Activation of α-secretase cleavage
Version of Record online: 28 NOV 2011
© 2011 The Author. Journal of Neurochemistry © 2011 International Society for Neurochemistry
Journal of Neurochemistry
Special Issue: Alzheimer’s Disease
Volume 120, Issue Supplement s1, pages 46–54, January 2012
How to Cite
Postina, R. (2012), Activation of α-secretase cleavage. Journal of Neurochemistry, 120: 46–54. doi: 10.1111/j.1471-4159.2011.07459.x
- Issue online: 23 DEC 2011
- Version of Record online: 28 NOV 2011
- Accepted manuscript online: 29 AUG 2011 11:37PM EST
- Received June 29, 2011; revised manuscript received August 10, 2011; accepted August 24, 2011.
- ADAM proteinase;
- Alzheimer’s disease;
- G protein-coupled receptors;
- regulated protein ectodomain shedding;
- signal transduction;
J. Neurochem. (2012) 120 (Suppl. 1), 46–54.
Alpha-secretase-mediated cleavage of the amyloid precursor protein (APP) releases the neuroprotective APP fragment sαAPP and prevents amyloid β peptide (Aβ) generation. Moreover, α-secretase-like cleavage of the Aβ transporter ‘receptor for advanced glycation end products’ counteracts the import of blood Aβ into the brain. Assuming that Aβ is responsible for the development of Alzheimer’s disease (AD), activation of α-secretase should be preventive. α-Secretase-mediated APP cleavage can be activated via several G protein-coupled receptors and receptor tyrosine kinases. Protein kinase C, mitogen-activated protein kinases, phosphatidylinositol 3-kinase, cAMP and calcium are activators of receptor-induced α-secretase cleavage. Selective targeting of receptor subtypes expressed in brain regions affected by AD appears reasonable. Therefore, the PACAP receptor PAC1 and possibly the serotonin 5-HT6 receptor subtype are promising targets. Activation of APP α-secretase cleavage also occurs upon blockade of cholesterol synthesis by statins or zaragozic acid A. Under physiological statin concentrations, the brain cholesterol content is not influenced. Statins likely inhibit Aβ production in the blood by α-secretase activation which is possibly sufficient to inhibit AD development. A disintegrin and metalloproteinase 10 (ADAM10) acts as α-secretase on APP. By targeting the nuclear retinoic acid receptor β, the expression of ADAM10 and non-amyloidogenic APP processing can be enhanced. Excessive activation of ADAM10 should be avoided because ADAM10 and also ADAM17 are not APP-specific. Both ADAM proteins cleave various substrates, and therefore have been associated with tumorigenesis and tumor progression.