Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcholinesterase / metabolism
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Alkaloids / therapeutic use*
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Alzheimer Disease / drug therapy*
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Alzheimer Disease / genetics
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Alzheimer Disease / metabolism
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Alzheimer Disease / pathology
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Amyloid beta-Peptides / metabolism*
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Amyloid beta-Protein Precursor / genetics
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Analysis of Variance
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Animals
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Blood-Retinal Barrier / drug effects
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Blood-Retinal Barrier / ultrastructure
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Bromodeoxyuridine / metabolism
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Cell Survival / drug effects
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Cell Survival / ethics
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Cholinesterase Inhibitors / therapeutic use*
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Disease Models, Animal
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Enzyme Inhibitors / pharmacology
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Enzyme-Linked Immunosorbent Assay / methods
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Gene Expression Regulation / drug effects
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Humans
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Microscopy, Confocal / methods
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Microscopy, Electron, Scanning / methods
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Mutation / genetics
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Neuroblastoma / pathology
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Neuroblastoma / ultrastructure
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Neurogenesis / drug effects
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Olfactory Bulb / metabolism
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Olfactory Bulb / ultrastructure
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Presenilin-1 / genetics
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RNA, Messenger / metabolism
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Sesquiterpenes / therapeutic use*
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Signal Transduction / drug effects*
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Transfection / methods
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Wnt Proteins / genetics
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Wnt Proteins / metabolism*
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beta Catenin / genetics
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beta Catenin / metabolism*
Substances
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Alkaloids
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Cholinesterase Inhibitors
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Enzyme Inhibitors
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Nerve Tissue Proteins
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Presenilin-1
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RNA, Messenger
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Sesquiterpenes
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Wnt Proteins
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beta Catenin
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huperzine A
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Acetylcholinesterase
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Bromodeoxyuridine