Jason Hutzler

 Introduction.  Alzheimer’s Disease (AD) is a progressive, and ultimately fatal neurodegenerative disorder that is currently the sixth leading cause of death in the United States, and the fifth leading cause of death for individuals over the age of 651. AD is characterized by, and can only be definitively diagnosed by the presence of accumulations of protein aggregates in the brain, including extracellular amyloid beta plaques, and neurofibrillary tangles (NFTs) made up of the protein tau2,3. Tau plays an important role in the assembly and stability of microtubules in CNS neurons, making it a critical player in the function of axonal transport in the central nervous system. Normal tau is natively unfolded, leaving it highly susceptible to post-translational modification, which in turn leads to altered structure and function of the protein4. Studies have shown that one such modification, hyperphosphorylation, leads to decreased stabilizing function and increased aggregation of tau, suggesting that this modification is an important step in the pathogenesis of AD and other tauopathies4. More recent studies have suggested a different post-translational modification, acetylation, as another mechanism of tau pathogenesis and a new target for therapy of AD5-9. Methods. Studies utilized human tau mutated to mimic acetylation of a key lysine residue (K280Q) to study its effects both in vitro and in vivo in Drosophila models. Samples with the acetylation-mimic were compared to samples with wild-type tau, and effects on rate and level of tau aggregation, neurotoxicity, and fragmentation were measured6,7,8. Results. Acetylation-mimic tau showed increased tendency to aggregate in vitro, and aggregated at a higher rate than wild-type tau. Additionally, the acetylation mimic showed fibril formation on electron microscopy that was similar to a mutant form of tau known to form NFTs6. Acetylation-mimic tau also showed increased neurotoxicity in Drosophila models, demonstrated by increased death of photoreceptor cells in flies with the mutant form of tau compared to those with the wild-type7. Studies also showed that tau, after undergoing auto-acetylation, showed a higher rate of cleavage to low molecular weight fragments than deacetylated tau8. Conclusions. Studies have found that acetylation of tau results in increased tau dysfunction and cell damage, and thus may play a significant role in the pathogenesis of Alzheimer’s Disease. Further research on the mechanisms of this acetylation may lead to better understanding of the progression of AD, and may reveal new strategies to modify the acetylation and treat the disease.

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