title: Modeling the complex pathology of Alzheimer's disease in Drosophila.
abstract: Alzheimer's disease (AD) is the leading cause of dementia and the most common neurodegenerative disorder. AD is mostly a sporadic disorder and its main risk factor is age, but mutations in three genes that promote the accumulation of the amyloid-β (Aβ42) peptide revealed the critical role of amyloid precursor protein (APP) processing in AD. Neurofibrillary tangles enriched in tau are the other pathological hallmark of AD, but the lack of causative tau mutations still puzzles researchers. Here, we describe the contribution of a powerful invertebrate model, the fruit fly Drosophila melanogaster, to uncover the function and pathogenesis of human APP, Aβ42, and tau. APP and tau participate in many complex cellular processes, although their main function is microtubule stabilization and the to-and-fro transport of axonal vesicles. Additionally, expression of secreted Aβ42 induces prominent neuronal death in Drosophila, a critical feature of AD, making this model a popular choice for identifying intrinsic and extrinsic factors mediating Aβ42 neurotoxicity. Overall, Drosophila has made significant contributions to better understand the complex pathology of AD, although additional insight can be expected from combining multiple transgenes, performing genome-wide loss-of-function screens, and testing anti-tau therapies alone or in combination with Aβ42.
authors.affiliation: McKnight Brain Institute, Department of Neurology, University of Florida, Gainesville, FL 32611, USA; Department of Neuroscience and Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL 32611, USA; Genetics Institute, University of Florida, Gainesville, FL 32611, USA. Electronic address: pedro.fernandez@neurology.ufl.edu.
authors.forename: Pedro
authors.initials: P
authors.lastname: Fernandez-Funez
authors.affiliation: McKnight Brain Institute, Department of Neurology, University of Florida, Gainesville, FL 32611, USA.
authors.forename: Lorena
authors.initials: L
authors.lastname: de Mena
authors.affiliation: McKnight Brain Institute, Department of Neurology, University of Florida, Gainesville, FL 32611, USA; Department of Neuroscience and Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL 32611, USA; Genetics Institute, University of Florida, Gainesville, FL 32611, USA. Electronic address: diego.rincon@neurology.ufl.edu.
authors.forename: Diego E
authors.initials: DE
authors.lastname: Rincon-Limas
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics*; D006801:Humans; D016874:Neurofibrillary Tangles / Q000235:genetics / Q000473:pathology
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D029721:Drosophila Proteins
keywords: APP; Alzheimer's disease; Aβ42; Disease models; Drosophila; Genetics; Neurodegeneration; Pathology; Tau