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The C-terminal fragment of the Alzheimer's disease amyloid protein precursor is degraded by a proteasome-dependent mechanism distinct from gamma-secretase

Citation

Nunan, J and Shearman, MS and Checler, F and Cappai, R and Evin, G and Beyreuther, K and Masters, CL and Small, DH, The C-terminal fragment of the Alzheimer's disease amyloid protein precursor is degraded by a proteasome-dependent mechanism distinct from gamma-secretase, European Journal of Biochemistry: The Febs Journal, 268, (20) pp. 5329-5336. ISSN 0014-2956 (2001) [Refereed Article]


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The definitive published version is available online at: http://www3.interscience.wiley.com/

DOI: doi:10.1046/j.0014-2956.2001.02465.x

Abstract

The β-amyloid protein (Aβ) is derived by proteolytic processing of the amyloid protein precursor (APP). Cleavage of APP by β-secretase generates a C-terminal fragment (APP-CTFβ), which is subsequently cleaved by γ-secretase to produce Aβ. The aim of this study was to examine the cleavage of APP-CTFβ by γ-secretase in primary cortical neurons from transgenic mice engineered to express the human APP-CTFβ sequence. Neurons were prepared from transgenic mouse cortex and proteins labelled by incubation with [35S]methionine and [35S]cysteine. Labelled APP-CTFβ and Aβ were then immunoprecipitated with a monoclonal antibody (WO2) specific for the transgene sequences. Approximately 30% of the human APP-CTFβ (hAPP-CTFβ) was converted to human Aβ (hAβ), which was rapidly secreted. The remaining 70% of the hAPP-CTFβ was degraded by an alternative pathway. The cleavage of hAPP-CTFβ to produce hAβ was inhibited by specific γ-secretase inhibitors. However, treatment with proteasome inhibitors caused an increase in both hAPP-CTFβ and hAβ levels, suggesting that the alternative pathway was proteasome-dependent. A preparation of recombinant 20S proteasome was found to cleave a recombinant cytoplasmic domain fragment of APP (APPcyt) directly. The study suggests that in primary cortical neurons, APP-CTFβ is degraded by two distinct pathways, one involving γ-secretase, which produces Aβ, and a second major pathway involving direct cleavage of APP-CTFβ within the cytoplasmic domain by the proteasome. These results raise the possibility that defective proteasome function could lead to an increase in Aβ production in the AD brain.

Item Details

Item Type:Refereed Article
Keywords: Alzheimer's disease; Aβ; γ-secretase; proteasome; amyloid
Research Division:Medical and Health Sciences
Research Group:Neurosciences
Research Field:Neurosciences not elsewhere classified
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Neurodegenerative Disorders Related to Ageing
Author:Small, DH (Professor David Small)
ID Code:75360
Year Published:2001
Web of Science® Times Cited:97
Deposited By:Research Division
Deposited On:2012-01-25
Last Modified:2012-02-02
Downloads:0

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