Increasing Tip60 HAT levels rescues axonal transport defects and associated behavioral phenotypes in a Drosophila Alzheimers disease model. Ashley A. Zervos, William Reube, Felice Elefant. Dept Biol, Drexel Univ, Philadelphia, PA.

   Axonal transport defects and axonopathy are prominent in early pre-clinical stages of Alzheimers disease (AD), often preceding known disease-related pathology by over a year. As epigenetic transcriptional regulatory mechanisms such as histone acetylation are critical for neurogenesis, it is postulated that their misregulation might be linked to early pathophysiological mechanisms that contribute to AD. The histone acetyltransferase (HAT) Tip60 epigenetically regulates genes enriched for neuronal functions and is implicated in AD via its formation of a transcriptional regulatory complex with the amyloid precursor protein (APP) intracellular domain. Disruption of APP function is associated with axonal transport defects, raising the possibility that an epigenetic role for Tip60 might also be involved. Here, we examine whether Tip60 HAT activity functions in axonal transport using Drosophila CNS motor neurons as a well characterized transport model. We show that reduction of Tip60 HAT activity in the nervous system causes axonopathy and transport defects associated with misregulation of certain axonal transport linked genes. Functional consequences of these defects are evidenced by reduced locomotion activity of the mutant Tip60 larvae and these phenotypes can be partially rescued with the HDAC inhibitor ms-275. Finally, we demonstrate that Tip60 function in axonal transport is mediated by APP and that remarkably, excess Tip60 exerts a neuroprotective role in APP induced axonal transport and functional locomotion defects. Our observations highlight a novel functional interactive role between Tip60 HAT activity and APP in axonal transport and provide insight into the importance of specific HAT modulators for the treatment of cognitive disorders.