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Better utilization of mouse models of neurodegenerative diseases in preclinical studies: from the bench to the clinic


Janus, Christopher; Hernandez, Carolina; deLelys, Victoria; Roder, Hanno; Welzl, Hans (2016). Better utilization of mouse models of neurodegenerative diseases in preclinical studies: from the bench to the clinic. In: Proetzel, Gabriele; Wiles, Michael V. Mouse models for drug discovery: Methods and protocols. New York: Springer, 311-347.

Abstract

The major symptom of Alzheimer’s disease is dementia progressing with age. Its clinical diagnosis is preceded by a long prodromal period of brain pathology that encompasses both formation of extracellular amyloid and intraneuronal tau deposits in the brain and widespread neuronal death. At present, familial cases of dementia provide the most promising foundation for modeling neurodegenerative tauopathies, a group of heterogeneous disorders characterized by prominent intracellular accumulation of hyperphosphorylated tau protein. In this chapter, we describe major behavioral hallmarks of tauopathies, briefly outline the genetics underlying familial cases, and discuss the arising implications for modeling the disease in transgenic mouse systems. The selection of tests performed to evaluate the phenotype of a model should be guided by the key behavioral hallmarks that characterize human disorder and their homology to mouse cognitive systems. We attempt to provide general guidelines and establish criteria for modeling dementia in a mouse; however, interpretations of obtained results should avoid a reductionist “one gene, one disease” explanation of model characteristics. Rather, the focus should be directed to the question of how the mouse genome can cope with the over-expression of the protein coded by transgene(s). While each model is valuable within its own constraints and the experiments performed are guided by specific hypotheses, we seek to expand upon their methodology by offering guidance spanning from issues of mouse husbandry to choices of behavioral tests and routes of drug administration that might increase the external validity of studies and consequently optimize the translational aspect of preclinical research.

Abstract

The major symptom of Alzheimer’s disease is dementia progressing with age. Its clinical diagnosis is preceded by a long prodromal period of brain pathology that encompasses both formation of extracellular amyloid and intraneuronal tau deposits in the brain and widespread neuronal death. At present, familial cases of dementia provide the most promising foundation for modeling neurodegenerative tauopathies, a group of heterogeneous disorders characterized by prominent intracellular accumulation of hyperphosphorylated tau protein. In this chapter, we describe major behavioral hallmarks of tauopathies, briefly outline the genetics underlying familial cases, and discuss the arising implications for modeling the disease in transgenic mouse systems. The selection of tests performed to evaluate the phenotype of a model should be guided by the key behavioral hallmarks that characterize human disorder and their homology to mouse cognitive systems. We attempt to provide general guidelines and establish criteria for modeling dementia in a mouse; however, interpretations of obtained results should avoid a reductionist “one gene, one disease” explanation of model characteristics. Rather, the focus should be directed to the question of how the mouse genome can cope with the over-expression of the protein coded by transgene(s). While each model is valuable within its own constraints and the experiments performed are guided by specific hypotheses, we seek to expand upon their methodology by offering guidance spanning from issues of mouse husbandry to choices of behavioral tests and routes of drug administration that might increase the external validity of studies and consequently optimize the translational aspect of preclinical research.

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Additional indexing

Item Type:Book Section, refereed, further contribution
Communities & Collections:04 Faculty of Medicine > Institute of Anatomy
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:6 May 2016
Deposited On:25 Jan 2017 08:22
Last Modified:29 Jan 2017 08:02
Publisher:Springer
Series Name:Methods in Molecular Biology
Number:1438
ISSN:1064-3745
ISBN:978-1-4939-3659-5
Publisher DOI:https://doi.org/10.1007/978-1-4939-3661-8_18
PubMed ID:27150098

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