Mouse and stem cell models of frontotemporal dementia
Alzheimer's disease (AD) is the most prevalent brain disease in the United States, and an escalating health concern. AD patient brains acquire hallmark protein aggregates, referred to as senile A beta plaques and neurofibrillary tangles (NFTs), that coincide with brain cell loss and dementia. A subset of AD patients carry mutant genes. Our understanding of AD largely relies on model systems that express these gene variants. Mice engineered to express AD-mutant human genes develop A beta plaques, but fail to develop the tau-containing NFTs or cell loss. Mutant tau variants are required to induce NFTs and neuronal loss in mice, but AD patients carry normal tau genes. The inability of mouse tau to become a pathogenic protein in the presence of AD-mutant gene variants, and the general insufficiency of the current systems to recapitulate AD, inspired the research described here. To determine if species differences between mouse and human tau inhibit the progression of AD in mice, I utilized a well-characterized mouse model of a related disease, frontotemporal dementia (FTD). FTD mice carry mutant human tau and develop NFTs and cell loss. I ablated mouse tau in FTD mice and looked for signs of more severe pathology. I compared the FTD mice, with and without mouse tau, to FTD mice with and without wild type human tau to investigate potential tau species-specific differences. My studies indicated that wild type tau, mouse or human, dampened the pathological effects of FTD tau implying a general, not mouse-specific, effect of normal tau protein. Our data suggest that unknown factors, distinct from endogenous mouse tau, contribute to the inability of mice to model AD. The recent interest in patient-specific stem cell (SC) models to study disease necessitates a thorough evaluation of their ability to recapitulate key characteristics of disease, reproducibility, and longevity. I generated and characterized brain SC cultures from FTD fetal mice and compared them to those generated from mice with normal human tau. Significant genotype associated differences were discovered in the SC system and later verified in adult mice to reinforce the potential of patient-specific SC models to study disease.