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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

Following 2 hours of OGD, cells died exclusively from apoptosis. Cultures were treated with either NAP (10−5 M) or QVD-OPH (2∗10−5 M) and subjected to 2 h of ischemic insult. Cell viability was evaluated immediately following the ischemic period using MTS viability assay. Data was normalized to % of control. Results are shown as mean ± SE; *significantly different from all other groups, P ≤ 0.05 (ANOVA, with post hoc Scheffe).
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fig3: Following 2 hours of OGD, cells died exclusively from apoptosis. Cultures were treated with either NAP (10−5 M) or QVD-OPH (2∗10−5 M) and subjected to 2 h of ischemic insult. Cell viability was evaluated immediately following the ischemic period using MTS viability assay. Data was normalized to % of control. Results are shown as mean ± SE; *significantly different from all other groups, P ≤ 0.05 (ANOVA, with post hoc Scheffe).

Mentions: Using the broad spectrum caspase inhibitor QVD-OPH, we tested the extent of apoptotic death following 5-minute of gassing and 2 hours of OGD. Cell viability was evaluated and compared to the control group (Figure 3). Under this paradigm, ~55% cell death was observed. Here, QVD-OPH (2∗10−5 M) treatment significantly increased cell viability to the control levels. In the same experiment, NAP in the same experiment, NAP (10−5 M) treatment rescued from the apoptotic cell death (F = 16.090, df = 7, P < 0.001). Post hoc pairwise comparisons did not detect any significant differences between the caspase inhibitor, NAP, and control no-ischemia groups.


Tau and caspase 3 as targets for neuroprotection.

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

Following 2 hours of OGD, cells died exclusively from apoptosis. Cultures were treated with either NAP (10−5 M) or QVD-OPH (2∗10−5 M) and subjected to 2 h of ischemic insult. Cell viability was evaluated immediately following the ischemic period using MTS viability assay. Data was normalized to % of control. Results are shown as mean ± SE; *significantly different from all other groups, P ≤ 0.05 (ANOVA, with post hoc Scheffe).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: Following 2 hours of OGD, cells died exclusively from apoptosis. Cultures were treated with either NAP (10−5 M) or QVD-OPH (2∗10−5 M) and subjected to 2 h of ischemic insult. Cell viability was evaluated immediately following the ischemic period using MTS viability assay. Data was normalized to % of control. Results are shown as mean ± SE; *significantly different from all other groups, P ≤ 0.05 (ANOVA, with post hoc Scheffe).
Mentions: Using the broad spectrum caspase inhibitor QVD-OPH, we tested the extent of apoptotic death following 5-minute of gassing and 2 hours of OGD. Cell viability was evaluated and compared to the control group (Figure 3). Under this paradigm, ~55% cell death was observed. Here, QVD-OPH (2∗10−5 M) treatment significantly increased cell viability to the control levels. In the same experiment, NAP in the same experiment, NAP (10−5 M) treatment rescued from the apoptotic cell death (F = 16.090, df = 7, P < 0.001). Post hoc pairwise comparisons did not detect any significant differences between the caspase inhibitor, NAP, and control no-ischemia groups.

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