Overexpression of neprilysin reduces alzheimer amyloid-β42 (Aβ42)-induced neuron loss and intraneuronal Aβ42 deposits but causes a reduction in cAMP-responsive element-binding protein-mediated transcription, age-dependent axon pathology, and premature death in Drosophila

Kanae Iijima-Ando, Stephen A. Hearn, Linda Granger, Christopher Shenton, Anthony Gatt, Hsueh Cheng Chiang, Inessa Hakker, Yi Zhong, Koichi Iijima

研究成果: Article同行評審

70 引文 斯高帕斯(Scopus)

摘要

The amyloid-β42 (Aβ42) peptide has been suggested to play a causative role in Alzheimer disease (AD). Neprilysin (NEP) is one of the rate-limiting Aβ-degrading enzymes, and its enhancement ameliorates extracellular amyloid pathology, synaptic dysfunction, and memory defects in mouse models of Aβ amyloidosis. In addition to the extracellular Aβ, intraneuronal Aβ42 may contribute to AD pathogenesis. However, the protective effects of neuronal NEP expression on intraneuronal Aβ42 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 Aβ42, we demonstrated that NEP efficiently suppressed the formation of intraneuronal Aβ42 deposits and Aβ42-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.

原文English
頁(從 - 到)19066-19076
頁數11
期刊Journal of Biological Chemistry
283
發行號27
DOIs
出版狀態Published - 2008 7月 4

All Science Journal Classification (ASJC) codes

  • 生物化學
  • 分子生物學
  • 細胞生物學

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