Overexpression of neprilysin reduces Alzheimer amyloid-beta 42 (A beta 42)-induced neuron loss and intraneuronal A beta 42 deposits but causes a reduction in cAMP-responsive element-binding protein-mediated transcription, age-dependent axon pathology, and premature death in Drosophila

Iijima-Ando, K., Hearn, S. A., Granger, L., Shenton, C., Gatt, A., Chiang, H. C., Hakker, I., Zhong, Y., Iijima, K. (July 2008) Overexpression of neprilysin reduces Alzheimer amyloid-beta 42 (A beta 42)-induced neuron loss and intraneuronal A beta 42 deposits but causes a reduction in cAMP-responsive element-binding protein-mediated transcription, age-dependent axon pathology, and premature death in Drosophila. Journal of Biological Chemistry, 283 (27). pp. 19066-19076. ISSN 0021-9258

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URL: https://www.ncbi.nlm.nih.gov/pubmed/18463098
DOI: 10.1074/jbc.M710509200

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.

Item Type: Paper
Subjects: diseases & disorders > mental disorders > delirium dementia cognitive disorders > Alzheimer's disease
organism description > animal > insect > Drosophila
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene expression
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein expression
CSHL Authors:
Communities: CSHL labs > Zhong lab
Depositing User: CSHL Librarian
Date: 4 July 2008
Date Deposited: 29 Mar 2012 19:05
Last Modified: 16 Mar 2018 16:49
PMCID: PMC2441542
Related URLs:
URI: http://repository.cshl.edu/id/eprint/25590

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