title: Characterization of a Drosophila Alzheimer's disease model: pharmacological rescue of cognitive defects.
abstract: Transgenic models of Alzheimer's disease (AD) have made significant contributions to our understanding of AD pathogenesis, and are useful tools in the development of potential therapeutics. The fruit fly, Drosophila melanogaster, provides a genetically tractable, powerful system to study the biochemical, genetic, environmental, and behavioral aspects of complex human diseases, including AD. In an effort to model AD, we over-expressed human APP and BACE genes in the Drosophila central nervous system. Biochemical, neuroanatomical, and behavioral analyses indicate that these flies exhibit aspects of clinical AD neuropathology and symptomology. These include the generation of Aβ(40) and Aβ(42), the presence of amyloid aggregates, dramatic neuroanatomical changes, defects in motor reflex behavior, and defects in memory. In addition, these flies exhibit external morphological abnormalities. Treatment with a γ-secretase inhibitor suppressed these phenotypes. Further, all of these phenotypes are present within the first few days of adult fly life. Taken together these data demonstrate that this transgenic AD model can serve as a powerful tool for the identification of AD therapeutic interventions.
authors.affiliation: Department of Biology, Drexel University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Ranjita
authors.initials: R
authors.lastname: Chakraborty
authors.forename: Vidya
authors.initials: V
authors.lastname: Vepuri
authors.forename: Siddhita D
authors.initials: SD
authors.lastname: Mhatre
authors.forename: Brie E
authors.initials: BE
authors.lastname: Paddock
authors.forename: Sean
authors.initials: S
authors.lastname: Miller
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Michelson
authors.forename: Radha
authors.initials: R
authors.lastname: Delvadia
authors.forename: Arkit
authors.initials: A
authors.lastname: Desai
authors.forename: Marianna
authors.initials: M
authors.lastname: Vinokur
authors.forename: David J
authors.initials: DJ
authors.lastname: Melicharek
authors.forename: Suruchi
authors.initials: S
authors.lastname: Utreja
authors.forename: Preeti
authors.initials: P
authors.lastname: Khandelwal
authors.forename: Sara
authors.initials: S
authors.lastname: Ansaloni
authors.forename: Lee E
authors.initials: LE
authors.lastname: Goldstein
authors.forename: Robert D
authors.initials: RD
authors.lastname: Moir
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Lee
authors.forename: Loni P
authors.initials: LP
authors.lastname: Tabb
authors.forename: Aleister J
authors.initials: AJ
authors.lastname: Saunders
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Marenda
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism / Q000503:physiopathology; D002219:Carbamates / Q000494:pharmacology* / Q000627:therapeutic use; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D004151:Dipeptides / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004331:Drosophila melanogaster; D004353:Drug Evaluation, Preclinical; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010641:Phenotype; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D012018:Reflex / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
chemical_list: D016564:Amyloid beta-Protein Precursor; D002219:Carbamates; D004151:Dipeptides; C410009:L 685458; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases