Increasing Tip60 HAT Levels Rescues Axonal Transport Defects and Associated Behavioral Phenotypes in aDrosophilaAlzheimer's Disease Model

• DOI: 10.1523/jneurosci.3739-12.2013
• Publication Date: 2013-04-24T17:23:53Z
• Authors: Ashley A. Johnson; Jessica Sarthi; Sheila K. Pirooznia; William Reube; Felice Elefant
• Keywords: Axoplasmic transport; Histone acetyltransferase

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