title: Tip60 HAT activity mediates APP induced lethality and apoptotic cell death in the CNS of a Drosophila Alzheimer's disease model.
abstract: Histone acetylation of chromatin promotes dynamic transcriptional responses in neurons that influence neuroplasticity critical for cognitive ability. It has been demonstrated that Tip60 histone acetyltransferase (HAT) activity is involved in the transcriptional regulation of genes enriched for neuronal function as well as the control of synaptic plasticity. Accordingly, Tip60 has been implicated in the neurodegenerative disorder Alzheimer's disease (AD) via transcriptional regulatory complex formation with the AD linked amyloid precursor protein (APP) intracellular domain (AICD). As such, inappropriate complex formation may contribute to AD-linked neurodegeneration by misregulation of target genes involved in neurogenesis; however, a direct and causative epigenetic based role for Tip60 HAT activity in this process during neuronal development in vivo remains unclear. Here, we demonstrate that nervous system specific loss of Tip60 HAT activity enhances APP mediated lethality and neuronal apoptotic cell death in the central nervous system (CNS) of a transgenic AD fly model while remarkably, overexpression of Tip60 diminishes these defects. Notably, all of these effects are dependent upon the C-terminus of APP that is required for transcriptional regulatory complex formation with Tip60. Importantly, we show that the expression of certain AD linked Tip60 gene targets critical for regulating apoptotic pathways are modified in the presence of APP. Our results are the first to demonstrate a functional interaction between Tip60 and APP in mediating nervous system development and apoptotic neuronal cell death in the CNS of an AD fly model in vivo, and support a novel neuroprotective role for Tip60 HAT activity in AD neurodegenerative pathology.
authors: Department of Biology, Drexel University, Philadelphia, Pennsylvania, United States of America.
authors: Sheila K
authors: SK
authors: Pirooznia
authors: Jessica
authors: J
authors: Sarthi
authors: Ashley A
authors: AA
authors: Johnson
authors: Meridith S
authors: MS
authors: Toth
authors: Kellie
authors: K
authors: Chiu
authors: Sravanthi
authors: S
authors: Koduri
authors: Felice
authors: F
authors: Elefant
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000201:enzymology / Q000254:growth & development / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000201:enzymology / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006801:Humans; D008297:Male; D009474:Neurons / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic
chemical_list: D016564:Amyloid beta-Protein Precursor; D029721:Drosophila Proteins; D051548:Histone Acetyltransferases; C511056:Tip60 protein, Drosophila