Tip60 HAT Activity Mediates APP Induced Lethality and Apoptotic Cell Death in the CNS of a Drosophila Alzheimer's Disease Model

Department of Biology, Drexel University, Philadelphia, Pennsylvania, United States of America.
PLoS ONE (Impact Factor: 3.23). 07/2012; 7(7):e41776. DOI: 10.1371/journal.pone.0041776
Source: PubMed


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.

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    • "We chose the CA1 region because of its well-established role in memory consolidation and neurodegenerative diseases (Gallagher & Koh, 2011) A c c e p t e d m a n u s c r i p t 10 (Howard & Eichenbaum, 2013). Notably, also Kat5 showed very high expression in the CA1, which was recently implicated in neuronal function in a Drosophila model of Alzheimer's disease (Pirooznia et al, 2012). More research to investigate the function of this and the other HATs in memory formation is therefore warranted. "
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    • "PCR products were visualized by 2% agarose gel electrophoresis containing ethidium bromide. The primer sequences were as follows: for human APP, 5′-GCCGTGGCATTCTTTTGGGGC-3′(forward) and 5′-GTGGTCAGTCCTCGGTCGGC-3′ (reverse) [26]; for human BACE-1, 5′-GCAGGGCTACTACGTGGAGA-3′ (forward) and 5′-GTATCCACCAGGATGTTGAGC-3′ (reverse) [27]. RP49, which encodes the Drosophila ribosomal protein 49, was used as an internal standard and reference gene using forward and reverse primer pairs 5′-CTGCTCATGCAGAACCGCGT-3′ and 5′-GGACCGACAGCTGCTTGGCG-3′ [26], respectively. "
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    • "Importantly, the Drosophila ventrolateral neurons (LNvs) have been previously used as a wellcharacterized axonal growth model system to demonstrate that the AD-linked APP functions in mediating the axonal arborization outgrowth pattern of the sLNv (Leyssen et al. 2005). Based on these results, and our previous studies reporting that Tip60 HAT activity itself is required for neural function (Lorbeck et al. 2011; Sarthi and Elefant 2011) and mediates APP-induced lethality and CNS neurodegeneration in an AD fly model (Pirooznia et al. 2012), we hypothesized that both APP and Tip60 are required to mediate selective neuronal processes such as sLNv morphology and function that, when misregulated, are linked to AD pathology. In the present study, we test this hypothesis by utilizing the sLNvs as a model system to examine whether Tip60-mediated epigenetic dysregulation under neurodegenerative conditions such as that induced by APP overexpression leads to axonal outgrowth defects and if there is a corresponding effect on sLNv function in sleep regulation, a process that is also affected in neurodegenerative diseases like AD. "
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