Proteases and Proteolysis in Alzheimer Disease: A Multifactorial View on the Disease Process

Proteases and Proteolysis in Alzheimer Disease: A Multifactorial View on the Disease Process Abstract Alzheimer disease is characterized by the accumulation of abnormally folded protein fragments, i.e., amyloid beta peptide (Aβ) and tau that precipitate in amyloid plaques and neuronal tangles, respectively. In this review we discuss the complicated proteolytic pathways that are responsible for the generation and clearance of these fragments, and how disturbances in these pathways interact and provide a background for a novel understanding of Alzheimer disease as a multifactorial disorder. Recent insights evolve from the static view that the morphologically defined plaques and tangles are disease driving towards a more dynamic, biochemical view in which the intermediary soluble Aβ oligomers and soluble tau fragments are considered as the main mediators of neurotoxicity. The relevance of proteolytic pathways, centered on the generation and clearance of toxic Aβ, on the cleavage and nucleation of tau, and on the general proteostasis of the neurons, then becomes obvious. Blocking or stimulating these pathways provide, or have the potential to provide, interesting drug targets, which raises the hope that we will be able to provide a cure for this dreadful disorder. Footnotes Copyright © 2010 the American Physiological Society http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Physiological Reviews The American Physiological Society

Proteases and Proteolysis in Alzheimer Disease: A Multifactorial View on the Disease Process

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Publisher
The American Physiological Society
Copyright
Copyright © 2011 the American Physiological Society
ISSN
0031-9333
eISSN
1522-1210
D.O.I.
10.1152/physrev.00023.2009
Publisher site
See Article on Publisher Site

Abstract

Abstract Alzheimer disease is characterized by the accumulation of abnormally folded protein fragments, i.e., amyloid beta peptide (Aβ) and tau that precipitate in amyloid plaques and neuronal tangles, respectively. In this review we discuss the complicated proteolytic pathways that are responsible for the generation and clearance of these fragments, and how disturbances in these pathways interact and provide a background for a novel understanding of Alzheimer disease as a multifactorial disorder. Recent insights evolve from the static view that the morphologically defined plaques and tangles are disease driving towards a more dynamic, biochemical view in which the intermediary soluble Aβ oligomers and soluble tau fragments are considered as the main mediators of neurotoxicity. The relevance of proteolytic pathways, centered on the generation and clearance of toxic Aβ, on the cleavage and nucleation of tau, and on the general proteostasis of the neurons, then becomes obvious. Blocking or stimulating these pathways provide, or have the potential to provide, interesting drug targets, which raises the hope that we will be able to provide a cure for this dreadful disorder. Footnotes Copyright © 2010 the American Physiological Society

Journal

Physiological ReviewsThe American Physiological Society

Published: Apr 1, 2010

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