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Therapeutic effectsof PKC activators inAlzheimer's diseasetransgenic mice René EtcheberrigarayMathew TanIlse Dewachter2004 год

Therapeutic effects of PKC activators in Alzheimer's disease transgenic mice
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Аннотация: 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 APPα 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 α-secretase product sAPPα in fibroblasts from AD patients. We also show that BL significantly increased the amount of sAPPα and reduced Aβ40 in the brains of APP[V717I] transgenic mice. In a more recently developed AD double-transgenic mouse, bryostatin was effective in reducing both brain Aβ40 and Aβ42. 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.
Год издания: 2004
Авторы: René Etcheberrigaray, Mathew Tan, Ilse Dewachter, Cuno Kuipéri, Ingrid Van der Auwera, Stefaan Wera, Lixin Qiao, Barry Bank, Thomas J. Nelson, Alan P. Kozikowski, Fred Van Leuven, Daniel L. Alkon
Издательство: National Academy of Sciences
Источник: Proceedings of the National Academy of Sciences
Ключевые слова: Alzheimer's disease research and treatments, Cholinesterase and Neurodegenerative Diseases, Neuroscience and Neuropharmacology Research
Другие ссылки: Proceedings of the National Academy of Sciences (HTML)
Europe PMC (PubMed Central) (PDF)
Europe PMC (PubMed Central) (HTML)
PubMed Central (HTML)
PubMed (HTML)