Modelling early responses to neurodegenerative mutations in mice

Abstract

Considering the many differences between mice and humans, it is perhaps surprising how well mice model late-onset human neurodegenerative disease. Models of Alzheimer's disease, frontotemporal dementia, Parkinson's disease and Huntington's disease show some striking similarities to the corresponding human pathologies in terms of axonal transport disruption, protein aggregation, synapse loss and some behavioural phenotypes. However, there are also major differences. To extrapolate from mouse models to human disease, we need to understand how these differences relate to intrinsic limitations of the mouse system and to the effects of transgene overexpression. In the present paper, we use examples from an amyloid-overexpression model and a mutant-tau-knockin model to illustrate what we learn from each type of approach and what the limitations are. Finally, we discuss the further contributions that knockin and similar approaches can make to understanding pathogenesis and how best to model disorders of aging in a short-lived mammal.

Axonal degeneration in Alzheimer's disease: When signaling abnormalities meet the axonal transport system

“…Currently, no model accurately recapitulates all aspects of AD (Ashe and Zahs, 2010, Gilley, et al, 2011a). Still, fAD models illuminated dysfunctional signaling pathways linked to specific fAD variants.…”

“…Behavioral, electrophysiological, and pathological studies in fAD mouse models based on expression of pathogenic forms of APP, presenilin, and/or tau documented early abnormalities in synaptic function, and signs of axonal pathology (i.e. axonal swellings and spheroids) prior to overt cell death (Bell and Claudio Cuello, 2006, Gilley, et al, 2011a). Transgenic expression of fAD-related mutant APP V717A (PDAPP line) (Games, et al, 1995) and other fAD-related APP mutants (i.e.…”

Production of Transgenic Nonhuman Primates

“…Although significant advancement in the transgenic rodent model of human diseases has been made using these novel technologies, there are fundamental limitations in rodents that suggest the need for a model system that could better capture clinical features, or an animal model with higher anatomical/physiological similarity to humans. Due to physiologic differences between rodents and higher primates such as cellular metabolism (Finger et al, 1988;MacDonald et al, 2011), life span (Gilley et al, 2011), brain size and complexity Chen et al, 2000;Hsiao et al, 1996;Miller et al, 2010;Polymeropoulos et al, 1997), and motor repertoire (Rice, 2012;Courtine et al, 2007), as well as the availability of cognitive behavioral testing (Bachevalier et al, 2001(Bachevalier et al, , 2011Bachevalier and Nemanic, 2008;Ewing-Cobbs et al, 2012), nonhuman primates (NHPs) are considered one of the best animal models for complex and neurological disorders such as those correlated with aging, mental, and psychiatric dysfunctions. It is also important to note that the prolonged life span of NHPs (e.g., rhesus macaque) (Makris et al, 2010) allows for longitudinal study of disease trajectories.…”

“…Although transgenic rodent models have been widely used for evaluating the genetic abnormalities observed in human patients, there are limitations in nonprimate models for studying psychiatric disorders. Indeed, many human-associated behaviors cannot be recapitulated in rodents (Robertson and Feng, 2011), simply due to the physiological differences between rodents and humans Finger et al, 1988;MacDonald et al, 2011;Gilley et al, 2011;Chen et al, 2000;Hsiao et al, 1996;Miller et al, 2010;Polymeropoulos et al, 1997;Rice, 2012;Courtine et al, 2007). An ASD transgenic NHP model will not only mimic patient conditions but most importantly it will aid in determining the longitudinal trajectory of ASD, thus advancing our understanding of ASD development and the critical need for new diagnostics and therapeutic options.…”

Mapping Changes in Mouse Brain Metabolism with PET/CT

“…However, back-translating these techniques into rodent models used to study brain disorders (5,6) presents significant challenges due to brain size relative to the resolution of preclinical PET scanners. Such challenges are particularly acute in mice, yet these make up most of the genetically modified models currently in use (7)(8)(9). Although the resolution of a preclinical PET scanner is around 100 times better than that of a clinical scanner in volume terms, the volume of a mouse brain is around 3,000 times lower than that of a human brain.…”