Limits...
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

An increase in active caspase-3 levels induced by 2 hours of OGD was diminished by NAP treatment (10−5 M). Cultures were treated with 10−5  M NAP or with 20 μM QVD-OPH (broad spectrum caspase inhibitor) exposed to OGD insult for 2 hours. Proteins were extracted and analyzed using immunoblot with a specific antiactive caspase-3 antibody. A representative blot of active caspase-3 antibody is exhibited in (a). (ANOVA with post hoc LSD, P ≤ 0.05) (b).
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3369463&req=5

fig4: An increase in active caspase-3 levels induced by 2 hours of OGD was diminished by NAP treatment (10−5 M). Cultures were treated with 10−5  M NAP or with 20 μM QVD-OPH (broad spectrum caspase inhibitor) exposed to OGD insult for 2 hours. Proteins were extracted and analyzed using immunoblot with a specific antiactive caspase-3 antibody. A representative blot of active caspase-3 antibody is exhibited in (a). (ANOVA with post hoc LSD, P ≤ 0.05) (b).

Mentions: The levels of active caspase-3 were evaluated immediately after the OGD period using immunoblots with a specific active caspase-3 antibody and further quantified and normalized to actin. As shown in a representative blot in Figure 4(a), OGD treatment increased active caspases-3 levels. This increase was prevented by NAP treatment (10−5 M) or QVD-OPH (caspase inhibitor) treatment (2∗10−5 M). Figure 4(b) depicts the level of active caspase-3 expressed as % of control. A significant increase in active caspase-3 expression was induced by OGD and partially but significantly prevented by NAP treatment (F = 7.880, df = 2,  P = 0.004).


Tau and caspase 3 as targets for neuroprotection.

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

An increase in active caspase-3 levels induced by 2 hours of OGD was diminished by NAP treatment (10−5 M). Cultures were treated with 10−5  M NAP or with 20 μM QVD-OPH (broad spectrum caspase inhibitor) exposed to OGD insult for 2 hours. Proteins were extracted and analyzed using immunoblot with a specific antiactive caspase-3 antibody. A representative blot of active caspase-3 antibody is exhibited in (a). (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

fig4: An increase in active caspase-3 levels induced by 2 hours of OGD was diminished by NAP treatment (10−5 M). Cultures were treated with 10−5  M NAP or with 20 μM QVD-OPH (broad spectrum caspase inhibitor) exposed to OGD insult for 2 hours. Proteins were extracted and analyzed using immunoblot with a specific antiactive caspase-3 antibody. A representative blot of active caspase-3 antibody is exhibited in (a). (ANOVA with post hoc LSD, P ≤ 0.05) (b).
Mentions: The levels of active caspase-3 were evaluated immediately after the OGD period using immunoblots with a specific active caspase-3 antibody and further quantified and normalized to actin. As shown in a representative blot in Figure 4(a), OGD treatment increased active caspases-3 levels. This increase was prevented by NAP treatment (10−5 M) or QVD-OPH (caspase inhibitor) treatment (2∗10−5 M). Figure 4(b) depicts the level of active caspase-3 expressed as % of control. A significant increase in active caspase-3 expression was induced by OGD and partially but significantly prevented by NAP treatment (F = 7.880, df = 2,  P = 0.004).

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