Validation of the APP23 Transgenic Mouse Model of Alzheimer’s Disease through Evaluation of Risperidone Treatment on Aggressive Behaviour

Abstract

Valid animal models are indispensable in the drug discovery pipeline for dementia. Transgenic APP23 mice model Alzheimer’s disease patients’ memory deficits and additionally present with various behavioural disturbances, such as aggressive behaviour. The present study investigated and confirmed significant sensitivity of the model to the aggression-lowering ability of the antipsychotic agent risperidone (CAS 106266-06-2). The sensitivity for such anti-aggressive action contributes to the therapeutic predictive validity of the APP23 model of Alzheimer’s disease, which can be used as a pre-clinical screening tool for the identification of novel anti-aggressive agents.

Key words

Aggressive behaviour - Alzheimer’s disease - Antipsychotic agents - CAS 106266-06-2 - Risperidone, aggression-lowering ability, transgenic mouse model - Transgenic mouse model, validation

• References

• 1 Mega MS, Cummings JL, Fiorello T, Gornbein J. The spectrum of behavioral changes in Alzheimer’s disease. Neurology. 1996; 46: 130-135
• 2 Reisberg B, Borenstein J, Salob SP, Ferris SH, Franssen E, Georgotas A. Behavioral symptoms in Alzheimer’s disease: phenomenology and treatment. J Clin Psychiat. 1987; 48: 9-15
• 3 Ballard CG, O’Brien J, James I, Swann A. Aggression. In Ballard CG, O’Brien J, James I, Swann A. editors Dementia: management of behavioural and psychological symptoms. Oxford: Oxford University Press; 2001. p 61-78
• 4 De Deyn PP. Belasting voor de patiënt en zijn omgeving. In De Deyn PP. editor Dementie: medische, psychosociale, ethische en preventieve aspecten. Mechelen: Kluwer; 2004. p 105-117
• 5 Ryden MB. Aggressive behavior in persons with dementia who live in the community. Alz Dis Assoc Dis. 1988; 2: 342-355
• 6 Burns A, Jacoby R, Levy R. Psychiatric phenomena in Alzheimer’s disease. IV: Disorders of behaviour. Brit J Psychiat. 1990; 157: 86-94
• 7 De Deyn PP, Katz IR. Control of aggression and agitation in patients with dementia: efficacy and safety of risperidone. Int J Geriatr Psych. 2000; 15: 14-22
• 8 De Deyn PP, Wirshing WC. Scales to assess efficacy and safety of pharmacologic agents in the treatment of behavioural and psychological symptoms of dementia. J Clin Psychiat. 2001; 62: 19-22
• 9 Rabinowitz J, Katz IR, De Deyn PP, Brodaty H, Greenspan A, Davidson M. Behavioural and psychological symptoms in patients with dementia as a target for pharmacotherapy with risperidone. J Clin Psychiat. 2004; 65: 1329-1334
• 10 De Deyn PP, Katz IR, Brodaty H, Lyons B, Greenspan A, Burns A. Management of agitation, aggression, and psychosis associated with dementia: a pooled analysis including three randomized, placebo-controlled double-blind trials in nursing home residents treated with risperidone. Clin Neurol Neurosur. 2005; 107: 497-508
• 11 De Deyn PP, Buitelaar J. Risperidone in the management of agitation and aggression associated with psychiatric disorders. Eur Psychiat. 2006; 21: 21-28
• 12 Rabinowitz J, Katz I, De Deyn PP, Greenspan A, Brodaty H. Treating behavioral and psychological symptoms in patients with psychosis of Alzheimer’s disease using risperidone. Int Psychogeriatr. 2007; 19: 227-240
• 13 Alexopoulos GS, Jeste DV, Chung H, Carpenter D, Ross R, Docherty JP. The expert consensus guideline series. Treatment of dementia and its behavioural disturbances. Introduction: methods, commentary, and summary. Postgrad Med. 2005; Jan Spec No 6-22
• 14 Burns A, De Deyn PP. Risperidone for the treatment of neuropsychiatric features in dementia. Drug Aging. 2006; 23: 887-896
• 15 Van DDam, D’Hooge R, Staufenbiel M, Van CGinneken, Van FMeir, De Deyn PP. Age-dependent cognitive decline in the APP23 model precedes amyloid deposition. Eur J Neurosci. 2003; 17: 388-396
• 16 Van DDam, Vloeberghs E, Abramowski D, Staufenbiel M, De Deyn PP. APP23 mice as a model of Alzheimer’s Disease. An example of a transgenic breeding approach to modelling a CNS disorder. CNS Spectr. 2005; 10: 207-222
• 17 Vloeberghs E, Van Dam D, Engelborghs S, Nagels G, Staufenbiel M, De Deyn PP. Altered circadian locomotor activity in APP23 mice: A model for BPSD disturbances. EUR J Neurosci. 2004; 20: 2757-2766
• 18 Vloeberghs E, Van DDam, Coen K, Staufenbiel M, De Deyn PP. Aggressive male APP23 mice modelling behavioural alterations in dementia. Behav Neurosci. 2006; 120: 1380-1383
• 19 Meltzer HY, Lee MA, Ranjan R. Recent advances in the pharmacotherapy of schizophrenia. Acta Psychiat Scand. 1994; 90: 95-101
• 20 Alexopoulos GS, Streim J, Carpenter D, Docherty JP. Expert Consensus Panel for Using Antipsychotic Drugs in Older Patients. Using antipsychotic agents in older patients. J Clin Psychiatry. 2004; 65 (Suppl 2) 5-99 discussion 100–102
• 21 Moechars D, Gilis M, Kuipéri C, Laenen I, Van FLeuven. Aggressive behaviour in transgenic mice expressing APP is alleviated by serotonergic drugs. Neuroreport. 1998; 9: 3561-3564
• 22 Van DDam, De Deyn PP. Drug discovery in dementia: The role of rodent models. Nat Rev Drug Discov. 2006; 5: 956-970
• 23 Sturchler-Pierrat C, Abramowski D, Duke M, Wiederhold KH, Mistl C, Rothacher S et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci USA. 1997; 94: 13287-13292
• 24 Vloeberghs E, Van DDam, D’Hooge R, Staufenbiel M, De Deyn PP. APP23 mice display working memory impairment in the plus-shaped water maze. Neurosci Lett. 2006; 407: 6-10
• 25 Van DDam, Abramowski D, Staufenbiel M. De Deyn PR Symptomatic effect of donepezil rivastigmine galantamine and memantine on cognitive deficits in the APP23 model. Psychopharmacology (Berl). 2005; 180: 177-190