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, HsuehCheng Chinag, Inessa Hakker, Yi Zhong, Koichi Iijima

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)19066-19076
Number of pages11
JournalJournal of Biological Chemistry
Volume283
Issue number27
DOIs
Publication statusPublished - 2008 Jul 4

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Neprilysin
Premature Mortality
Amyloid Plaques
Pathology
Transcription
Amyloid
Drosophila
Neurons
Axons
Carrier Proteins
Deposits
Brain
Diptera
Alzheimer Disease
Aging of materials
Peptides
Mammals
Amyloidosis
Down-Regulation
Genes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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title = "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",
abstract = "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.",
author = "Kanae Iijima-Ando and Hearn, {Stephen A.} and Linda Granger and Christopher Shenton and Anthony Gatt and HsuehCheng Chinag and Inessa Hakker and Yi Zhong and Koichi Iijima",
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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. / Iijima-Ando, Kanae; Hearn, Stephen A.; Granger, Linda; Shenton, Christopher; Gatt, Anthony; Chinag, HsuehCheng; Hakker, Inessa; Zhong, Yi; Iijima, Koichi.

In: Journal of Biological Chemistry, Vol. 283, No. 27, 04.07.2008, p. 19066-19076.

Research output: Contribution to journalArticle

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T1 - 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

AU - Iijima-Ando, Kanae

AU - Hearn, Stephen A.

AU - Granger, Linda

AU - Shenton, Christopher

AU - Gatt, Anthony

AU - Chinag, HsuehCheng

AU - Hakker, Inessa

AU - Zhong, Yi

AU - Iijima, Koichi

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N2 - 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.

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