Enhanced proteolysis of β-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death

Malcolm A. Leissring, Wesley Farris, Alice Y. Chang, Dominic M. Walsh, Xining Wu, Xiaoyan Sun, Matthew P. Frosch, Dennis J. Selkoe

Research output: Contribution to journalArticle

545 Citations (Scopus)

Abstract

Converging evidence suggests that the accumulation of cerebral amyloid β-protein (Aβ) in Alzheimer's disease (AD) reflects an imbalance between the production and degradation of this self-aggregating peptide. Upregulation of proteases that degrade Aβ thus represents a novel therapeutic approach to lowering steady-state Aβ levels, but the consequences of sustained upregulation in vivo have not been studied. Here we show that transgenic overexpression of insulin-degrading enzyme (IDE) or neprilysin (NEP) in neurons significantly reduces brain Aβ levels, retards or completely prevents amyloid plaque formation and its associated cytopathology, and rescues the premature lethality present in amyloid precursor protein (APP) transgenic mice. Our findings demonstrate that chronic upregulation of Aβ-degrading proteases represents an efficacious therapeutic approach to combating Alzheimer-type pathology in vivo.

Original languageEnglish (US)
Pages (from-to)1087-1093
Number of pages7
JournalNeuron
Volume40
Issue number6
DOIs
StatePublished - Dec 18 2003
Externally publishedYes

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Premature Mortality
Amyloid beta-Protein Precursor
Amyloid
Transgenic Mice
Proteolysis
Up-Regulation
Pathology
Peptide Hydrolases
Insulysin
Serum Amyloid A Protein
Neprilysin
Amyloid Plaques
Alzheimer Disease
Neurons
Peptides
Brain
Therapeutics

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Leissring, M. A., Farris, W., Chang, A. Y., Walsh, D. M., Wu, X., Sun, X., ... Selkoe, D. J. (2003). Enhanced proteolysis of β-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron, 40(6), 1087-1093. https://doi.org/10.1016/S0896-6273(03)00787-6

Enhanced proteolysis of β-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. / Leissring, Malcolm A.; Farris, Wesley; Chang, Alice Y.; Walsh, Dominic M.; Wu, Xining; Sun, Xiaoyan; Frosch, Matthew P.; Selkoe, Dennis J.

In: Neuron, Vol. 40, No. 6, 18.12.2003, p. 1087-1093.

Research output: Contribution to journalArticle

Leissring, MA, Farris, W, Chang, AY, Walsh, DM, Wu, X, Sun, X, Frosch, MP & Selkoe, DJ 2003, 'Enhanced proteolysis of β-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death', Neuron, vol. 40, no. 6, pp. 1087-1093. https://doi.org/10.1016/S0896-6273(03)00787-6
Leissring, Malcolm A. ; Farris, Wesley ; Chang, Alice Y. ; Walsh, Dominic M. ; Wu, Xining ; Sun, Xiaoyan ; Frosch, Matthew P. ; Selkoe, Dennis J. / Enhanced proteolysis of β-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. In: Neuron. 2003 ; Vol. 40, No. 6. pp. 1087-1093.
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