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

Abstract

Alzheimer's disease is a neurodegenerative condition characterized by an accumulation of toxic amyloid beta- (A𝛽-)peptides in the brain causing progressive neuronal death. A𝛽-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 A𝛽 region thereby precluding the formation of intact A𝛽-peptides. In addition, other members of the zinc metalloproteinase family can degrade preformed A𝛽-peptides. As such, the zinc metalloproteinases, collectively, are key to downregulating A𝛽 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.