Investigating the Serial Pathologies Related to Plasma Biomarkers in NLFTaum/h Mice: A New Mouse Model Featuring Neurofibrillary Tangles as a Result of Rising Amyloid Beta without Microtubule-Associated Protein Tau (MAPT) Mutations

This application takes advantage of the development of a new mouse model of Alzheimer’s disease that has translational potential that was not previously available. There has been much criticism of mouse models of Alzheimer’s disease (AD) because promising results in mice have translated poorly to humans. This is largely because there has been no mouse in which the entire progression of the disease from preclinical to clinical stages has been reproduced. Previous mouse lines have modelled the preclinical development of plaques very well. Indeed, treatments that remove plaques in mice have worked to remove plaques in humans. However, AD is only diagnosed once tau tangles develop inside neurons, and it is this pathology that causes the ongoing damage to and, ultimately, death of nerve cells in the brain, resulting in the devastating effects of the disease. Breaking the link between the sequential pathologies of amyloid plaques and tau tangles would be the key to preventing AD progression. Previous mouse models do not show this link. They do not go on to develop tau tangles unless changes are made to the tau protein that are relevant to other neurodegenerative diseases but not relevant to Alzheimer’s disease. While useful for studying interactions between amyloid beta and tau once they are both present, the introduction of such mutations bypasses the link between plaques and the initiation of tau tangles, so studying this link has been out of the reach of mouse models. Unlike any previous model, our recently developed mouse model, “NLFTaum/h,” progressively shows plaque deposition starting slowly from middle to late life and, in old age (24 months), the development of tau tangles. The difference from the previous NLF model is that they have a mixture of mouse and human tau protein, and this, together with old age, interacts to give us a complete model of AD. Moreover, many features of the progression through these pathologies in the new NLFTaum/h mouse model mirror what is known of the progression of AD in humans.

In this proposal, we take advantage of our already developed colonies of aged mice to compare the NLFTaum/h mice (that have plaques and tangles) to the NLF mice (with only plaques) and Taum/h mice (with neither plaques nor tangles). In a preliminary trial, we have established that biomarkers for AD, found in human studies, are detectable in mice and increase as expected in our new model. In the proposed study, we will test ages representing all stages of disease progression in the new model, from the start of plaque development to the initiation of tau tangles and then their further disease development. We will take plasma samples approximately every 4 months from 8 months, shortly before plaques become evident, through 24 or 28 months when these very old mice have developed tau tangles. The plasma will be analysed with a new highly sensitive platform for analysing a wide range of proteins relevant to the nervous system and the immune system of the brain. The brain pathology of the same mice will then be compared at 24 months or 28 months of age. We will compare our new mouse model that shows plaques and tangles to the mice of the same age that only have plaques or mice with no plaques. This will allow us to map the changes in the plasma markers over time and establish the pattern of biomarkers most likely to lead to clinical outcomes. In parallel, we will sample another group of mice at each of the ages above but then take the brains immediately to study the pathology at each age. This will allow us to understand what changes are happening in the brain as different biomarkers become evident in the plasma.

This approach will bring several valuable outcomes: 1. In the mice studied at each age, we will compare biomarkers already reported from human studies that our preliminary data show are evident in the plasma of our mice to determine at what stage disease progression has reached when these biomarkers appear. We can then study in detail what is happening in the brains at that stage with a view to finding drug targets for different disease stages 2. We can sample a wide range of proteins in the plasma of the mice and so potentially find novel biomarkers that can then be tested in humans. 3. The mice that are serially sampled will give us a pattern of biomarkers that can then be correlated to the variable pathology seen at 24 or 28 months, enabling us to understand the likely outcomes of different patterns of biomarkers. By comparing the mice with and without different pathologies, we can determine which markers are related specifically to the initiation of tangle pathology rather than plaque development or old age. 4. The final group of mice, which will be studied at 28 months of age, will allow an extension of the model to more advanced disease stages than we have studied. 5. Establishing a pattern of serial plasma biomarkers related to the progressive changes in the brains of the new mouse model will then allow the serial, low-cost, non-invasive testing of different potential treatments and progressive understanding of disease outcomes.

Overall, this will give us a new tool for understanding disease progression and testing drugs or other disease-modifying interventions in a mouse model that promises for the first time to be a truly translational model of the full course of Alzheimer’s disease.