title: Drosophila Eye Model to Study Neuroprotective Role of CREB Binding Protein (CBP) in Alzheimer's Disease.
abstract: BACKGROUND
  The progressive neurodegenerative disorder Alzheimer's disease (AD) manifests as loss of cognitive functions, and finally leads to death of the affected individual. AD may result from accumulation of amyloid plaques. These amyloid plaques comprising of amyloid-beta 42 (Aβ42) polypeptides results from the improper cleavage of amyloid precursor protein (APP) in the brain. The Aβ42 plaques have been shown to disrupt the normal cellular processes and thereby trigger abnormal signaling which results in the death of neurons. However, the molecular-genetic mechanism(s) responsible for Aβ42 mediated neurodegeneration is yet to be fully understood.
  
  
  RESULTS
  We have utilized Gal4/UAS system to develop a transgenic fruit fly model for Aβ42 mediated neurodegeneration. Targeted misexpression of human Aβ42 in the differentiating photoreceptor neurons of the developing eye of transgenic fly triggers neurodegeneration. This progressive neurodegenerative phenotype resembles Alzheimer's like neuropathology. We identified a histone acetylase, CREB Binding Protein (CBP), as a genetic modifier of Aβ42 mediated neurodegeneration. Targeted misexpression of CBP along with Aβ42 in the differentiating retina can significantly rescue neurodegeneration. We found that gain-of-function of CBP rescues Aβ42 mediated neurodegeneration by blocking cell death. Misexpression of Aβ42 affects the targeting of axons from retina to the brain but misexpression of full length CBP along with Aβ42 can restore this defect. The CBP protein has multiple domains and is known to interact with many different proteins. Our structure function analysis using truncated constructs lacking one or more domains of CBP protein, in transgenic flies revealed that Bromo, HAT and polyglutamine (BHQ) domains together are required for the neuroprotective function of CBP. This BHQ domain of CBP has not been attributed to promote survival in any other neurodegenerative disorders.
  
  
  CONCLUSIONS
  We have identified CBP as a genetic modifier of Aβ42 mediated neurodegeneration. Furthermore, we have identified BHQ domain of CBP is responsible for its neuroprotective function. These studies may have significant bearing on our understanding of genetic basis of AD.
authors.affiliation: Premedical Program, University of Dayton, Dayton, Ohio, 45469, United States of America.
authors.forename: Timothy
authors.initials: T
authors.lastname: Cutler
authors.affiliation: Department of Biology, University of Dayton, Dayton, Ohio, 45469, United States of America.
authors.forename: Ankita
authors.initials: A
authors.lastname: Sarkar
authors.affiliation: Department of Biology, University of Dayton, Dayton, Ohio, 45469, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Moran
authors.affiliation: Premedical Program, University of Dayton, Dayton, Ohio, 45469, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: Steffensmeier
authors.affiliation: Department of Biology, University of Dayton, Dayton, Ohio, 45469, United States of America.
authors.forename: Oorvashi Roy
authors.initials: OR
authors.lastname: Puli
authors.affiliation: Premedical Program, University of Dayton, Dayton, Ohio, 45469, United States of America.
authors.forename: Greg
authors.initials: G
authors.lastname: Mancini
authors.affiliation: Department of Biology, University of Dayton, Dayton, Ohio, 45469, United States of America.
authors.forename: Meghana
authors.initials: M
authors.lastname: Tare
authors.affiliation: Department of Biology, University of Dayton, Dayton, Ohio, 45469, United States of America.
authors.forename: Neha
authors.initials: N
authors.lastname: Gogia
authors.affiliation: Premedical Program, University of Dayton, Dayton, Ohio, 45469, United States of America; Department of Biology, University of Dayton, Dayton, Ohio, 45469, United States of America; Center for Tissue Regeneration and Engineering at Dayton (TREND), University of Dayton, Dayton, Ohio, 45469, United States of America.
authors.forename: Amit
authors.initials: A
authors.lastname: Singh
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D006801:Humans; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000096:biosynthesis / Q000235:genetics; D012160:Retina / Q000378:metabolism* / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D029721:Drosophila Proteins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D050882:CREB-Binding Protein