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Better Utilization of Mouse Models of Neurodegenerative Diseases in Preclinical Studies: From the Bench to the Clinic

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Mouse Models for Drug Discovery

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1438))

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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Abbreviations

Aβ:

β-Amyloid peptide

AD:

Alzheimer’s disease

ApoE:

Apolipoprotein E

ApoE-ε4:

One of the three major alleles of ApoE gene

APP:

Amyloid-β precursor protein

A2M:

α-2 Macroglobulin

BVAAWF:

British Veterinary Association Animal Welfare Foundation

CLU:

Clusterin

CNS:

Central nervous system

CR:

Complement receptor

DLB:

Dementia with Lewy body

ES:

Embryonic stem

FAD:

Familial Alzheimer’s disease

FTD:

Frontotemporal dementias

FTDP-17:

Frontotemporal dementia and parkinsonism linked to chromosome 17

FRAME:

Fund for the Replacement of Animals in Medical Experiments

GLM:

General linear model

GWAS:

Genome-wide association studies

IDE:

Insulin-degrading enzyme

LB:

Lewy body

LRP:

Lipoprotein receptor-related protein

MAPT:

Microtubule-associated tau protein

MCI:

Mild cognitive impairment

MSA:

Multiple system atrophy

MWM:

Morris water maze

NFT:

Neurofibrillary tangles

PHF:

Paired helical filaments

PS1, PS2:

Presenilin 1, presenilin 2

RSPCA:

Royal Society for the Prevention of Cruelty to Animals

TREM2:

Triggering receptor expressed on myeloid cell 2 protein

UFAW:

Universities Federation of Animal Welfare

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Authors and Affiliations

  1. Department of Neuroscience and CTRND, McKnight Brain Institute, University of Florida, 1275 Center Drive, Gainesville, FL, 32610, USA

    Christopher Janus, Carolina Hernandez & Victoria deLelys

  2. TauTaTis, Inc., 3680 Hartsfield Forest Circle, Jacksonville, FL, 32277, USA

    Hanno Roder

  3. Division of Neuroanatomy and Behavior, Institute of Anatomy, University of Zürich, Winterthurerstrasse 190, 8057, Zürich, Switzerland

    Hans Welzl

Authors
  1. Christopher Janus
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  2. Carolina Hernandez
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  3. Victoria deLelys
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  4. Hanno Roder
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  5. Hans Welzl
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Corresponding author

Correspondence to Christopher Janus .

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Editors and Affiliations

  1. Takeda Pharmaceutical Company, Cambridge, Massachusetts, USA

    Gabriele Proetzel

  2. The Jackson Laboratory, Bar Harbor, Maine, USA

    Michael V. Wiles

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Janus, C., Hernandez, C., deLelys, V., Roder, H., Welzl, H. (2016). Better Utilization of Mouse Models of Neurodegenerative Diseases in Preclinical Studies: From the Bench to the Clinic. In: Proetzel, G., Wiles, M. (eds) Mouse Models for Drug Discovery. Methods in Molecular Biology, vol 1438. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-3661-8_18

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  • DOI: https://doi.org/10.1007/978-1-4939-3661-8_18

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