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

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 APP␣ 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 ␣-secretase product sAPP␣ in fibroblasts from AD patients. We also show that BL significantly increased the amount of sAPP␣ and reduced A␤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␤40 and A␤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.

Bryostatin-1: Pharmacology and Therapeutic Potential as a CNS Drug

“…Bryostatin-1 activates á-secretase, probably through PKC á, ä, or å (14,21,47,50). At subnanomolar concentrations, it enhances the secretion of á-secretase product soluble amyloid precursor protein (sAPP) á in fibroblasts from AD patients and reduces brain Aâ 40 and Aâ 42 accumulation in AD double-transgenic mice (14). In APP[V7171] transgenic mice, PKC activation has also been found to reduce Aâ 40 accumulation in the brain (14).…”

“…1) possesses a unique pharmacological profile as a cancer chemotherapeutic. It is currently in phases I and II trials against a variety of cancers (8,13,19,27) and produces behavioral and cognitive effects when appropriate drug levels are achieved in the brain (14,39). It inhibits tumor invasion, tumor growth in vitro and in vivo, and angiogenesis.…”

Application of Surface-Enhanced Raman Spectroscopy for Detection of Beta Amyloid Using Nanoshells

“…With an annual cost of over $100 billion per year, AD is the third most costly disease in the USA after heart disease and cancer [6]. In recent years, there has been great interest and progress made in the development of molecular level strategies to target steps in the pathogenesis of AD [7][8][9][10][11][12][13][14][15][16][17][18], with the expectation that even a modest delay of onset of AD of as little as 5 years would result in a 50% reduction in the number of AD patients [19]. However, if these new molecular therapeutics are to be successfully applied, a definitive premortem diagnosis of AD is necessary.…”

L-3-n-Butylphthalide Improves Cognitive Impairment and Reduces Amyloid- in a Transgenic Model of Alzheimer's Disease

“…The ␣APPs fragment has been shown to have both neurotrophic (Wallace et al, 1997) and neuroprotective (Mattson et al, 1993;SmithSwintosky et al, 1994;Gralle et al, 2009) activities. Recent studies suggest that ␣APPs might serve as an AD therapeutic target (Etcheberrigaray et al, 2004;Small et al, 2005;Turner et al, 2007).…”