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Tau and caspase 3 as targets for neuroprotection.

Idan-Feldman A, Ostritsky R, Gozes I - Int J Alzheimers Dis (2012)

Bottom Line: The peptide drug candidate NAP (davunetide) has demonstrated protective effects in various in vivo and in vitro models of neurodegeneration.NAP was shown to reduce tau hyperphosphorylation as well as to prevent caspase-3 activation and cytochrome-3 release from mitochondria, both characteristic of apoptotic cell death.The purpose of this study was to evaluate the effect of NAP on tau hyperphosphorylation and caspase activity in the same biological system.

View Article: PubMed Central - PubMed

Affiliation: The Adams Super Center for Brain Studies, The Lily and Avraham Gildor Chair for The Investigation of Growth Factors, The Elton Laboratory for Molecular Neuroendocrinology, and Department of Human Molecular Genetics and Biochemistry, Sagol School of Neuroscience, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel.

ABSTRACT
The peptide drug candidate NAP (davunetide) has demonstrated protective effects in various in vivo and in vitro models of neurodegeneration. NAP was shown to reduce tau hyperphosphorylation as well as to prevent caspase-3 activation and cytochrome-3 release from mitochondria, both characteristic of apoptotic cell death. Recent studies suggest that caspases may play a role in tau pathology. The purpose of this study was to evaluate the effect of NAP on tau hyperphosphorylation and caspase activity in the same biological system. Our experimental setup used primary neuronal cultures subjected to oxygen-glucose deprivation (OGD), with and without NAP or caspase inhibitor. Cell viability was assessed by measuring mitochondrial activity (MTS assay), and immunoblots were used for analyzing protein level. It was shown that apoptosis was responsible for all cell death occurring following ischemia, and NAP treatment showed a concentration-dependent protection from cell death. Ischemia caused an increase in the levels of active caspase-3 and hyperphosphorylated tau, both of which were prevented by either NAP or caspase-inhibitor treatment. Our data suggest that, in this model system, caspase activation may be an upstream event to tau hyperphosphorylation, although additional studies will be required to fully elucidate the cascade of events.

No MeSH data available.


Related in: MedlinePlus

2 hours of OGD caused an increase in p-tau202 levels, prevented by either NAP or QVD-OPH treatment. Cultures were treated with 10−5 M NAP or with 20 μM QVD-OPH (broad spectrum caspase inhibitor, indicated as OGD + Q) and exposed to OGD insult for 2 hours. Proteins were extracted and analyzed using immunoblot with a specific anti-p-tau202 and antitotal tau antibodies. A representative blot of p-tau202 and total tau is exhibited in (a). P-tau levels were quantified and normalized to total tau levels (ANOVA with post hoc LSD, P ≤ 0.05) (b).
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fig5: 2 hours of OGD caused an increase in p-tau202 levels, prevented by either NAP or QVD-OPH treatment. Cultures were treated with 10−5 M NAP or with 20 μM QVD-OPH (broad spectrum caspase inhibitor, indicated as OGD + Q) and exposed to OGD insult for 2 hours. Proteins were extracted and analyzed using immunoblot with a specific anti-p-tau202 and antitotal tau antibodies. A representative blot of p-tau202 and total tau is exhibited in (a). P-tau levels were quantified and normalized to total tau levels (ANOVA with post hoc LSD, P ≤ 0.05) (b).

Mentions: phospho-tau (p-tau) levels were detected by immunoblot, with a p-tau202-specific antibody. A representative blot is shown in Figure 5(a). P-tau levels, were quantified, normalized to total tau levels and expressed as % of the p-tau levels in the control culture (Figure 5(b)). Phospho-tau levels were significantly increased following the OGD insult. Both NAP treatment (10−5 M) and QVD-OPH (caspases inhibitor) treatment (2∗10−5 M) prevented p-tau increase (ANOVA with post hoc LSD, P ≤ 0.05), (F = 5.633, df = 2, P = 0.012).


Tau and caspase 3 as targets for neuroprotection.

Idan-Feldman A, Ostritsky R, Gozes I - Int J Alzheimers Dis (2012)

2 hours of OGD caused an increase in p-tau202 levels, prevented by either NAP or QVD-OPH treatment. Cultures were treated with 10−5 M NAP or with 20 μM QVD-OPH (broad spectrum caspase inhibitor, indicated as OGD + Q) and exposed to OGD insult for 2 hours. Proteins were extracted and analyzed using immunoblot with a specific anti-p-tau202 and antitotal tau antibodies. A representative blot of p-tau202 and total tau is exhibited in (a). P-tau levels were quantified and normalized to total tau levels (ANOVA with post hoc LSD, P ≤ 0.05) (b).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3369463&req=5

fig5: 2 hours of OGD caused an increase in p-tau202 levels, prevented by either NAP or QVD-OPH treatment. Cultures were treated with 10−5 M NAP or with 20 μM QVD-OPH (broad spectrum caspase inhibitor, indicated as OGD + Q) and exposed to OGD insult for 2 hours. Proteins were extracted and analyzed using immunoblot with a specific anti-p-tau202 and antitotal tau antibodies. A representative blot of p-tau202 and total tau is exhibited in (a). P-tau levels were quantified and normalized to total tau levels (ANOVA with post hoc LSD, P ≤ 0.05) (b).
Mentions: phospho-tau (p-tau) levels were detected by immunoblot, with a p-tau202-specific antibody. A representative blot is shown in Figure 5(a). P-tau levels, were quantified, normalized to total tau levels and expressed as % of the p-tau levels in the control culture (Figure 5(b)). Phospho-tau levels were significantly increased following the OGD insult. Both NAP treatment (10−5 M) and QVD-OPH (caspases inhibitor) treatment (2∗10−5 M) prevented p-tau increase (ANOVA with post hoc LSD, P ≤ 0.05), (F = 5.633, df = 2, P = 0.012).

Bottom Line: The peptide drug candidate NAP (davunetide) has demonstrated protective effects in various in vivo and in vitro models of neurodegeneration.NAP was shown to reduce tau hyperphosphorylation as well as to prevent caspase-3 activation and cytochrome-3 release from mitochondria, both characteristic of apoptotic cell death.The purpose of this study was to evaluate the effect of NAP on tau hyperphosphorylation and caspase activity in the same biological system.

View Article: PubMed Central - PubMed

Affiliation: The Adams Super Center for Brain Studies, The Lily and Avraham Gildor Chair for The Investigation of Growth Factors, The Elton Laboratory for Molecular Neuroendocrinology, and Department of Human Molecular Genetics and Biochemistry, Sagol School of Neuroscience, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel.

ABSTRACT
The peptide drug candidate NAP (davunetide) has demonstrated protective effects in various in vivo and in vitro models of neurodegeneration. NAP was shown to reduce tau hyperphosphorylation as well as to prevent caspase-3 activation and cytochrome-3 release from mitochondria, both characteristic of apoptotic cell death. Recent studies suggest that caspases may play a role in tau pathology. The purpose of this study was to evaluate the effect of NAP on tau hyperphosphorylation and caspase activity in the same biological system. Our experimental setup used primary neuronal cultures subjected to oxygen-glucose deprivation (OGD), with and without NAP or caspase inhibitor. Cell viability was assessed by measuring mitochondrial activity (MTS assay), and immunoblots were used for analyzing protein level. It was shown that apoptosis was responsible for all cell death occurring following ischemia, and NAP treatment showed a concentration-dependent protection from cell death. Ischemia caused an increase in the levels of active caspase-3 and hyperphosphorylated tau, both of which were prevented by either NAP or caspase-inhibitor treatment. Our data suggest that, in this model system, caspase activation may be an upstream event to tau hyperphosphorylation, although additional studies will be required to fully elucidate the cascade of events.

No MeSH data available.


Related in: MedlinePlus