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Effects of huperzine A on amyloid precursor protein processing and β-amyloid generation in human embryonic kidney 293 APP Swedish mutant cells

Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Journal of Neuroscience Research (Impact Factor: 2.73). 09/2006; 84(4):903-11. DOI: 10.1002/jnr.20987
Source: PubMed

ABSTRACT The amyloid precursor protein (APP) is cleaved enzymatically by nonamyloidogenic and amyloidogenic pathways. alpha-Secretase (alpha-secretase), cleaves APP within the beta-amyloid (Abeta) sequence, resulting in the release of a secreted fragment of APP (alphaAPPs) and precluding Abeta generation. In this study, we investigated the effects of an acetylcholinesterase inhibitor, huperzine A (Hup A), on APP processing and Abeta generation in human embryonic kidney 293 cells transfected with human APP bearing the Swedish mutation (HEK293 APPsw). Hup A dose dependently (0-10 microM) increased alphaAPPs release and membrane-coupled APP CTF-C83, suggesting increased APP metabolism toward the nonamyloidogenic alpha-secretase pathway. The metalloprotease inhibitor TAPI-2 inhibited the Hup A-induced increase in alphaAPPs release, further suggesting a modulatory effect of Hup A on alpha-secretase activity. The synthesis of full-length APP and cell viability were unchanged after Hup A incubation, whereas the level of Abeta(Total) was significantly decreased, suggesting an inhibitory effect of Hup A on Abeta production. Hup A-induced alphaAPPs release was significantly reduced by the protein kinase C (PKC) inhibitors GF109203X and Calphostin C. These data, together with the finding that the PKCalpha level was enhanced prior to the increase of alphaAPPs secretion, indicate that PKC may be involved in Hup A-induced alphaAPPs secretion by HEK293 APPsw cells. Our data suggest alternative pharmacological mechanisms of Hup A relevant to the treatment of Alzheimer's disease.

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    • "HupA has several beneficial effects for AD patients (Wang et al, 2006a) and, in China it is one of the most commonly prescribed drugs for many forms of dementia, including AD (Zhang et al, 2008b). Apart from its well-known inhibitory effect on AChE (Zhu and Giacobini, 1995; Cheng et al, 1996; Cheng and Tang, 1998), HupA is considered to have multiple neuroprotective effects including anti-inflammatory and antioxidant properties (Wang and Tang, 2007; Wang et al, 2008; Zhang et al, 2008a), stimulation of the release of soluble a-secretasederived fragments of APP (sAPPa) (Zhang et al, 2004; Peng et al, 2006; Yan et al, 2007), protection against Ab and glutamate-induced neurotoxicity, and regulation of nerve growth factor (Ved et al, 1997; Tang et al, 2005). "
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    • "Western blot was performed as previously reported (Peng et al., 2006). TBS-brain homogenates were used to detect αAPPs, C3, and iNOS levels, while TBS-T brain homogenates were used to examine total APP, CD68, F4/80 and synaptophysin levels. "
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    ABSTRACT: In recent years, the most common pharmacological treatment for Alzheimer's disease (AD) has been acetylcholinesterase (AChE) inhibition. However, this single-target approach has limited effectiveness and there is evidence that a multitarget approach might be more effective. Huperzine A (HupA), a novel alkaloid isolated from a Chinese herb, has neuroprotective effects that go beyond the inhibition of AChE. Recent data have demonstrated that HupA can ameliorate the learning and memory deficiency in animal models and AD patients. Its potentially beneficial actions include modification of beta-amyloid peptide processing, reduction of oxidative stress, neuronal protection against apoptosis, and regulation of the expression and secretion of nerve growth factor (NGF) and NGF signaling.
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