Document Detail

Tip60 HAT activity mediates APP induced lethality and apoptotic cell death in the CNS of a Drosophila Alzheimer's disease model.
MedLine Citation:
PMID:  22848598     Owner:  NLM     Status:  MEDLINE    
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.
Sheila K Pirooznia; Jessica Sarthi; Ashley A Johnson; Meridith S Toth; Kellie Chiu; Sravanthi Koduri; Felice Elefant
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-07-26
Journal Detail:
Title:  PloS one     Volume:  7     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2012  
Date Detail:
Created Date:  2012-07-31     Completed Date:  2013-04-09     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e41776     Citation Subset:  IM    
Department of Biology, Drexel University, Philadelphia, Pennsylvania, United States of America.
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MeSH Terms
Alzheimer Disease / enzymology,  metabolism*,  pathology*
Amyloid beta-Protein Precursor / metabolism*
Brain / enzymology,  growth & development,  metabolism,  pathology*
Disease Models, Animal
Drosophila Proteins / metabolism*
Drosophila melanogaster / enzymology,  metabolism*
Gene Expression Regulation
Histone Acetyltransferases / metabolism*
Neurons / enzymology,  metabolism,  pathology
Transcription, Genetic
Grant Support
Reg. No./Substance:
0/Amyloid beta-Protein Precursor; 0/Drosophila Proteins; EC Acetyltransferases; EC protein, Drosophila

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