Human Molecular Genetics, 2001, Vol. 10, No. 16 1665-1671
© 2001 Oxford University Press
Pathogenic APP mutations near the 
-secretase cleavage site differentially affect Aß secretion and APP C-terminal fragment stability
Laboratory of Neurogenetics, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Belgium, 1Laboratory of Neuronal Cell Biology, Department of Human Genetics, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Belgium and 2Institut de Pharmacologie Moléculaire et Cellulaire du Centre National de la Recherche Scientifique, Valbonne, France
Release of amyloid ß (Aß) from the amyloid precursor protein (APP) requires cleavages by ß- and 
-secretases and plays a crucial role in Alzheimer’s disease (AD) pathogenesis. Missense mutations in the APP gene causing familial AD are clustered around the ß-, 
- and particular -secretase cleavage sites. We systematically compare in primary neurons the effect on APP processing of a series of clinical APP mutations (two of which not characterized before) located in close proximity to the -secretase cleavage site. We confirm and extend previous observations showing that all these mutations (T714I, V715M, V715A, I716V, V717I and V717L) affect -secretase cleavage causing an increased relative ratio of Aß42 to Aß40. Taking advantage of these extended series of APP mutations we were able to demonstrate an inverse correlation between these ratios and the age at onset of the disease in the different families. In addition, a subset of mutations caused the accumulation of APP C-terminal fragments indicating that these mutations also influence the stability of APP C-terminal fragments. However, it is unlikely that these fragments contribute significantly to the disease process.
+ To whom correspondence should be addressed. Tel: +32 16 346227; Fax: +32 16 347181; Email: ad@med.kuleuven.ac.be
To whom correspondence should be addressed. Tel: +32 16 346227; Fax: +32 16 347181; Email: ad@med.kuleuven.ac.be
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  W. J. Meilandt, G.-Q. Yu, J. Chin, E. D. Roberson, J. J. Palop, T. Wu, K. Scearce-Levie, and L. Mucke Enkephalin Elevations Contribute to Neuronal and Behavioral Impairments in a Transgenic Mouse Model of Alzheimer's Disease J. Neurosci., May 7, 2008; 28(19): 5007 - 5017. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. I. Yin, B. Bassit, L. Zhu, X. Yang, C. Wang, and Y.-M. Li {gamma}-Secretase Substrate Concentration Modulates the Abeta42/Abeta40 Ratio: IMPLICATIONS FOR ALZHEIMER DISEASE J. Biol. Chem., August 10, 2007; 282(32): 23639 - 23644. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. L. Lambourne, L. A. Sellers, T. G. Bush, S. K. Choudhury, P. C. Emson, Y.-H. Suh, and L. S. Wilkinson Increased tau Phosphorylation on Mitogen-Activated Protein Kinase Consensus Sites and Cognitive Decline in Transgenic Models for Alzheimer's Disease and FTDP-17: Evidence for Distinct Molecular Processes Underlying tau Abnormalities Mol. Cell. Biol., January 1, 2005; 25(1): 278 - 293. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.C. Janssen, J.A. Beck, T.A. Campbell, A. Dickinson, N.C. Fox, R.J. Harvey, H. Houlden, M.N. Rossor, and J. Collinge Early onset familial Alzheimer's disease: Mutation frequency in 31 families Neurology, January 28, 2003; 60(2): 235 - 239. [Abstract] [Full Text] [PDF]
|
|