Acetylcholinesterase inhibitors ameliorate behavioral deficits in the Tg2576 mouse model of Alzheimer’s disease

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 b-amyloid (Ab) and behavioral deficits during adulthood are useful for investigating this question. Objectives: The effects of administration of two acetylcholinesterase inhibitors, physostigmine and donepezil, on Ab 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 Ab 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 0.3mg/kg), donepezil (0.1, 0.3 and 1.0mg/kg) or saline were administered over six 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 Ab 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 Aß plaques. Conclusions: These studies suggest that acetylcholinesterase inhibitors can ameliorate memory deficits in Tg(+) mice without necessarily altering the deposition of Aß 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.

Effects of Memantine on Neuronal Structure and Conditioned Fear in the Tg2576 Mouse Model of Alzheimer's Disease

“…The behavior deficits we observed in Tg + mice replicated earlier findings using Tg2576 mice (Hsiao et al, 1996;Corcoran et al, 2002;Arendash et al, 2004;Barnes and Good, 2005;Dong et al, 2005) and thus imply validity of the behavioral test employed here. At present, the effects of memantine on behavior in transgenic mouse models of AD (Minkeviciene et al, 2004;Van Dam et al, 2005;Van Dam and De Deyn, 2006), as well as other models (Barnes et al, 1996;MiguelHidalgo et al, 2002;Lang et al, 2004;Woodruff-Pak et al, 2007; for review see Yuede et al, 2007) are inconsistent.…”

“…The assessment of contextual and cued memory within a fear-conditioning paradigm was performed using methods previously described (Bardgett et al, 2003;Dong et al, 2005). Animals were trained and tested in two Plexiglas conditioning chambers (26 Â 18 Â 18 cm) (Med Associates Inc., Georgia, VT), with a metal grid floor, within a larger sound-attenuating chamber.…”

Involvement of hippocampal excitability in amyloid β-induced behavioral and psychological symptoms of dementia

“…icits but also BPSD-like symptoms such as aggression, hyperactivity, and impulsive behavior have been observed in the transgenic mice (Lalonde et al, 2003;Stackman et al, 2003;Ognibene et al, 2005;Dong et al, 2005;Adriani et al, 2006;Quinn et al, 2007). These symptoms may age-dependently occur in transgenic mice (Hsiao et al, 1996;Moechars et al, 1999;Chen et al, 2000).…”

Age-related changes in memory and in acetylcholine functions in the hippocampus in the Ts65Dn mouse, a model of Down syndrome

“…Similarly, acetylcholinesterase inhibitors are particularly effective in enhancing memory in rats and mice with compromised cholinergic functions and with other memoryimpairing pharmacological manipulations (Chang and Gold, 2004;Degroot and Parent, 2000;Ukai et al, 1995;Walker and Gold, 1992;Beracochea et al, 1992;Stone et al, 1991;Murray and Fibiger, 1986). Acetylcholinesterase inhibitors are also effective enhancers of memory in several rodent models of Alzheimer's Disease (Maurice et al, 1996;Dong et al, 2005;Popovi et al, 1997;Santucci et al, 1991). Thus, based on the results seen in the Ts65Dn mice, physostigmine might be effective in older control mice only if the cholinergic system has sufficient remaining function.…”

“…The acetylcholinesterase inhibitor, physostigmine, was selected as the drug with which to enhance memory because of past findings indicating that the drug enhances memory in aging and other conditions (e.g., Rispoli et al, 2006;Flood et al, 1993;Normile and Altman, 1992;Riekkinen et al, 1991;Ohta et al, 1991;Castellano et al, 1989;Chang and Gold, 2004;Degroot and Parent, 2000;Ukai et al, 1995;Walker and Gold, 1992;Beracochea et al, 1992;Stone et al, 1991;Murray and Fibiger, 1986;Maurice et la., 1996;Dong et al, 2005;Popovi et al, 1997;Santucci et al, 1991). In addition, physostigmine was selected because it is an indirect agonist that requires at least some remaining release of ACh in order to exert its pharmacological actions.…”