Huperzine A Activates Wnt/β-Catenin Signaling and Enhances the Nonamyloidogenic Pathway in an Alzheimer Transgenic Mouse Model
| Autor: | Bao-Lu Zhao, Zhan-You Wang, Jing-Wei Xie, Chun-Yan Wang, Si-Ling Wang, Wei-Ping Teng, Tao Wang, Wei Zheng |
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| Rok vydání: | 2011 |
| Předmět: |
Male
ADAM10 Pharmacology Amyloid beta-Protein Precursor Mice Neuroblastoma chemistry.chemical_compound GSK-3 Blood-Retinal Barrier Enzyme Inhibitors beta Catenin Huperzine A Microscopy Confocal Wnt signaling pathway Olfactory Bulb Acetylcholinesterase Psychiatry and Mental health Original Article Sesquiterpenes Signal Transduction medicine.drug Genetically modified mouse Beta-catenin Cell Survival Neurogenesis Enzyme-Linked Immunosorbent Assay Mice Transgenic Nerve Tissue Proteins Biology Transfection Neuroprotection Alkaloids Alzheimer Disease Presenilin-1 medicine Animals Humans RNA Messenger Analysis of Variance Amyloid beta-Peptides Molecular biology Mice Inbred C57BL Wnt Proteins Disease Models Animal Bromodeoxyuridine Gene Expression Regulation chemistry Mutation Microscopy Electron Scanning biology.protein Cholinesterase Inhibitors |
| Zdroj: | Neuropsychopharmacology. 36:1073-1089 |
| ISSN: | 1740-634X 0893-133X |
| DOI: | 10.1038/npp.2010.245 |
| Popis: | Huperzine A (HupA) is a reversible and selective inhibitor of acetylcholinesterase (AChE), and it has multiple targets when used for Alzheimer's disease (AD) therapy. In this study, we searched for new mechanisms by which HupA could activate Wnt signaling and reduce amyloidosis in AD brain. A nasal gel containing HupA was prepared. No obvious toxicity of intranasal administration of HupA was found in mice. HupA was administered intranasally to β-amyloid (Aβ) precursor protein and presenilin-1 double-transgenic mice for 4 months. We observed an increase in ADAM10 and a decrease in BACE1 and APP695 protein levels and, subsequently, a reduction in Aβ levels and Aβ burden were present in HupA-treated mouse brain, suggesting that HupA enhances the nonamyloidogenic APP cleavage pathway. Importantly, our results further showed that HupA inhibited GSK3α/β activity, and enhanced the β-catenin level in the transgenic mouse brain and in SH-SY5Y cells overexpressing Swedish mutation APP, suggesting that the neuroprotective effect of HupA is not related simply to its AChE inhibition and antioxidation, but also involves other mechanisms, including targeting of the Wnt/β-catenin signaling pathway in AD brain. |
| Databáze: | OpenAIRE |
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