Lab Mice are Center Stage in Search for Alzheimer’s Disease Therapies
July 3, 2019
The biomedical discovery enterprise is replete with research breakthroughs and successful therapies. Last year the FDA approved a record 59 novel drugs compared to an average of 33 drugs approvals per year. None of the 59 newly approved drugs is for treating the symptoms of Alzheimer’s Disease. Indeed, only four new medicines have been approved to treat Alzheimer’s Disease out of more than 150 attempts over the past two decades. With the rapidly mounting social and financial burden of Alzheimer’s Disease, and with each Alzheimer drug development program now costing an average of $5.5 billion, no translational research field is in greater need of a winning streak.
Any such winning streak will depend on the creation and development of accurate, validated disease models, perhaps most of all with lab mice that mimic human disease. LMP associate professor Michael Koob is an expert at creating and validating mouse models for studying human disease.
Koob is corresponding author with Karen Ashe of the Department of Neurology of “Factors other than hTau overexpression that contribute to tauopathy-like phenotype in rTg4510 mice” published in Nature Communications in early June. Ashe developed rTg4510 mice, the leading mouse model for studying the neurofibrillary tau protein tangles found in the brains of Alzheimer Disease patients at autopsy. Tauopathy from tau tangles is considered to be a key pathogenic factor in Alzheimer Disease. Ashe reported in 2005 that she and her colleagues had engineered rTg4510 mice to express the human tau gene containing a pathogenic mutation, with transgene overexpression producing tauopathy in their forebrains leading to progressive memory loss and other neurodegenerative symptoms.
In their study, Koob and Ashe and their University colleagues used new mouse models developed in Koob’s laboratory and whole genome sequencing to show that expression of the human tau gene with a pathogenic mutation in rTg4510 mice and the tauopathy manifested in rTg4510 mice are not necessarily linked in a direct cause-and-effect manner. Confounding factors including mutagenic DNA insertions and deletions [called INDELS] in genes key to neural development and function, notably fibroblast growth factor 14 [Fgf 14], may be playing a critical role in the resulting tauopathy. “What we know now is that the mechanisms that are making these mice sick may well be unrelated to what makes people sick,” Koob said. These findings, if confirmed, would suggest that therapeutic strategies based on the widely used rTg4510 mouse model are misguided.
One of the problems in creating rTg4510 mice was the use of pronuclear injection of the synthetic tau gene construct into the mouse embryo. At the time there was no ability to control the genomic placement of the transgene construct in the experimental cell destined to be taken up by the early embryo and replicated so that the construct wouldn’t disrupt the function of other genes. Koob has developed techniques that allow him to put such a construct exactly where he wants it to reside in the mouse genome. That serves as a critical experimental control. “In our experiments, we were able to put the construct where we knew it wouldn’t cause problems with other genes in the mouse genome,” Koob said.
Koob created mice similar to rTg4510 but that lack the Fgf14 mutation present in the original rTg4510 mice. These mice show no evident signs of tauopathy unless the human tau transgene is artificially overexpressed well beyond normal physiological levels. Koob and his coauthors write: “…the targeted-insertion mouse models we are developing offer a system in which the Fgf14-TgINDEL mutation and the potential confounding contributions from this mutation are eliminated.”
Koob said tens to hundreds of millions of dollars have been spent trying to understand the exact pathogenic mechanism of rTg4510 mice and how exactly the model relates to human tau pathogenesis in patients with Alzheimer’s Disease.
Studies show that numerous therapeutic agents are able to treat deficits in transgenic mouse models of Alzheimer’s Disease effectively but to date they show few if any significant clinical benefits in human trials. “The NIH recognizes that there have been some issues with Alzheimer Disease modeling and that a new approach is needed,” he said. “Model-AD is a funded group of collaborators that are trying to make better mouse models.”
Model-AD [Alzheimer’s Disease] is a multi-institutional research consortium established by NIH’s National Institute on Aging. Its goals include an effort “to institute a standardized and rigorous process for characterization of animal models” and “to establish guidelines for rigorous preclinical testing in animal models.”
Abnormal tau protein gathers in specific regions of the human brain involved in memory, regions that strongly influence how we remember, what we remember, and why we forget. With powerful new molecular and imaging tools and deeper insights, the research community is better positioned than ever to create research animals that can disentangle the complex role of tau in memory loss that confounding experimental factors, which are always present, cannot seriously challenge.