Abstract
The field of Alzheimer’s disease (AD) research has been quite fortunate – in contrast to some other neurodegenerative psychiatric diseases – in that a number of animal models have been developed based on genetic and neuropathological information. These animal models have been “validated” based on the fact that they reflect one or a few of the neuropathological features found in postmortem brain of AD patients. However, the predictive value of these models for drug discovery has been far from spectacular. Limitations of these models include the failure to capture the dynamics of the ongoing pathology in a clinical setting and to display the total neuropathology. However, animal models – because of the species barrier – have a number of additional limitations for a successful drug development program, which are not always fully appreciated. This chapter discusses (1) differences in drug affinities between human and rodent targets, (2) the absence of key human functional genotypes in rodent models, (3) the intrinsic difference in some neurotransmitter circuits, and (4) the difficulty of simulating the same amount of drug exposure as in the clinical situation. In addition, the problems associated with extrapolating cognitive tests in animal studies with actual performance of treated AD patients on clinical scales are explored. Possible solutions to this dilemma include (1) developing multitarget directed ligands where cholinesterase inhibition is combined with disease modification, (2) a better translation of clinical endophenotypes, (3) capitalizing on drug discovery efforts for cognition in other disease areas, (4) the introduction of realistic polypharmacy in early stages of preclinical tests, and (5) the systematic testing of the face-value of a specific preclinical model/readout combination using marketed drugs with documented clinical effects. Finally, Computational Neuropharmacology, a novel and highly innovative computer modeling approach of interacting brain circuits is introduced. When added to the toolbox of preclinical drug discovery, this approach intends to bridge the difference between preclinical animal models and the clinical situation and reduce the rate of attrition.
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References
Geerts H (2004) NC-531 (Neurochem). Curr Opin Investig Drugs 5:95–100.
Lidow MS, Roberts A, Zhang L, et al. (2001) Receptor crosstalk protein, calcyon, regulates affinity state of dopamine D1 receptors. Eur J Pharmacol 427:187–193.
Trantham-Davidson H, Neely LC, et al. (2004) Mechanisms underlying differential D1 versus D2 dopamine receptor regulation of inhibition in prefrontal cortex. J Neurosci 24:10652–10659.
Bonnin A, Peng W, Hewlett W, et al. (2006) Expression mapping of 5-HT1 serotonin receptor subtypes during fetal and early postnatal mouse forebrain development. Neuroscience 141:781–794.
Muly EC, Maddox M, Smith Y (2003) Distribution of mGluR1alpha and mGluR5 immunolabeling in primate prefrontal cortex. J Comp Neurol 467:521–535.
Hubert GW, Paquet M, Smith Y (2001) Differential subcellular localization of mGluR1a and mGluR5 in the rat and monkey Substantia nigra. J Neurosci 21:1838–1847.
Marazziti D, Betti L, Giannaccini G, Rossi A, et al. (2001) Distribution of [3H]GR65630 binding in human brain postmortem. Neurochem Res 26:187–190.
Hirst WD, Abrahamsen B, Blaney FE, et al. (2003) Differences in the central nervous system distribution and pharmacology of the mouse 5-hydroxytryptamine-6 receptor compared with rat and human receptors investigated by radioligand binding, site-directed mutagenesis, and molecular modeling. Mol Pharmacol 64:1295–1308.
Garcia-Alloza M, Hirst WD, Chen CP, et al. (2004) Differential involvement of 5-HT(1B/1D) and 5-HT6 receptors in cognitive and non-cognitive symptoms in Alzheimer’s disease. Neuropsychopharmacology 29:410–416.
Aerssens J, Parys W, Lilienfeld S, et al. (2001) “APOE genotype: No influence on galantamine treatment efficacy nor on rate of decline in AD”. Dement Geriatr Cogn Disord 12:69–77.
Bales KR, Dodart JC, DeMattos RB, et al. (2002) Apolipoprotein E, amyloid, and Alzheimer disease. Mol Interv 2:363–375.
Maloney B, Ge YW, Alley GM, et al. (2007) Important differences between human and mouse APOE gene promoters: Limitation of mouse APOE model in studying Alzheimer’s disease. J Neurochem 103:1237–1257.
Diaz-Asper CM, Weinberger DR, Goldberg TE (2006) Catechol-O-methyltransferase polymorphisms and some implications for cognitive therapeutics. NeuroRx 3:97–105.
Bertolino A, Caforio G, Blasi G, et al. (2004) Interaction of COMT (Val(108/158)Met) genotype and olanzapine treatment on prefrontal cortical function in patients with schizophrenia. Am J Psychiatry 161:1798–1805.
Uhr M, Tontsch A, Namendorf C, et al. (2008) Polymorphisms in the drug transporter gene ABCB1 predict antidepressant treatment response in depression. Neuron 57:203–209.
Kapur S, VanderSpek SC, Brownlee BA, et al. (2003) Antipsychotic dosing in preclinical models is often unrepresentative of the clinical condition: A suggested solution based on in vivo occupancy. J Pharmacol Exp Ther 305:625–631.
Oddo S, Caccamo A, Shepherd JD, et al. (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: Intracellular Abeta and synaptic dysfunction. Neuron 39:409–421.
Oddo S, Caccamo A, Green KN, et al. (2005) Chronic nicotine administration exacerbates tau pathology in a transgenic model of Alzheimer’s disease. Proc Natl Acad Sci U S A 102:3046–3051.
O’Brien JT, Colloby SJ, Pakrasi S, et al. (2007) Alpha4beta2 nicotinic receptor status in Alzheimer’s disease using 123I-5IA-85380 single-photon-emission computed tomography. J Neurol Neurosurg Psychiatr 78:356–362.
Carnevale D, De Simone R, Minghetti L (2007) Microglia-neuron interaction in inflammatory and degenerative diseases: Role of cholinergic and noradrenergic systems. CNS Neurol Disord Drug Targets 6:388–397.
Kelly PH, Bondolfi L, Hunziker D, et al. (2003) Progressive age-related impairment of cognitive behavior in APP23 transgenic mice. Neurobiol Aging 24:365–378.
Pike KE, Savage G, Villemagne VL, et al. (2007) Beta-amyloid imaging and memory in non-demented individuals: Evidence for preclinical Alzheimer’s disease. Brain 130:2837–2844.
Woodruff-Pak DS, Agelan A, Del Valle L (2007) A rabbit model of Alzheimer’s disease: Valid at neuropathological, cognitive, and therapeutic levels. J Alzheimers Dis 11:371–383.
Fisher A (2007) M1 muscarinic agonists target major hallmarks of Alzheimer’s disease–an update. Curr Alzheimer Res 4:577–580.
Coyle JT, Geerts H, Sorra K, et al. (2007) Beyond in vitro data: A review of in vivo evidence regarding the allosteric potentiating effect of galantamine on nicotinic acetylcholine receptors in Alzheimer’s neuropathology. J Alzheimers Dis 11:491–507.
Lee RK, Wurtman RJ, Cox AJ, et al. (1995) Amyloid precursor protein processing is stimulated by metabotropic glutamate receptors. Proc Natl Acad Sci U S A 92:8083–8087.
Sahay A, Hen R (2007) Adult hippocampal neurogenesis in depression. Nat Neurosci 10:1110–1115.
Newton SS, Duman RS (2007) Neurogenic actions of atypical antipsychotic drugs and therapeutic implications. CNS Drugs 21:715–725.
Peña-Casanova J (1997) Alzheimer’s disease assessment scale–cognitive in clinical practice. Int Psychogeriatr 9:105–114.
Gilman S, Koller M, Black R, Jenkins L, et al. (2005) Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 9:1553–1562.
Saumier D, Murtha S, Bergman H, et al. (2007) Cognitive predictors of donepezil therapy response in Alzheimer disease. Dement Geriatr Cogn Disord 24:28–35.
Riepe MW, Adler G, Ibach B, et al. (2007) Domain-specific improvement of cognition on memantine in patients with Alzheimer’s disease treated with rivastigmine. Dement Geriatr Cogn Disord 23:301–306.
Bilder RM, Goldman RS, Robinson D, et al. (2000) Neuropsychology of first-episode schizophrenia: Initial characterization and clinical correlates. Am J Psychiatry 157:549–559.
Arneric S, Holladay M, Williams M (2007) Neural nicotinic receptors: A perspective on two decades of drug discovery. Biol Psych 74:1092–1102.
Goff DC, Lamberti JS, Leon AC, Green MF, et al. (2008) A Placebo-controlled add-on trial of the Ampakine, CX516, for cognitive deficits in schizophrenia. Neuropsychopharmacology 33:465–472.
El-Ghundi M, O’Dowd BF, George SR (2007) Insights into the role of dopamine receptor systems in learning and memory. Rev Neurosci 18:37–66.
Mitchell ES, Neumaier JF (2005) 5-HT6 receptors: A novel target for cognitive enhancement. Pharmacol Ther 108:320–333.
Maillet M, Robert SJ, Lezoualc’h F (2004) New insights into serotonin 5-HT4 receptors: A novel therapeutic target for Alzheimer’s disease? Curr Alzheimer Res 1:79–85.
El Mouedden M, Haseldonckx M, Mackie C, et al. (2005) Method for the determination of the levels of beta-amyloid peptide in the CSF sampled from freely moving rats. J Pharmacol Toxicol Methods 52:229–233.
Ferrarini L, Palm WM, Olofsen H, et al. (2008) MMSE scores correlate with local ventricular enlargement in the spectrum from cognitively normal to Alzheimer disease. Neuroimage 39:1832–1838.
Yavuz BB, Ariogul S, Cankurtaran M, et al. (2007) Hippocampal atrophy correlates with the severity of cognitive decline. Int Psychogeriatr 19:767–777.
Bozzali M, Falini A, Franceschi M, et al. (2002) White matter damage in Alzheimer’s disease assessed in vivo using diffusion tensor magnetic resonance imaging. J Neurol Neurosurg Psychiatry 72:742–746.
Tretter F, Albus M (2007) Computational neuropsychiatry of working memory disorders in schizophrenia: The network connectivity in prefrontal cortex - data and models. Pharmacopsychiatry 40:S2–S16.
Williams GV, Castner SA (2006) Under the curve: Critical issues for elucidating D1 receptor function in working memory. Neuroscience 139:263–276.
Di Cara B, Panayi F, Gobert A, et al. (2007) Activation of dopamine D1 receptors enhances cholinergic transmission and social cognition: A parallel dialysis and behavioural study in rats. Int J Neuropsychopharmacol 10:383–399.
Durstewitz D, Seamans JK, Sejnowski TJ (2000) Dopamine-mediated stabilization of delay-period activity in a network model of prefrontal cortex. J Neurophysiol 83:1733–1750.
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Geerts, H. (2011). Pharmacological Validation in Animal Models of Dementia. In: De Deyn, P., Van Dam, D. (eds) Animal Models of Dementia. Neuromethods, vol 48. Humana Press. https://doi.org/10.1007/978-1-60761-898-0_9
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DOI: https://doi.org/10.1007/978-1-60761-898-0_9
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