Overactivation of calcineurin induced by amyloid-β and prion proteins

Institute of Biochemistry, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal. <>
Neurochemistry International (Impact Factor: 3.09). 06/2008; 52(6):1226-33. DOI: 10.1016/j.neuint.2008.01.005
Source: PubMed


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.

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Available from: Zélia Velez, Oct 06, 2015
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    • "It has been suggested that calcineurin plays an important role in apoptosis in the central nervous system. Activation of calcineurin induces the dephosphorylation of BAD (a pro-apoptotic member of the Bcl-2 family) and activation of caspase-3, thereby causing apoptosis in several types of cells including neurons [28] [29] [30]. Protection of neurons from apoptosis by ApoE3 involves inhibition of calcineurin [31]. "
    Journal of Alzheimer's disease: JAD 01/2013; · 4.15 Impact Factor
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    • "Several clinical and pathological features of AD appear to involve a strong bidirectional interaction between Aβ peptides and CN/NFAT signaling (Agostinho et al., 2008; Reese et al., 2008; Abdul et al., 2009; Hong et al., 2010; Wu et al., 2010; Mohmmad Abdul et al., 2011; Wu et al., 2012). In the present study, Aβ peptide levels and amyloid plaque load were reduced in Tg mice treated with Gfa2-VIVIT (Figure 4), suggesting that astrocytes are a critical site for CN/NFAT-amyloid interactions. "
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    ABSTRACT: Astrocytes are the most abundant cell type in the brain and play a critical role in maintaining healthy nervous tissue. In Alzheimer's disease (AD) and most other neurodegenerative disorders, many astrocytes convert to a chronically "activated" phenotype characterized by morphologic and biochemical changes that appear to compromise protective properties and/or promote harmful neuroinflammatory processes. Activated astrocytes emerge early in the course of AD and become increasingly prominent as clinical and pathological symptoms progress, but few studies have tested the potential of astrocyte-targeted therapeutics in an intact animal model of AD. Here, we used adeno-associated virus (AAV) vectors containing the astrocyte-specific Gfa2 promoter to target hippocampal astrocytes in APP/PS1 mice. AAV-Gfa2 vectors drove the expression of VIVIT, a peptide that interferes with the immune/inflammatory calcineurin/NFAT (nuclear factor of activated T-cells) signaling pathway, shown by our laboratory and others to orchestrate biochemical cascades leading to astrocyte activation. After several months of treatment with Gfa2-VIVIT, APP/PS1 mice exhibited improved cognitive and synaptic function, reduced glial activation, and lower amyloid levels. The results confirm a deleterious role for activated astrocytes in AD and lay the groundwork for exploration of other novel astrocyte-based therapies.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 11/2012; 32(46):16129-16140. DOI:10.1523/JNEUROSCI.2323-12.2012 · 6.34 Impact Factor
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    • "In SY5Y human neuroblastoma cells treated with increased concentrations of oligomeric Aβ there is a dose-dependent decrease in pBAD levels [74]. Treatment of primary cortical neurons with synthetic Aβ peptides increases CaN activity; reduces the level of phosphorylated BAD; and increases the amount of BAD found in the mitochondria [80]. These effects on cortical neurons were attenuated by the CaN inhibitor FK506, suggesting that some of the neurodegeneration seen in AD may be due to the ability of CaN to induce apoptosis via BAD. "
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    ABSTRACT: Alzheimer's disease (AD) is an incurable age-related neurodegenerative disorder characterized by profound memory dysfunction. This bellwether symptom suggests involvement of the hippocampus -- a brain region responsible for memory formation -- and coincidentally an area heavily burdened by hyperphosphorylated tau and neuritic plaques of amyloid beta (Aβ). Recent evidence suggests that pre-fibrillar soluble Aβ underlies an early, progressive loss of synapses that is a hallmark of AD. One of the downstream effects of soluble Aβ aggregates is the activation of the phosphatase calcineurin (CaN). This review details the evidence of CaN hyperactivity in 'normal' aging, models of AD, and actual disease pathogenesis; elaborates on how this could manifest as memory impairment, neuroinflammation, hyperphosphorylated tau, and neuronal death.
    DNA research: an international journal for rapid publication of reports on genes and genomes 12/2011; 9(4):685-92. DOI:10.2174/157015911798376316 · 3.05 Impact Factor
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