Clearance of Amyloid-β Peptide by Neuronal and Non-Neuronal Cells: Proteolytic Degradation by Secreted and Membrane associated Proteases

Author(s): Mai Panchal , Noureddine Lazar , Noeli Munoz , Christine Fahy , Christine Clamagirand , Jean-Paul Brouard , Lionel Dubost , Paul Cohen , Noureddine Brakch , Mohamed Rholam .

Journal Name: Current Neurovascular Research

Volume 4 , Issue 4 , 2007

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Abstract:

Deposition of amyloid-β peptide (Aβ) in the brain is an early and invariant feature of all forms of Alzheimers disease (AD). As for all proteins or peptides, the steady-state level of Aβ peptide is determined not only by its production, but also by its degradation. So, overactive proteases involved in generating Aβ from amyloid precursor protein or underactive Aβ-degrading enzymes could lead to abnormal Aβ deposition in the brain. Since in the sporadic forms of AD (90% of all AD cases) an impaired clearance of Aβ appears to be at the origin of its aggregation and tissue deposition, we have investigated its proteolytic degradation by several neuronal and nonneuronal cells. In this report, we show that these cell types exhibit a similar profile of Aβ-degradation by cell-surface and secreted proteases which were respectively characterized as metallo- and serine proteases. By using a combination of the liquid chromatography/on-line mass spectrometry, we demonstrate that: (i)-the membrane associated protease(s) hydrolizes Aβ40 essentially at Lys28↓Gly29, Phe19↓Phe20 and Val18↓Phe19 bonds; and (ii)-the secreted protease(s) cleaves the generating fragments Aβ(1-28), Aβ(1-19), Aβ(1-18) at His14↓Gln15 bond and also Aβ(1-28) at Phe20↓Ala21 and Asp23↓Val24 sites. This is the first time our results define a proteolytic degradation process of Aβ40 that appears to be independent of the cell type and may represent a general pattern of its enzymatic clearance.

Keywords: Alzheimer's disease, catabolism, Aβ clearance, cell lines, proteases, LC-MS

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Article Details

VOLUME: 4
ISSUE: 4
Year: 2007
Page: [240 - 251]
Pages: 12
DOI: 10.2174/156720207782446315
Price: $58

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