Abstract
Rationale
Acetylcholinesterase inhibitors are widely used for the treatment of patients with Alzheimer’s disease (AD). However, the relationship between the capacity of such drugs to ameliorate the symptoms of AD and their ability to alter the underlying disease process is not well understood. Transgenic mice that overexpress the human form of amyloid precursor protein and develop deposits of β-amyloid (Aβ) and behavioral deficits during adulthood are useful for investigating this question.
Objectives
The effects of administration of two acetylcholinesterase inhibitors, physostigmine and donepezil, on Aβ plaque formation and memory-related behaviors were investigated in the Tg2576-transgenic mouse model of AD. At 9–10 months of age, Tg2576-transgenic [Tg(+)] mice develop Aβ plaques and impairments on paradigms related to learning and memory as compared to transgene-negative [Tg(−)] mice.
Methods
Beginning at 9 months of age, increasing doses of physostigmine (0.03, 0.1, and 0.3 mg/kg), donepezil (0.1, 0.3, and 1.0 mg/kg), or saline were administered over 6 weeks to cohorts of Tg(+) and Tg(−) mice. Performance on tests of spatial reversal learning and fear conditioning was evaluated at each drug dose throughout the period of drug administration. After drug administration was completed, the animals were sacrificed and Aβ plaque number was quantified.
Results
Administration of physostigmine and donepezil improved deficits in contextual and cued memory in Tg(+) mice so that their behaviors became more similar to Tg(−) mice. However, administration of physostigmine and donepezil tended to improve cued memory and deficits in spatial learning in both Tg(+) and Tg(−) mice. Physostigmine administration demonstrated more prominent effects in improving contextual memory than donepezil, while donepezil was more effective than physostigmine in improving deficits in the acquisition of the spatial memory paradigm. Administration of neither drug altered the deposition of Aβ plaques.
Conclusions
These studies suggest that acetylcholinesterase inhibitors can ameliorate memory deficits in Tg(+) mice without necessarily altering the deposition of Aβ plaques. Tg2576 mice may be useful as an animal model to further investigate the mechanisms by which aceytlcholinesterase inhibitors improve cognitive deficits in patients with AD.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Apelt J, Kumar A, Schliebs R (2002) Impairment of cholinergic neurotransmission in adult and aged transgenic Tg2576 mouse brain expressing the Swedish mutation of human beta-amyloid precursor protein. Brain Res 953:17–30
Bardgett ME, Boeckman R, Krochmal D, Fernando H, Ahrens R, Csernansky JG (2003) NMDA receptor blockade and hippocampal neuronal loss impair fear conditioning and position habit reversal in C57Bl/6 mice. Brain Res Bull 60:131–142
Bartolini M, Bertucci C, Vavrini V, Andrisano V (2003) Beta-amyloid aggregation induced by human acetylcholinesterase: inhibition studies. Biochem Pharmacol 65:407–416
Beach TG, Kuo Y, Schwab C, Walker D, Roher A (2001) Reduction of cortical amyloid levels in guinea pig brain after systemic administration of physostigmine. Neurosci Lett 310:21–24
Boncristiano S, Calhoun ME, Kelly PH, Pfeifer M, Bondolfi L, Stalder M, Phinney AL, Abramowski D, Sturchler-Pierrat C, Enz A, Sommer B, Staufenbiel M, Jucker M (2002) Cholinergic changes in the APP23 transgenic mouse model of cerebral amyloidosis. J Neurosci 22:3234–3243
Chapman PF, White GL, Jones MW, Cooper-Blacketer D, Marshall VJ, Irizarry M, Younkin L, Good MA, Bliss TV, Hyman BT, Younkin SG, Hsiao KK (1999) Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice. Nat Neurosci 2:271–276
Csernansky J, Bargett M, Dong H, Humphrey W, Wang L (2002) Hippocampal structure and the action of cholinomimetic drugs. Drug Dev Res 51:1–10
Cummings JL, Vinters HV, Cole GM, Khachaturian ZS (1998) Alzheimer’s disease: etiologies, pathophysiology, cognitive reserve, and treatment opportunities. Neurology 51:S2–S17
Darvesh S, Walsh R, Kumar R, Caines A, Roberts S, Magee D, Rockwood K, Martin E (2003) Inhibition of human cholinesterase by drugs used to treat Alzheimer disease. Alzheimer Dis Assoc Disord 17:117–126
Davis KL, Thal LJ, Gamzu ER, Davis CS, Woolson RF, Gracon SI, Drachman DA, Schneider LS, Whitehouse PJ, Hoover TM, The Tacrine Collaborative Study Group (1992) A double-blind placebo-controlled multicenter study of tacrine for Alzheimer’s disease. N Engl J Med 327:1253–1259
Dong H, Goico B, Martin M, Csernansky CA, Bertchume A, Csernansky JG (2004) Modulation of hippocampal cell proliferation, memory, and amyloid plaque deposition in APPsw (Tg2576) mutant mice by isolation stress. Neuroscience 127:601–609
Francis PT, Palmer AM, Snape M, Wilcock GK (1999) The cholinergic hypothesis of Alzheimer’s disease: a review of progress. J Neurol Neurosurg Psychiatry 66:137–147
Fodero LR, Saez-Valero J, McLean CA, Martins RN, Beyreuther K, Masters CL, Robertson TA, Small DH (2002) Altered glycosylation of acetylcholinesterse in APP (SW) Tg2576 transgenic mice occurs prior to amyloid plaque deposition. J Neurochem 81:441–448
Gong Y, Chang L, Viola KL, Lacor PN, Lambert MP, Finch CE, Krafft GA, Klein WL (2003) Alzheimer’s disease-affected brain: presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc Natl Acad Sci U S A 100:10417–10422
Guntern E, Bouras C, Hoff PR, Vallet PG (1992) An improved thioflavine S method for staining neurofibrillary tangles ad senile plaques in Alzheimer’s disease. Experientia 48:8–10
Hsiao K (2001) Learning and memory in transgenic mice modeling Alzheimer’s disease. Learn Mem 8:301–308
Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G (1996) Correlative memory deficits, Aβ elevation and amyloid plaques in transgenic mice. Science 274:99–102
Inestrosa NC, Alvarez A, Perez CA, Moreno RD, Vicente M, Linker C, Casanueva OI, Soto C, Garrido J (1996) Acetylcholinesterase accelerates assembly of amyloid-β-peptides into Alzheimer’s fibrils: possible role of the peripheral site of the enzyme. Neuron 16:881–891
Irizarry M, McNamara M, Fedorchak K, Hsiao K, Hyman B (1997) APPsw transgenic mice develop age-related Aβ deposits and neuropil abnormalities, but no neuronal loss in CA1. J Neuropathol Exp Neurol 56:965–973
Jaffar S, Counts SE, Ma SY, Dadko E, Gordon MN, Morgan D, Mufson EJ (2001) Neuropathology of mice carrying mutant APP(swe) and/or PS1 (M146L) transgenes: alterations in the p75(NTR) cholinergic basal forebrain septohippocampal pathway. Exp Neurol 170:227–243
Liu L, Ikonen S, Tapiola T, Tanila H, Van Groen T (2002) Fimbria–fornix lesion does not affect APP levels and amyloid deposition in the hippocampus of APP+PS1 double transgenic mice. Exp Neurol 177:565–574
Mazzucchelli M, Porrello E, Villetti G, Pietra C, Govoni S, Racchi M (2003) Characterization of the effect of ganstigmine (CHF2819) on amyloid precursor protein metabolism in SH-SY5Y neuroblastoma cells. J Neural Transm 110:935–947
Moghul S, Wilkinson D (2001) Use of acetylcholinesterase inhibitors in Alzheimer’s disease. Expert Rev Neurotherapeutics 1:61–69
Mullan M (2000) Genetic contributions to causes of Alzheimer’s disease: current perspectives and future directions, pp 307–309. In: New insights into genetics and pathophysiology of Alzheimer’s disease: what are the clinical and therapeutic implications? J Clin Psychiatry 61:307–315
Nilsberth C, Basun H, Eckman C, Lannfelt L, Younkin S (2002) Plasma levels of Aβ42 and Aβ40 in Alzheimer patients during treatment with the acetylcholinesterase inhibitor tacrine. Dement Geriatr Cogn Disord 14:156–160
Nitsch RM, Slack BE, Wurtman RJ, Growdon JH (1992) Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science 258:304–307
Pakaski M, Kasa P (2003) Role of acetycholinesterase inhibitors in the metabolism of amyloid precursor protein. Curr Drug Target CNS Neurol Disord 2:163–171
Piazzi L, Rampa A, Bisi A, Gobbi S, Belluti F, Cavalli A, Bartolini M, Andrisano V, Valenti P, Recanatini M (2003) 3-(4-[[Benzyl(methyl)amino]methyl]phenyl)-6,7-dimethoxy-2H-2-chromenone (AP2238) inhibits both acetylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation: a dual function lead for Alzheimer’s disease therapy. J Med Chem 46(12):2279–2282
Price D (1986) New perspectives on Alzheimer’s disease. Annu Rev Neurosci 9:489–512
Rees T, Hammond PI, Soreq H, Younkin S, Brimijoin S (2003) Acetylcholinesterase promotes beta-amyloid plaques in cerebral cortex. Neurobiol Aging 24:777–787
Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT (1998) A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. Neurology 50:136–145
Shigeta M, Homma A (2001) Donepezil for Alzheimer’s disease: pharmacodynamic, pharmacokinetic, and clinical profiles. CNS Drug Rev 7:353–368
Storch A, Schrattenholz A, Cooper JC, Abdel Ghani EM, Gutbrod O, Weber KH, Reinhardt S, Lobron C, Hermsen B, Soskic V et al (1995) Physostigmine, galanthamine and codeine act as noncompetitive nicotinic agonists on clonal rat pheochromocytoma cells. Eur J Pharmacol 290:207–219
Sturchler-Pierrat C, Abramowski D, Duke M, Wiederhold KH, Mistl C, Rothacher S, Ledermann B, Burki K, Frey P, Paganetti PA, Waridel C, Calhoun ME, Jucker M, Probst A, Staufenbiel M, Sommer B (1997) Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci U S A 94(24):13287–13292
Tariot PN, Solomon PR, Morris JC, Kershaw P, Lilienfeld S, Ding C, Galatamine USA-10 Study Group (2000) A 5-month, randomized placebo-controlled trial of galantamine in AD. Neurology 54:2269–2276
West M, Gundersen H (1990) Unbiased stereological estimation of the number of neurons in the human hippocampus. J Comp Neurol 296:1–22
Westerman MA, Cooper-Blacketer D, Mariash A, Kotilinek L, Kawarabayashi T, Younkin LH, Carlson GA, Younkin SG, Ashe KH (2002) The relationship between Aβ and memory in the Tg2576 mouse model of Alzheimer’s disease. J Neurosci 22:1858–1867
Acknowledgements
This research was supported by PHS grant R-01 MH60883. Donepezil was provided free of charge by Pfizer/Eisai Inc.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Dong, H., Csernansky, C.A., Martin, M.V. et al. Acetylcholinesterase inhibitors ameliorate behavioral deficits in the Tg2576 mouse model of Alzheimer’s disease. Psychopharmacology 181, 145–152 (2005). https://doi.org/10.1007/s00213-005-2230-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-005-2230-6