title: Better Utilization of Mouse Models of Neurodegenerative Diseases in Preclinical Studies: From the Bench to the Clinic.
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.
authors.affiliation: Department of Neuroscience and CTRND, McKnight Brain Institute, University of Florida, 1275 Center Drive, Gainesville, FL, 32610, USA. cjanus@ufl.edu.
authors.forename: Christopher
authors.initials: C
authors.lastname: Janus
authors.affiliation: Department of Neuroscience and CTRND, McKnight Brain Institute, University of Florida, 1275 Center Drive, Gainesville, FL, 32610, USA.
authors.forename: Carolina
authors.initials: C
authors.lastname: Hernandez
authors.affiliation: Department of Neuroscience and CTRND, McKnight Brain Institute, University of Florida, 1275 Center Drive, Gainesville, FL, 32610, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: deLelys
authors.affiliation: TauTaTis, Inc., 3680 Hartsfield Forest Circle, Jacksonville, FL, 32277, USA.
authors.forename: Hanno
authors.initials: H
authors.lastname: Roder
authors.affiliation: Division of Neuroanatomy and Behavior, Institute of Anatomy, University of Zürich, Winterthurerstrasse 190, 8057, Zürich, Switzerland.
authors.forename: Hans
authors.initials: H
authors.lastname: Welzl
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000473:pathology; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D004353:Drug Evaluation, Preclinical; D017408:Guidelines as Topic; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009483:Neuropsychological Tests; D024801:Tauopathies / Q000473:pathology* / Q000523:psychology*
keywords: Alzheimer’s disease; Behavioral tests; Drug delivery; Handling; Phenotype; Tauopathy; Transgenic models