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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

NAP protects from cell death in a dose dependent manner following 2 hours of OGD insult, but not after additional 24 hours reperfusion. Primary neuronal cultures (5-6DIV) were subjected to 2 h of ischemic insult. Cell viability was evaluated using MTS viability assay. Data was normalized to % of control. Results are shown as mean ± SE. *Significantly different from OGD with no NAP, OGD + NAP10−15 M, OGD + NAP 10−13 M, OGD+NAP 10−11 M (3 independent experiments are summarized, ANOVA, with post hoc Scheffe, significant difference considered to be P ≤ 0.05). Using LSD post hoc, NAP 10−5 M (+), 10−7 M are significantly different from the OGD group (P < 0.05).
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fig2: NAP protects from cell death in a dose dependent manner following 2 hours of OGD insult, but not after additional 24 hours reperfusion. Primary neuronal cultures (5-6DIV) were subjected to 2 h of ischemic insult. Cell viability was evaluated using MTS viability assay. Data was normalized to % of control. Results are shown as mean ± SE. *Significantly different from OGD with no NAP, OGD + NAP10−15 M, OGD + NAP 10−13 M, OGD+NAP 10−11 M (3 independent experiments are summarized, ANOVA, with post hoc Scheffe, significant difference considered to be P ≤ 0.05). Using LSD post hoc, NAP 10−5 M (+), 10−7 M are significantly different from the OGD group (P < 0.05).

Mentions: Cell viability was evaluated following a 25-minute gassing period and an additional 2 hours of OGD. The results were calculated and expressed as % of the control group (Figure 2). Under this paradigm, ~70% cell death was observed. Treatment with NAP increased cell viability immediately following OGD (F = 17.667, df = 7, P < 0.001). Post hoc pairwise comparisons (LSD) indicated that NAP concentrations of 10−7 M and 10−5 M significantly protected against ischemia (Figure 2, P ≤ 0.05).


Tau and caspase 3 as targets for neuroprotection.

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

NAP protects from cell death in a dose dependent manner following 2 hours of OGD insult, but not after additional 24 hours reperfusion. Primary neuronal cultures (5-6DIV) were subjected to 2 h of ischemic insult. Cell viability was evaluated using MTS viability assay. Data was normalized to % of control. Results are shown as mean ± SE. *Significantly different from OGD with no NAP, OGD + NAP10−15 M, OGD + NAP 10−13 M, OGD+NAP 10−11 M (3 independent experiments are summarized, ANOVA, with post hoc Scheffe, significant difference considered to be P ≤ 0.05). Using LSD post hoc, NAP 10−5 M (+), 10−7 M are significantly different from the OGD group (P < 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig2: NAP protects from cell death in a dose dependent manner following 2 hours of OGD insult, but not after additional 24 hours reperfusion. Primary neuronal cultures (5-6DIV) were subjected to 2 h of ischemic insult. Cell viability was evaluated using MTS viability assay. Data was normalized to % of control. Results are shown as mean ± SE. *Significantly different from OGD with no NAP, OGD + NAP10−15 M, OGD + NAP 10−13 M, OGD+NAP 10−11 M (3 independent experiments are summarized, ANOVA, with post hoc Scheffe, significant difference considered to be P ≤ 0.05). Using LSD post hoc, NAP 10−5 M (+), 10−7 M are significantly different from the OGD group (P < 0.05).
Mentions: Cell viability was evaluated following a 25-minute gassing period and an additional 2 hours of OGD. The results were calculated and expressed as % of the control group (Figure 2). Under this paradigm, ~70% cell death was observed. Treatment with NAP increased cell viability immediately following OGD (F = 17.667, df = 7, P < 0.001). Post hoc pairwise comparisons (LSD) indicated that NAP concentrations of 10−7 M and 10−5 M significantly protected against ischemia (Figure 2, P ≤ 0.05).

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