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Purification and Aggregation of the Amyloid Precursor Protein Intracellular Domain
10:08

Purification and Aggregation of the Amyloid Precursor Protein Intracellular Domain

Published on: August 28, 2012

Cleavage of amyloid-beta precursor protein (APP) by membrane-type matrix metalloproteinases

Munirah Ahmad1, Takahisa Takino, Hisashi Miyamori

  • 1Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Takara-machi, Ishikawa.

Journal of Biochemistry
|March 29, 2006
PubMed

Insights

Matrix metalloproteinases (MMPs), including MT1-MMP, MT3-MMP, and MT5-MMP, can cleave amyloid-beta precursor protein (APP). This shedding of APP ectodomain by MMPs may regulate APP functions in the central nervous system.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Neuroscience

Background:

  • Amyloid-beta precursor protein (APP) is crucial in cellular functions.
  • Matrix metalloproteinases (MMPs) are enzymes involved in extracellular matrix remodeling and protein processing.
  • The interaction between APP and MMPs, particularly MT1-MMP, is not fully understood.

Purpose of the Study:

  • To investigate the role of MMPs in the processing and function of APP.
  • To identify specific MMPs that can cleave APP and characterize the cleavage sites.
  • To explore the impact of APP shedding on APP-mediated transactivation.

Main Methods:

  • Expression cloning of APP from a human placenta cDNA library.
  • Co-expression of APP with various MT-MMPs (MT1-MMP, MT3-MMP, MT5-MMP) in HEK293T cells.
  • In vitro cleavage assays using recombinant APP and MT3-MMP.
  • Analysis of APP shedding, amyloid-beta peptide production, and Fe65-dependent transactivation.

Main Results:

  • MT1-MMP, MT3-MMP, and MT5-MMP were found to induce cleavage and shedding of the APP ectodomain.
  • MT3-MMP cleaved recombinant APP at multiple sites, including within the amyloid-beta peptide region.
  • The Swedish-type mutant of APP was more efficiently cleaved by MT3-MMP.
  • MT3-MMP expression enhanced Fe65-dependent transactivation mediated by APP.

Conclusions:

  • MT1-MMP, MT3-MMP, and MT5-MMP play a significant role in regulating APP processing and function.
  • APP shedding by MMPs may influence cellular signaling pathways involving Fe65.
  • These findings highlight a novel mechanism for APP regulation with implications for neurological tissues.

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