Alzheimer's Disease Tau Core-based Mouse Models and RT-QuiC Biomarker Assay.

Background The brain cell's nutrient and energy transport system is organized in parallel strands like railroad tracks. These tracks allow nutrients to travel across the cell, delivering key materials to the cells, providing them with energy and keeping them healthy. The tau protein helps keep these tracks straight. However, in Alzheimer's and other brain diseases like frontotemporal dementia and over 20 other brain diseases, the shape of tau protein becomes modified or 'misfolded' and this could contribute to tau tangles (a hallmark brain change observed in these diseases) and subsequent nerve cell damage. Scientists have found that core portions of the tau protein may act as 'seeds' in the brain and may be associated with the formation, transportation and clumping of abnormal tau to each other and ultimately forming the tau tangles. For their experiments, Dr. Leonard Petrucelli's team has adapted a test called real-time quaking-induced conversion (RT-QuiC) that enables researchers to measure tau seeding activity in brain tissue samples and in cerebrospinal fluid (CSF, the biological fluid surrounding the brain and spinal cord). Research Plan In the current study, Dr. Petrucelli will develop a new model of Alzheimer's by injecting core portions of human tau protein into the brains of mice. Dr. Leonard Petrucelli is leveraging the phenomenon of tau seeding to help produce tau tangles in the brains of these mice. Dr. Petrucelli believes the new approach may more closely model how tau tangles form in the human brain. This approach differs from other models that usually use another protein such as heparin, that has been shown to interact with tau and is thought to be associated with the formation of tau tangles in the brain. Using the Alzheimer's-like mice, Dr. Petrucelli's team will study the formation of tau tangles and movement of abnormal tau across brain regions. Further, the researchers will also measure nerve cell damage, in the brains of these mice at multiple timepoints. Further, Dr. Petrucelli's team will analyze tau seeding in CSF from individuals with and without Alzheimer's, and in brain tissue from individuals with Alzheimer's. The researchers will study whether their modified RT-QuiC technique might be useful as a diagnostic tool to help detect tau seeding in CSF. To validate their findings, the researchers will then test their modified technique across a large collection of CSF samples from cognitively unimpaired individuals and those with Alzheimer's, from the Mayo Brain Bank. In addition to allowing them to better validate their technique, Dr. Petrucelli believes that these experiments may help provide insights into whether tau seeding activity may be associated with the progression of Alzheimer's and cognitive decline. Impact This study could provide new insights into the underlying biology of tau and the formation of tau tangles in Alzheimer's and other brain diseases. Increased understanding of the biological underpinnings may lead to novel targets for therapy or development of diagnostic tools. In addition, the research team aims to create new research resources including a new mouse model, and potential research method to study abnormal tau-related brain diseases including Alzheimer's. The results could also help determine how the process of tau 'seeding' may be associated with disease progression.