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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Available from: Felice Elefant, Oct 05, 2015
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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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    ABSTRACT: Neuronal histone acetylation has been linked to memory consolidation, and targeting histone acetylation has emerged as a promising therapeutic strategy for neuropsychiatric diseases. However, the role of histone-modifying enzymes in the adult brain is still far from being understood. Here we use RNA sequencing to screen the levels of all known histone acetyltransferases (HATs) in the hippocampal CA1 region and find that K-acetyltransferase 2a (Kat2a)—a HAT that has not been studied for its role in memory function so far—shows highest expression. Mice that lack Kat2a show impaired hippocampal synaptic plasticity and long-term memory consolidation. We furthermore show that Kat2a regulates a highly interconnected hippocampal gene expression network linked to neuroactive receptor signaling via a mechanism that involves nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). In conclusion, our data establish Kat2a as a novel and essential regulator of hippocampal memory consolidation.
    The EMBO Journal 07/2014; DOI:10.15252/embj.201487870 · 10.43 Impact Factor
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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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    ABSTRACT: Alzheimer's disease (AD) is the most common type of presenile and senile dementia. The human beta-amyloid precursor cleavage enzyme (BACE-1) is a key enzyme responsible for amyloid plaque production, which implicates the progress and symptoms of AD. Here we assessed the anti-BACE-1 and behavioral activities of curcuminoids from rhizomes of Curcuma longa (Zingiberaceae), diarylalkyls curcumin (CCN), demethoxycurcumin (DMCCN), and bisdemethoxycurcumin (BDMCCN) against AD Drosophila melanogaster models. Neuro-protective ability of the curcuminoids was assessed using Drosophila melanogaster model system overexpressing BACE-1 and its substrate APP in compound eyes and entire neurons. Feeding and climbing activity, lifespan, and morphostructural changes in fly eyes also were evaluated. BDMCCN has the strongest inhibitory activity toward BACE-1 with 17 muM IC50, which was 20 and 13 times lower than those of CCN and DMCCN respectively. Overexpression of APP/BACE-1 resulted in the progressive and measurable defects in morphology of eyes and locomotion. Remarkably, supplementing diet with either 1 mM BDMCCN or 1 mM CCN rescued APP/BACE1-expressing flies and kept them from developing both morphological and behavioral defects. Our results suggest that structural characteristics, such as degrees of saturation, types of carbon skeleton and functional group, and hydrophobicity appear to play a role in determining inhibitory potency of curcuminoids on BACE-1. Further studies will warrant possible applications of curcuminoids as therapeutic BACE-1 blockers.
    BMC Complementary and Alternative Medicine 03/2014; 14(1):88. DOI:10.1186/1472-6882-14-88 · 2.02 Impact Factor
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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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    ABSTRACT: Tip60 is a histone acetyltransferase (HAT) enzyme that epigenetically regulates genes enriched for neuronal functions through interaction with the amyloid precursor protein (APP) intracellular domain. However, whether Tip60 mediated epigenetic dysregulation affects specific neuronal processes in vivo and contributes to neurodegeneration remains unclear. Here, we show that Tip60 HAT activity mediates axonal growth of the Drosophila pacemaker cells, termed small ventrolateral neurons (sLNvs), and their production of the neuropeptide pigment dispersing factor (PDF) that functions to stabilize Drosophila sleep-wake cycles. Using genetic approaches, we show that loss of Tip60 HAT activity in the presence of the Alzheimer's disease (AD) associated amyloid precursor protein (APP) affects PDF expression and causes retraction of the sLNv synaptic arbor required for presynaptic release of PDF. Functional consequence of these effects is evidenced by disruption of sleep-wake cycle in these flies. Notably, overexpression of Tip60 in conjunction with APP rescues these sleep-wake disturbances by inducing overelaboration of the sLNv synaptic terminals and increasing PDF levels, supporting a neuroprotective role for dTip60 on sLNv growth and function under APP induced neurodegenerative conditions. Our findings reveal a novel mechanism for Tip60 mediated sleep-wake regulation via control of axonal growth and PDF levels within the sLNv encompassing neural network and provide insight into epigenetic based regulation of sleep disturbances observed in neurodegenerative diseases like Alzheimer's disease.
    Genetics 09/2012; 192(4). DOI:10.1534/genetics.112.144667 · 5.96 Impact Factor
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