）在脑血管壁中的沉积是阿尔茨海默病（AD）的关键特征之一。携带“荷兰”突变的Aβ（1-40）（DAβ（1-40））可诱导培养的人脑周细胞（HBP）快速退化。为了研究这种Aβ诱导毒性的机制，进行了一项比较性cDNA表达阵列分析，以检测Aβ处理组和未处理组HBP的差异基因表达。在DAβ（1-40）处理的HBP中，白血病抑制因子（LIF）和胰岛素样生长因子结合蛋白3（IGFBP-3）的信使RNA表达增加，而早期生长反应因子-1（Egr-1）的表达则降低。在AD患者和对照者的大脑中研究了相应的蛋白表达情况。在所有检测的AD病例中，在老年斑和脑淀粉样血管病中均观察到LIF表达，而在这些病变中IGFBP-3表达仅在部分病例中观察到。LIF和IGFBP-3也在神经原纤维缠结中表达，在AD患者和对照者大脑的神经元中也有表达。Egr-1主要在星形胶质细胞中表达。鉴于细胞因子LIF已知参与对损伤的神经元和免疫反应，它可能是AD中所见炎症反应的介质。已知IGFBP-3可抑制细胞增殖并诱导细胞凋亡，因此可能在AD的神经元退化中起作用。
