Chapter One - Relevance of transgenic mouse models for Alzheimer's disease
Introduction
There are diseases that are uniquely human, since no orthologous disease has been identified in other species. Many adult-onset neurodegenerative diseases fall into this category, including Alzheimer's disease (AD). A corollary of this absence of equivalent diseases is that there are few, if any, effective treatments for this category of disease. Recent history suggests that we need to understand the molecular basis of pathogenesis in these diseases if we are to develop effective therapies. However, many kinds of analysis cannot be done in human patients. Therefore, we are often left with descriptions of postmortem patient tissues that retain few indications of early stage disease and often are confounded by generic neuronal damage (e.g., mitochondrial and other organelle dysfunction, markers of reactive oxygen species stress, lower neuronal marker levels, changes in neuron structure) that is not disease specific and has not been useful in developing treatments.
Sequencing of the human genome and identification of mutations that produce AD in humans led to hope that a genetic solution might be found, but this approach has failed to produce clinically useful therapies. This may reflect (at least in part) the delayed onset of these diseases, which in turn indicates a phenotypic complexity that is not simply a result of gene expression but instead reflects interactions with the environment and posttranslational effects. However, identification of gene mutations that result in AD has led to the generation of animal models expressing mutant human proteins as models. Typically, these models produce pathological changes that partially replicate changes seen in human patients but fail to capture the full characteristics of the disease. Undeterred, a wide range of therapeutic approaches have been considered and many that showed limited success in animal models have been taken to clinical trials and failed. Investigators have reacted by blaming the animal models for the failure to develop therapies, leading to ever more complex models or complete dismissal of animal models as a means to better understand the disease process. This creates a dilemma—if animal models are dismissed then how do we model AD? The time is right to consider the use of models in the study of AD and other adult-onset neurodegenerative diseases. We propose that animal models should not be dismissed but recognized for their strengths in modeling specific aspects of AD-relevant pathology.
Section snippets
AD is complex, therefore realistic research expectations are important
The first challenge is to define pathology and pathogenesis in a disease as complicated as AD. Not only are there multiple pathogenic elements involved, but there are extensive co-morbidities leading to multiple types of dementia with overlapping pathology. Here we take a simplistic view of AD but one that still reflects the complexity of the disease and research challenges faced by investigators. AD is an adult-onset neurodegenerative disease preferentially affecting specific brain regions
Why do we need AD animal models?
The failure of multiple clinical trials that were based on approaches reported to be effective in mouse models have led some investigators to question the validity of mouse models. AD is rightly characterized as a uniquely human disease, so why do we need a mouse model of AD? Undoubtedly, analysis of human patients and tissue is a critical part of AD research. Analysis of patient materials defines the disease, characterizes pathological changes (mostly late stage changes) and identifies likely
Modeling risk factors
Extensive epidemiological and genetic studies have identified a number of risk factors that increase (or in some cases decrease) the likelihood of developing SAD. These factors are distinct from the FAD mutations in APP and PS1/2. FAD mutations are typically autosomal dominant mutations with high penetrance. Essentially, individuals with one of these FAD mutations or with Down syndrome will develop AD pathology, although the age of onset may vary. In contrast, many patients with increased risk
Study designs for therapeutic interventions
In a room of researchers discussing AD models, one is likely to hear comments such as “we have cured AD mice hundreds of times, but they never work in humans, so we need better models.” As common as this sentiment may be, it fails to hold up under inspection. First, there are no mice with AD, so we can't cure AD in mice. Second, none of the available treatments have eliminated AD pathology, even in mice. At best, reductions in amyloid or tangle burden have been achieved with a modest
Do scientists and the press need to sensationalize data?
Another challenge facing the field is the question of how to present results of studies that identify potential treatments. The understandable desperate need to find causes and treatments for AD has often resulted in sensationalization of scientific findings. How often have we read articles where the complexity of science is distilled down to “scientists find that x causes AD” or “miracle drug cures AD in mice.” The intensity of overselling becomes even more extreme in press releases from the
Acknowledgments
LMT is supported by NIH/NIA R01AG061114, R21AG061715 and R21AG053876, and the College of Medicine at the University of Illinois at Chicago institutional start-up funds. JMW is supported by NIH/NIA R01 AG057008-03S1. MJL is supported by NIH/NIA R01 AG056472, R01 AG057008, UH2/3 NS10012, R56 AG058655, 1R44 AG060826, RF1 AG058068, Institutional funds from the College of Medicine at the University of Illinois at Chicago, and anonymous philanthropic contributions. STB is supported by NIH/NINDS
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