Therapeutic effects of PKC activators in Alzheimer's disease transgenic mice.
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.
Etcheberrigaray
René
R
NeuroLogic, Inc., Rockville, MD 20850, USA.
Tan
Mathew
M
Dewachter
Ilse
I
Kuipéri
Cuno
C
Van der Auwera
Ingrid
I
Wera
Stefaan
S
Qiao
Lixin
L
Bank
Barry
B
Nelson
Thomas J
TJ
Kozikowski
Alan P
AP
Van Leuven
Fred
F
Alkon
Daniel L
DL
D000544:Alzheimer Disease / Q000188:drug therapy*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D001570:Benzodiazepinones / Q000627:therapeutic use*; D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D011493:Protein Kinase C / Q000378:metabolism*; D021381:Protein Transport; D011994:Recombinant Proteins / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D001570:Benzodiazepinones; D011994:Recombinant Proteins; C120089:benzolactam V7; D011493:Protein Kinase C