Effects of huperzine A on amyloid precursor protein processing and beta-amyloid generation in human embryonic kidney 293 APP Swedish mutant cells.
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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ABSTRACT: Within the last years, a rapidly growing number of polyphenolic compounds with neuroprotective effects have been described. Many efforts have been made to explore the mechanisms behind the neuroprotective action of polyphenols. However, many pathways and mechanisms considered for mediating these effects are rather general than specific. Moreover, despite the beneficial effects of polyphenols in experimental treatment of neurodegeneration, little has been achieved in bringing them into routine clinical applications. In this review, we have summarized the protective effects of polyphenols against neurodegeneration, and we have also discussed some of the barricades in translating these biochemical compounds, into relevant therapeutics for neurodegenerative diseases.Ageing research reviews 02/2012; 11(2):329-45. · 5.62 Impact Factor
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ABSTRACT: We have previously identified presenilin-1 (PS1), the active component of the γ-secretase complex, as an interacting protein of the amyloid-associated enzyme acetylcholinesterase (AChE). In this study, we have explored the consequences of AChE-PS1 interactions. Treatment of SH-SY5Y cells with the AChE-inhibitor tacrine decreased PS1 levels, in parallel with increase in the secretion of amyloid precursor protein APPα, whereas the cholinergic agonist carbachol had no effect on PS1. AChE knockdown with siRNA also decreased PS1 levels, while AChE overexpression exerted opposing effect. AChE-deficient also had decreased PS1. Mice administered with tacrine or donepezil displayed lower levels of brain PS1. However, sustained AChE inhibition failed to exert long-term effect on PS1. This limited duration of response may be due to AChE upregulation caused by chronic inhibition. Finally, we exposed SH-SY5Y cells to β-amyloid (Aβ)42 which triggered elevation of both AChE and PS1 levels. The Aβ42-induced PS1 increase was abolished by siRNA AChE pretreatment, suggesting that AChE may participate in the pathological feedback loop between PS1 and Aβ. Our results provide insight into AChE-amyloid interrelationships.Neurobiology of aging 05/2011; 33(3):627.e27-37. · 5.94 Impact Factor
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ABSTRACT: Recent advances in neuroscience have revealed a greater, in-depth understanding of the complexities associated with memory. Contemporary theories hold that an integral relationship between memory formation, stabilization and consolidation revolve around plasticity of neuronal networks. The associated requisite receptors α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-d-aspartate (NMDA) and cellular mechanisms surrounding plasticity (posed to incite molecular functionality), also display strong correlations in the pathogenesis of dementias. When the brain is in a diseased state as a result of malignant neurotransmission (i.e. in Alzheimer's disease; AD), the homeostatic balance required for normal neuronal processes is disrupted, which leads to degeneration of neural circuitry. Present efforts to find new treatments aimed at reversing or halting neurodegeneration are immense, with increasing attention being placed on investigating various herbal medicines. A wide variety of herbal plants (i.e. Panax ginseng, Polygala tenuifolia, Acorus gramineus and Huperzia serrata, examined here within), extracts and compounds have, to date, already presented advantageous results when tested against known pathogenic markers related to AD-associated dementia. The efficaciousness of herbal medicines appears to be a modulatory effect on neurotrophins, kinases and their substrates that, in turn, initiate or take part in intracellular cascades related to memory processes.Phytotherapy Research 02/2011; 25(8):1105-18. · 2.07 Impact Factor