Zinc Metalloproteinases and Amyloid Beta-Peptide Metabolism: The Positive Side of Proteolysis in Alzheimer's Disease

Alzheimer's disease is a neurodegenerative condition characterized by an accumulation of toxic amyloid beta- (A β -)peptides in the brain causing progressive neuronal death. A β -peptides are produced by aspartyl proteinase-mediated cleavage of the larger amyloid precursor protein (APP). In contrast to this detrimental “amyloidogenic” form of proteolysis, a range of zinc metalloproteinases can process APP via an alternative “nonamyloidogenic” pathway in which the protein is cleaved within its A β region thereby precluding the formation of intact A β -peptides. In addition, other members of the zinc metalloproteinase family can degrade preformed A β -peptides. As such, the zinc metalloproteinases, collectively, are key to downregulating A β generation and enhancing its degradation. It is the role of zinc metalloproteinases in this “positive side of proteolysis in Alzheimer's disease” that is discussed in the current paper.