Graduate School of Integrated Science, Yokohama City University, 22-2 Seto, Kanazawa-ku, Yokohama 236-0027, Japan.
Neuroscience. 2009 Dec 15;164(3):1199-209. doi: 10.1016/j.neuroscience.2009.08.063. Epub 2009 Sep 4.
Soluble forms of amyloid-beta (Abeta) have been considered responsible for cognitive dysfunction prior to senile plaque formation in Alzheimer's disease (AD). As its mechanism is not well understood, we examined the effects of repeated i.c.v. infusion of soluble Alphabeta(25-35) on peptidergic system and glial cells in the pathogenesis of AD. The present study aims to investigate the protective effects of memantine on Abeta(25-35)-induced changes in peptidergic and glial systems. Infusion of Alphabeta(25-35) decreased the level of immunoreactive somatostatin (SS) and substance P (SP) in the hippocampus prior to neuronal loss or caspase activation, which is correlated with the loss of spine density and activation of inducible nitric-oxide synthase (iNOS). Biochemical experiment with peptide-degrading enzymes, prolyl oligopeptidase (POP) and endopeptidase 24.15 (EP 24.15) activities demonstrated a concomitant increase with the activation of glial marker proteins, glial fibrillary acidic protein (GFAP) and CD11b in the Abeta-treated hippocampus. Double immunostaining experiments of EP 24.15 and GFAP/CD11b antibodies clearly demonstrated the co-localization of neuro peptidases with astrocytes and microglia. Treatment with memantine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist significantly attenuated Abeta(25-35)-induced changes of neuropeptides, their metabolizing enzymes, glial marker proteins, and activation of iNOS. Taken together, the data implies that memantine exerts its protective effects by modulating the neuropeptide system as a consequence of suppressing the glial cells and oxidative stress in AD model rat brain regions.
可溶性淀粉样蛋白-β（Abeta）已被认为在阿尔茨海默病（AD）老年斑形成之前导致认知功能障碍。由于其机制尚不清楚，我们研究了重复脑室内输注可溶性 Abeta（25-35）对 AD 发病机制中肽能系统和神经胶质细胞的影响。本研究旨在探讨美金刚对 Abeta（25-35）诱导的肽能和神经胶质系统变化的保护作用。Abeta（25-35）输注会降低海马中免疫反应性生长抑素（SS）和 P 物质（SP）的水平，然后才会出现神经元丢失或半胱天冬酶激活，这与棘密度降低和诱导型一氧化氮合酶（iNOS）激活有关。用肽降解酶脯氨酰寡肽酶（POP）和内肽酶 24.15（EP 24.15）进行的生化实验表明，与 Abeta 处理海马中的神经胶质标记蛋白胶质纤维酸性蛋白（GFAP）和 CD11b 的激活同时增加。EP 24.15 和 GFAP/CD11b 抗体的双重免疫染色实验清楚地表明神经肽酶与星形胶质细胞和小胶质细胞的共定位。非竞争性 N-甲基-D-天冬氨酸（NMDA）受体拮抗剂美金刚的治疗显著减弱了 Abeta（25-35）诱导的神经肽、其代谢酶、神经胶质标记蛋白和 iNOS 激活的变化。总的来说，这些数据表明，美金刚通过抑制 AD 模型大鼠脑区的神经胶质细胞和氧化应激来调节神经肽系统，从而发挥其保护作用。
