Please use this identifier to cite or link to this item:
Title: Overactivation of calcineurin induced by amyloid-beta and prion proteins
Authors: Agostinho, Paula 
Lopes, João P. 
Velez, Zélia 
Oliveira, Catarina R. 
Keywords: Neurotoxicity; Amyloid-β; Prion protein; Calcineurin
Issue Date: 2008
Citation: Neurochemistry International. 52:6 (2008) 1226-1233
Abstract: Amyloid-beta protein (A[beta]) and the scrapie isoform of prion protein (PrPSs) have a central role in the pathogenesis of Alzheimer's disease (AD) and prion-related encephalopathies (PRE), respectively. In both disorders, the deposition of these misfolded proteins is accompanied by apoptotic neuronal loss. However, the pathogenesis and molecular basis of A[beta]- and PrPSc-neurotoxic effects are not completely understood. The Ca2+/calmodulin-dependent phosphatase calcineurin (CaN), through the dephosphorylation of the proapoptotic protein BAD, may be the link between Ca2+homeostasis deregulation and apoptotic neuronal death. In this study we used primary cultures of rat brain cortical neurons in order to investigate whether A[beta] and PrP affect CaN activity. We observed that synthetic peptides of A[beta] (A[beta]25-35 and A[beta]1-40) and PrP (PrP106-126) increased CaN activity, but did not affect the levels of this protein phosphatase. Moreover, we found that these peptides reduced the levels of BAD phosphorylated at serine residue 112, and this effect was prevented by the CaN inhibitor FK506. Since dephosphorylated BAD translocates to mitochondria, where it triggers cytochrome c release, we determined the levels of BAD in mitochondrial and cytosolic fractions. The data obtained showed that A[beta]- and PrP-treated neurons had higher levels of BAD in mitochondria than control neurons. This increase in mitochondrial BAD levels was matched by a decrease in cytochrome c. FK506 prevented the alterations of mitochondrial BAD and cytochrome c levels induced by A[beta] and PrP peptides. Taken together the data suggest that A[beta] and PrP increased CaN activity, inducing BAD dephosphorylation and translocation to mitochondria and, subsequently, cytochrome c release that may trigger an apoptotic cascade. Therefore, therapeutic strategies targeting CaN might be valuable for these neurodegenerative disorders.
DOI: 10.1016/j.neuint.2008.01.005
Rights: openAccess
Appears in Collections:FMUC Medicina - Artigos em Revistas Internacionais

Files in This Item:
File Description SizeFormat
filec3da5b8dbded46f9ae0cc418a719b855.pdf1.14 MBAdobe PDFView/Open
Show full item record


checked on Aug 2, 2022

Page view(s) 20

checked on Aug 11, 2022

Download(s) 20

checked on Aug 11, 2022

Google ScholarTM




Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.