Project Summary
The goal of our study is to mimic sporadically-occurring tauopathies, including Alzheimer’s disease and frontotemporal dementia, in a mouse population. To do so, we will generate a mouse model where tau tangles spread. This will be done without inducing overexpression of tau proteins, which normally is done in animal models mimicking Alzheimer’s disease in humans.
Recent studies from our lab and others suggest that tau aggregates can spread from one cell to another and act as “seeds” to corrupt the folding of normal tau in healthy cells. However, this process has only been robustly demonstrated in transgenic mice overexpressing high levels of tau.
A mouse model that replicates naturally-occurring tauopathies with normal tau levels has yet to be established. We hypothesize that tau tangles in the diseased brain of Alzheimer’s patients may be a potent initiator of a sequence of events known as a misfolding cascade, and therefore we will inject “seeds” of tau tangles derived from the brains of human Alzheimer’s patients into wild-type mice to test whether that will induce and propagate tau aggregation.
As another part of our project, we will explore the tremendous variations that have been observed in the distribution of tau pathologies and clinical symptoms. We hypothesize that such heterogeneity is caused by different “strains” of tau aggregates with distinct structures and seeding properties. We will conduct biochemical and biophysical analyses on tau aggregates isolated from different brains affected by tauopathy and compare their seeding properties in mouse brains.
We are very fortunate to have access to a large collection of frozen brain tissues from patients with various neurodegenerative diseases. Each of these specimens comes with a complete record of clinical history and neuropathological diagnosis stored in a search-friendly database. Our brain bank thus provides us with a unique opportunity to isolate and characterize tau aggregates naturally developed in different categories of tauopathy, and allows us to correlate pathological findings in mice with those from human patients.
Successful generation of a tauopathy mouse model without tau overexpression would provide strong support for the recently emerged “transmission” hypothesis, which proposes that cell-to-cell transmission of misfolded tau protein underlies the characteristic spread of tau pathology in diseased brains. This mouse model would also be useful for testing drugs that can potentially limit the progression of these devastating diseases. A better understanding of different strains of tau aggregates will help us understand how different classes of tauopathies develop and assist us in targeting therapies towards disease-specific tau strains.
