Alpha-Secretase Cleavage of the Amyloid Precursor Protein: Proteolysis Regulated by Signaling Pathways and Protein Trafficking

作者：Lichtenthaler Stefan F^*

来源：Current Alzheimer Research, 2012, 9(2): 165-177.

DOI：10.2174/156720512799361655

• Alzheimer's disease
• secretases
• metalloprotease
• signaling pathways
• protein trafficking
• neurodegeneration
• regulated intramembrane proteolysis
• ectodomain shedding

alpha-secretase is the name for a metalloprotease activity, which is assumed to play a key role in the prevention of the molecular mechanisms underlying Alzheimer's disease (AD). Proteases similar to alpha-secretase are essential for a wide range of biological processes, such as cell adhesion and embryonic development. The molecular culprit in AD is the amyloid beta peptide (A beta), which derives from the amyloid precursor protein (APP) through sequential cleavage by the two proteases beta- and gamma-secretase. In contrast, alpha-secretase, which is the metalloprotease ADAM10, cleaves APP within the A beta domain, thus preventing A beta generation. Additionally, it produces a secreted APP ectodomain with neurotrophic and neuroprotective properties. An increase in alpha-secretase cleavage is considered a therapeutic approach for AD, but the molecular mechanisms regulating alpha-secretase cleavage are only partly known. Protein kinase C and mitogen-activated protein kinase constitute central signaling hubs for the regulation of alpha-secretase cleavage. Additionally, recent studies increasingly demonstrate that the correct spatial and temporal localization of the two membrane proteins APP and alpha-secretase is essential for efficient alpha-secretase cleavage of APP. This review highlights the role of signaling pathways and protein trafficking in the control of APP alpha-secretase cleavage.

• 出版日期2012-2