文章基本信息

标题：Therapeutic effects of PKC activators in Alzheimer's disease transgenic mice
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作者：René Etcheberrigaray ; Mathew Tan ; Ilse Dewachter 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2004
卷号：101
期号：30
页码：11141-11146
DOI：10.1073/pnas.0403921101
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Alzheimer's disease (AD) characteristically presents with early memory loss. Regulation of K+ channels, calcium homeostasis, and protein kinase C (PKC) activation are molecular events that have been implicated during associative memory which are also altered or defective in AD. PKC is also involved in the processing of the amyloid precursor protein (APP), a central element in AD pathophysiology. In previous studies, we demonstrated that benzolactam (BL), a novel PKC activator, reversed K+ channels defects and enhanced secretion of APP{alpha} in AD cells. In this study we present data showing that another PKC activator, bryostatin 1, at subnanomolar concentrations dramatically enhances the secretion of the {alpha}-secretase product sAPP{alpha} in fibroblasts from AD patients. We also show that BL significantly increased the amount of sAPP{alpha} and reduced A{beta}40 in the brains of APP[V717I] transgenic mice. In a more recently developed AD double-transgenic mouse, bryostatin was effective in reducing both brain A{beta}40 and A{beta}42. In addition, bryostatin ameliorated the rate of premature death and improved behavioral outcomes. Collectively, these data corroborate PKC and its activation as a potentially important means of ameliorating AD pathophysiology and perhaps cognitive impairment, thus offering a promising target for drug development. Because bryostatin 1 is devoid of tumor-promoting activity and is undergoing numerous clinical studies for cancer treatment in humans, it might be readily tested in patients as a potential therapeutic agent for Alzheimer's disease.