Journal
NEURODEGENERATIVE DISEASES
Volume 7, Issue 6, Pages 379-388Publisher
KARGER
DOI: 10.1159/000287954
Keywords
Acetylcholinesterase inhibitor; beta-Amyloid; Alzheimer's disease; Nicotinic acetylcholine receptor; Transgenic mice
Categories
Funding
- Swedish Research Council [05817]
- Swedish Brain Power
- Swedish Alzheimer Foundation
- Gun and Bertil Stohne's Foundation
- Foundation for Old Servants
- Direccion General de Investigacion del Ministerio de Ciencia y Tecnolog a y FEDER [SAF2006-04339, SAF2006-13642]
- AGAUR by Generalitat of Catalunya [2006 BE-200066]
- Salvador de Madariaga, Ministerio de Educacion y Ciencia [PR2007-0095]
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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. Methods: Tg2576 (K670M/N671L) (APPswe) and 3xTg-AD (K670M/N671L, PS1M146V, tauP301L) mice were treated with HX (0.12 mu mol/kg, i.p., 21 days) or saline at 6-7 months. Human beta-amyloid (A beta) was measured by ELISA, synaptophysin by Western blot and alpha 7 neuronal nicotinic acetylcholine receptors (nAChRs) were analyzed by [I-125]alpha-bungarotoxin autoradiography. Results: Treatment with HX reduced insoluble A beta 1-40 (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 alpha 7 nAChRs in the caudate nucleus of 3xTg-AD mice, while increasing (about 10%) hippocampal alpha 7 nAChRs in APPswe mice. Conclusion: The two mouse models react differently to HX treatment, possibly due to their differences in brain neuropathology. The modulation of A beta 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. Copyright (C) 2010 S. Karger AG, Basel
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