A novel non-transgenic fly model for tauopathies

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SUMMARY Over 55 million people live with dementia worldwide, and this number is expected to reach 78 million by 2030, according to the projection by the World Health Organization. The main cause of dementia is Alzheimer’s disease (AD), whose distinguishing molecular feature is the presence of amyloid b (Ab) plaques, and abnormally phosphorylated tau in brain. Aggregates of hyperphosphorylated tau as neurofibrillary tangles (NFT) are seen in AD and about 20 other neurodegenerative disorders collectively known as tauopathies. It is noteworthy that except AD, tauopathies do not have significant Ab accumulation, suggesting a key causal role of tau in neurodegeneration. This notion has been supported by many studies based on mouse models. However, the exact nature of tau pathogenesis remains elusive, therefore hampering effective drug development. To dissect the mechanistic details of hyperphosphorylated tau-mediated neurodegeneration, and to take advantage of the advanced genetic tools offered by the fruit fly Drosophila melanogaster, we have established a novel in cibo (in food) model of Alzheimer’s disease and tauopathies. This model gives us the ability to induce the disease in adult flies, and precisely define the form of p-tau/tau that the organism is exposed to, both of which are not possible using a transgenic fly model. By feeding adult Drosophila with hyperphosphorylated tau, we have recapitulated critical neurological features of AD in flies, including the late onset and age-dependent neurodegeneration, disintegrated blood brain barrier, and conspicuous pathology in different areas of the brain. These pathological traits become evident in less than four weeks after the treatment, therefore providing a significant advantage over other animal models that take months to develop neurological pathology. The overarching goal of our research is to use this novel fly model to help develop efficacious means for AD therapy and prevention. To this end, we will use this exploratory R21 project to characterize the disease state of this model and lay the foundation for future comprehensive mechanistic studies to understand gut-brain signaling in neurodegenerative diseases, and drug discovery projects. We will use a variety of approaches to understand the molecular basis for hyperphosphorylated tau-inflicted pathology, and examine the interplay between p-tau and known and suspected AD contributors such as Ab, apolipoprotein E (APOE), and a-synuclein.