title: Overexpression of neprilysin reduces alzheimer amyloid-beta42 (Abeta42)-induced neuron loss and intraneuronal Abeta42 deposits but causes a reduction in cAMP-responsive element-binding protein-mediated transcription, age-dependent axon pathology, and premature death in Drosophila.
abstract: The amyloid-beta42 (Abeta42) peptide has been suggested to play a causative role in Alzheimer disease (AD). Neprilysin (NEP) is one of the rate-limiting Abeta-degrading enzymes, and its enhancement ameliorates extracellular amyloid pathology, synaptic dysfunction, and memory defects in mouse models of Abeta amyloidosis. In addition to the extracellular Abeta, intraneuronal Abeta42 may contribute to AD pathogenesis. However, the protective effects of neuronal NEP expression on intraneuronal Abeta42 accumulation and neurodegeneration remain elusive. In contrast, sustained NEP activation may be detrimental because NEP can degrade many physiological peptides, but its consequences in the brain are not fully understood. Using transgenic Drosophila expressing human NEP and Abeta42, we demonstrated that NEP efficiently suppressed the formation of intraneuronal Abeta42 deposits and Abeta42-induced neuron loss. However, neuronal NEP overexpression reduced cAMP-responsive element-binding protein-mediated transcription, caused age-dependent axon degeneration, and shortened the life span of the flies. Interestingly, the mRNA levels of endogenous fly NEP genes and phosphoramidon-sensitive NEP activity declined during aging in fly brains, as observed in mammals. Taken together, these data suggest both the protective and detrimental effects of chronically high NEP activity in the brain. Down-regulation of NEP activity in aging brains may be an evolutionarily conserved phenomenon, which could predispose humans to developing late-onset AD.
authors.affiliation: Laboratory of Neurogenetics and Pathobiology, Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. Kanae.Iijima-Ando@jefferson.edu
authors.forename: Kanae
authors.initials: K
authors.lastname: Iijima-Ando
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Hearn
authors.forename: Linda
authors.initials: L
authors.lastname: Granger
authors.forename: Christopher
authors.initials: C
authors.lastname: Shenton
authors.forename: Anthony
authors.initials: A
authors.lastname: Gatt
authors.forename: Hsueh-Cheng
authors.initials: HC
authors.lastname: Chiang
authors.forename: Inessa
authors.initials: I
authors.lastname: Hakker
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhong
authors.forename: Koichi
authors.initials: K
authors.lastname: Iijima
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000686:Amyloidosis / Q000201:enzymology / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D001369:Axons / Q000201:enzymology*; D005075:Biological Evolution; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004331:Drosophila melanogaster; D004789:Enzyme Activation / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D051379:Mice; D015260:Neprilysin / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D017362:Cyclic AMP Response Element-Binding Protein; D015260:Neprilysin