Alzheimer Disease (AD), a progressive neurological disorder, is characterized by the presence of amyloid plaques in the brain. These plaques are comprised of aggregates of amyloid beta-peptides (AB peptides), which are believed to play a central role in disease development. Most strategies to prevent AD have been aimed at reducing the generation of amyloid beta-peptides. This is done by targeting specific enzymes, beta- and gamma-secretase, in the amyloid precursor protein (APP) degradation pathway, which sequentially cleave APP to form the Ab peptide. Falk Fahrenholz and colleagues at the University of Mainz, Germany, now provide evidence that targeting and alternative enzyme, alpha-secretase, might be a useful alternative strategy for reducing AB peptide. In the APP processing pathway, alpha-secretase cleavage of APP generates an alternative breakdown product of the protein that cannot generate AB peptide. Here the researchers use a mouse model deficient in or over expressing the gene ADAM10, which codes for alpha-secretase protein. In these studies, they find that moderate increased expression of ADAM10 in mice reduced AB peptide formation, prevented plaque formation, and, from a functional standpoint provided improvement in both long-term potentiation and cognitive impairment. On the other hand, mice lacking ADAM10 had increased number and size of amyloid plaques. The data here provide evidence that a-secretase might be a useful therapeutic target for AD, and also suggest that impairment of this enzyme might underlie some forms of the disease.
An accompanying commentary by Christian Haas and Stefan F. Lichtenthaler provides details on the APP degradation pathway and places this work and AD in this context.
TITLE: A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model
University of Mainz, Mainz, Germany.
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View the PDF of this article at: http://www.jci.org/cgi/content/full/113/10/1456
ACCOMPANYING COMMENTARY: Amyloid at the cutting edge: activation of a-secretase prevents amyloidogenesis in an Alzheimer disease mouse model
Ludwig-Maximilians-Universitat, Munich, Germany.
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