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Effect of huprine X on β-amyloid, synaptophysin and α7 neuronal nicotinic acetylcholine receptors in the brain of 3xTg-AD and APPswe transgenic mice.
- Source :
-
Neuro-degenerative diseases [Neurodegener Dis] 2010; Vol. 7 (6), pp. 379-88. Date of Electronic Publication: 2010 Aug 04. - Publication Year :
- 2010
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Abstract
- Background: Several studies implicate acetylcholinesterase (AChE) in the pathogenesis of Alzheimer's disease (AD), raising the question of whether inhibitors of AChE also might act in a disease-modifying manner. Huprine X (HX), a reversible AChE inhibitor hybrid of tacrine and huperzine A, has shown to affect the amyloidogenic process in vitro. In this study, the aim was to investigate whether HX could affect the AD-related neuropathology in vivo in two mouse models.<br />Methods: Tg2576 (K670M/N671L) (APPswe) and 3xTg-AD (K670M/N671L, PS1M146V, tauP301L) mice were treated with HX (0.12 μmol/kg, i.p., 21 days) or saline at 6-7 months. Human β-amyloid (Aβ) was measured by ELISA, synaptophysin by Western blot and α7 neuronal nicotinic acetylcholine receptors (nAChRs) were analyzed by [(125)I]α-bungarotoxin autoradiography.<br />Results: Treatment with HX reduced insoluble Aβ1-40 (about 40%) in the hippocampus of 3xTg-AD mice, while showing no effect in APPswe mice. Additionally, HX markedly increased cortical synaptophysin levels (about 140%) and decreased (about 30%) the levels of α7 nAChRs in the caudate nucleus of 3xTg-AD mice, while increasing (about 10%) hippocampal α7 nAChRs in APPswe mice.<br />Conclusion: The two mouse models react differently to HX treatment, possibly due to their differences in brain neuropathology. The modulation of Aβ and synaptophysin by HX in 3xTg-AD mice might be due to its suggested interaction with the peripheral anionic site on AChE, and/or via cholinergic mechanisms involving activation of cholinergic receptors. Our results provide further evidence that drugs targeting AChE affect some of the fundamental processes that contribute to neurodegeneration, but whether HX might act in a disease-modifying manner in AD patients remains to be proven.<br /> (Copyright © 2010 S. Karger AG, Basel.)
- Subjects :
- Alzheimer Disease drug therapy
Alzheimer Disease pathology
Aminoquinolines therapeutic use
Amyloid beta-Protein Precursor genetics
Animals
Brain anatomy & histology
Brain metabolism
Bungarotoxins pharmacokinetics
Cerebral Cortex drug effects
Cerebral Cortex metabolism
Cholinesterase Inhibitors therapeutic use
Disease Models, Animal
Enzyme-Linked Immunosorbent Assay methods
Female
Gene Expression Regulation drug effects
Gene Expression Regulation genetics
Heterocyclic Compounds, 4 or More Rings therapeutic use
Hippocampus drug effects
Hippocampus metabolism
Iodine Isotopes pharmacokinetics
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mutation genetics
Peptide Fragments metabolism
Presenilin-1 genetics
Protein Binding drug effects
Statistics, Nonparametric
alpha7 Nicotinic Acetylcholine Receptor
tau Proteins genetics
Aminoquinolines pharmacology
Amyloid beta-Peptides metabolism
Brain drug effects
Cholinesterase Inhibitors pharmacology
Heterocyclic Compounds, 4 or More Rings pharmacology
Receptors, Nicotinic metabolism
Synaptophysin metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1660-2862
- Volume :
- 7
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Neuro-degenerative diseases
- Publication Type :
- Academic Journal
- Accession number :
- 20689242
- Full Text :
- https://doi.org/10.1159/000287954