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Current Alzheimer Research
ISSN (Print): 1567-2050
ISSN (Online): 1875-5828
VOLUME: 9
ISSUE: 2
DOI: 10.2174/156720512799361655      Price:  $58









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

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Author(s): Stefan F. Lichtenthaler
Pages 165-177 (13)
Abstract:
α-secretase is the name for a metalloprotease activity, which is assumed to play a key role in the prevention of the molecular mechanisms underlying Alzheimers disease (AD). Proteases similar to α-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 β peptide (Aβ), which derives from the amyloid precursor protein (APP) through sequential cleavage by the two proteases β- and γ-secretase. In contrast, α-secretase, which is the metalloprotease ADAM10, cleaves APP within the Aβ domain, thus preventing Aβ generation. Additionally, it produces a secreted APP ectodomain with neurotrophic and neuroprotective properties. An increase in α-secretase cleavage is considered a therapeutic approach for AD, but the molecular mechanisms regulating α-secretase cleavage are only partly known. Protein kinase C and mitogen-activated protein kinase constitute central signaling hubs for the regulation of α-secretase cleavage. Additionally, recent studies increasingly demonstrate that the correct spatial and temporal localization of the two membrane proteins APP and α-secretase is essential for efficient α-secretase cleavage of APP. This review highlights the role of signaling pathways and protein trafficking in the control of APP α-secretase cleavage.
Keywords:
Alzheimer's disease, secretases, metalloprotease, signaling pathways, protein trafficking, neurodegeneration, regulated, intramembrane proteolysis, ectodomain shedding, Phorbol esters
Affiliation:
Adolf Butenandt-Institute,Biochemistry, Ludwig-Maximilians-University, 80336 Munich, Germany.