Effect of huprine X on β-amyloid, synaptophysin and α7 neuronal nicotinic acetylcholine receptors in the brain of 3xTg-AD and APPswe transgenic mice.
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 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.


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.


CONCLUSIONS
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.
Hedberg
Monika M
MM
Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Division of Alzheimer Neurobiology, Karolinska University Hospital, Huddinge, Stockholm, Sweden. monika.m.hedberg@gmail.com
Clos
M Victoria
MV
Ratia
Miriam
M
Gonzalez
Daniel
D
Lithner
Christina Unger
CU
Camps
Pelayo
P
Muñoz-Torrero
Diego
D
Badia
Albert
A
Giménez-Llort
Lydia
L
Nordberg
Agneta
A
D000544:Alzheimer Disease / Q000188:drug therapy / Q000473:pathology; D000634:Aminoquinolines / Q000494:pharmacology* / Q000627:therapeutic use; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism; D002038:Bungarotoxins / Q000493:pharmacokinetics; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology* / Q000627:therapeutic use; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007456:Iodine Isotopes / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000378:metabolism*; D018709:Statistics, Nonparametric; D016708:Synaptophysin / Q000378:metabolism*; D064569:alpha7 Nicotinic Acetylcholine Receptor; D016875:tau Proteins / Q000235:genetics
D000634:Aminoquinolines; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002038:Bungarotoxins; D002800:Cholinesterase Inhibitors; C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; D006576:Heterocyclic Compounds, 4 or More Rings; D007456:Iodine Isotopes; D010446:Peptide Fragments; D053764:Presenilin-1; D011978:Receptors, Nicotinic; D016708:Synaptophysin; D064569:alpha7 Nicotinic Acetylcholine Receptor; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C404518:huprine X; D016875:tau Proteins