Therapeutic effects of PKC activators in Alzheimer's disease transgenic mice

René Etcheberrigaray, Mathew Tan, Ilse Dewachtert, Cuno Kuipéri, Ingrid Van Der Auwera, Stefaan Wera, Lixin Qiao, Barry Bank, Thomas J. Nelson, Alan P. Kozikowski, Fred Van Leuven, Daniel L. Alkon

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)11141-11146
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number30
DOIs
StatePublished - Jul 27 2004
Externally publishedYes

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Therapeutic Uses
Protein Kinase C
Transgenic Mice
Alzheimer Disease
Amyloid beta-Protein Precursor
Bryostatins
Amyloid Precursor Protein Secretases
Premature Mortality
Memory Disorders
Brain
Calcium Channels
Neoplasms
Homeostasis
Fibroblasts
Therapeutics
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Etcheberrigaray, R., Tan, M., Dewachtert, I., Kuipéri, C., Van Der Auwera, I., Wera, S., ... Alkon, D. L. (2004). Therapeutic effects of PKC activators in Alzheimer's disease transgenic mice. Proceedings of the National Academy of Sciences of the United States of America, 101(30), 11141-11146. https://doi.org/10.1073/pnas.0403921101

Therapeutic effects of PKC activators in Alzheimer's disease transgenic mice. / Etcheberrigaray, René; Tan, Mathew; Dewachtert, Ilse; Kuipéri, Cuno; Van Der Auwera, Ingrid; Wera, Stefaan; Qiao, Lixin; Bank, Barry; Nelson, Thomas J.; Kozikowski, Alan P.; Van Leuven, Fred; Alkon, Daniel L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 101, No. 30, 27.07.2004, p. 11141-11146.

Research output: Contribution to journalArticle

Etcheberrigaray, R, Tan, M, Dewachtert, I, Kuipéri, C, Van Der Auwera, I, Wera, S, Qiao, L, Bank, B, Nelson, TJ, Kozikowski, AP, Van Leuven, F & Alkon, DL 2004, 'Therapeutic effects of PKC activators in Alzheimer's disease transgenic mice', Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 30, pp. 11141-11146. https://doi.org/10.1073/pnas.0403921101
Etcheberrigaray, René ; Tan, Mathew ; Dewachtert, Ilse ; Kuipéri, Cuno ; Van Der Auwera, Ingrid ; Wera, Stefaan ; Qiao, Lixin ; Bank, Barry ; Nelson, Thomas J. ; Kozikowski, Alan P. ; Van Leuven, Fred ; Alkon, Daniel L. / Therapeutic effects of PKC activators in Alzheimer's disease transgenic mice. In: Proceedings of the National Academy of Sciences of the United States of America. 2004 ; Vol. 101, No. 30. pp. 11141-11146.
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