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Tara Tracy, Ph.D.
Acetylated Tau in Alzheimer’s Disease: Pathogenic Mechanisms Underlying Memory Loss
Research Scientist, J. David Gladstone Institutes, Gladstone Institute of Neurological Disease, Department of Neurology, University of California, San Francisco
2 Riverside Circle, Roanoke, VA 24016
More than 5 million people in the United States are living with Alzheimer’s disease (AD), and the prevalence of AD is expected to rise rapidly with our aging populations. Memory loss in AD has a devastating impact on people’s lives and there are no effective treatments to counteract progressive cognitive decline. Accumulation of tau, a microtubule-associated protein, in the brain is a hallmark of AD. Research to identify the tau-dependent mechanisms that trigger pathogenesis is crucial to find new molecular targets for drug intervention. Dr. Tracy and colleagues found that the increased acetylation of tau on two lysines, K274 and K281, is linked to severe dementia in AD. To examine the role of acetylated tau in AD pathogenesis, they generated a transgenic mouse expressing human tau with mutations to substitute K274 and K281 with glutamines to mimic the structure and charge of acetylated lysines. They found that acetylated tau inhibits postsynaptic actin cytoskeletal dynamics and obstructs synaptic plasticity underlying memory deficits. Moreover, they discovered a novel mechanism for the tau-mediated plasticity deficit involving the loss of KIBRA, a memory-associated postsynaptic protein. Dr. Tracy will discuss this work, which highlights the pathogenic role of acetylated tau in AD progression and supports the therapeutic potential of agents that reduce tau acetylation.