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Patient-derived Reprogrammed Neurons as a Model to Study Neurodegenerative Diseases in a Dish

Funding year(s): 
2014
Funding to date: 
$100,000

Alzheimer's disease is the most common form of dementia, affecting over 5 million people in the United States alone; it is the sixth-leading cause of death and is expected to cost the nation over $200 billion in 2013, with costs projected to exceed $1 trillion by 2050. Currently, there is no cure for Alzheimer's disease, nor are there effective treatments that delay or improve symptoms. Progress in understanding the underlying etiology and molecular mechanisms that cause progressive neuronal cell death has been hampered by a lack of research models that faithfully recapitulate the disease, including mouse models carrying genetic mutations that predispose humans to Alzheimer's disease. The brief lifespan of mice (age of onset for Alzheimer's is usually over 65) and intrinsic differences between mouse and human neuron physiology are two factors that likely contribute to the failure of mouse models. These obstacles were particularly difficult, or impossible, to overcome until recently.

Advances in stem cell technology have given researchers new hope by making it possible to study cultured human neurons derived from Alzheimer's patient fibroblasts. Here, we will take advantage of these technological advances to examine neurons from patients carrying mutations in MAPT(Microtubule-Associated Protein Tau), which encodes the tau protein. Postmortem brains from a broad range of dementia patients, including Alzheimer's and frontotemporal dementia (FTD) patients, show altered tau biology that includes tau tangles and elevated levels of hyperphosphorylated tau. To determine how tau misregulation perturbs normal neuronal function and leads to neurodegeneration, we will perform a comprehensive biochemical and cell biological analysis of tau-mutant human neurons and compare to gene-edited isogenic controls. In addition to examining neurons longitudinally, we will assess changes that may occur in response to premature aging. Finally, we aim to determine whether tau is required for AP-induced toxicity in human neurons, as has been reported for mouse neurons, and whether MAPT mutations sensitize neurons to AP-induced degeneration . We expect this research to provide new insights into tau biology in Alzheimer's disease and to potentially reveal novel disease mechanisms that could be beneficial for developing therapeutics for treating dementia.