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Andrographolide reduces cognitive impairment in young and mature AβPPswe/PS-1 mice.

Serrano FG, Tapia-Rojas C, Carvajal FJ, Hancke J, Cerpa W, Inestrosa NC - Mol Neurodegener (2014)

Bottom Line: This impairment includes synaptic failure associated with the loss of synaptic proteins that contribute to AD progression.Additionally, we observed that ANDRO recovers spatial memory functions that correlate with protecting synaptic plasticity and synaptic proteins in two different age groups.Our results suggest that ANDRO could be used in a potential preventive therapy during AD progression.

View Article: PubMed Central - PubMed

Affiliation: Centro de Envejecimiento y Regeneración (CARE), Santiago, Chile. faserran@uc.cl.

ABSTRACT
Alzheimer's disease (AD) is a neurodegenerative disorder in which the amyloid-β (Aβ) oligomers are a key factor in synaptic impairment and in spatial memory decline associated with neuronal dysfunction. This impairment includes synaptic failure associated with the loss of synaptic proteins that contribute to AD progression. Interestingly, the use of natural compounds is an emergent conceptual strategy in the search for drugs with therapeutic potentials for treating neurodegenerative disorders. In the present study, we report that andrographolide (ANDRO), which is a labdane diterpene extracted from Andrographis paniculata, increases slope of field excitatory postsynaptic potentials (fEPSP) in the CA1 region of hippocampal slices and inhibits long-term depression (LTD), protecting the long-term potentiation (LTP) against the damage induced by Aβ oligomers in vitro, most likely by inhibiting glycogen synthase kinase-3β (GSK-3β). Additionally, ANDRO prevents changes in neuropathology in two different age groups (7- and 12-month-old mice) of an AβPPswe/PS-1 Alzheimer's model. ANDRO reduces the Aβ levels, changing the ontogeny of amyloid plaques in hippocampi and cortices in 7-month-old mice, and reduces tau phosphorylation around the Aβ oligomeric species in both age groups. Additionally, we observed that ANDRO recovers spatial memory functions that correlate with protecting synaptic plasticity and synaptic proteins in two different age groups. Our results suggest that ANDRO could be used in a potential preventive therapy during AD progression.

No MeSH data available.


Related in: MedlinePlus

ANDRO increases the synaptic transmission and protect the LTP against the Aβ oligomers in vitro. (a) fEPSP recordings in the presence of 10 μM ANDRO. (b) Plot of paired pulse facilitation (PPF) in the presence or absence of ANDRO. Inset shows representative recordings. Bars represent the mean ± SE from 7 different slices, *p < 0.05. (c) fEPSP amplitude induced by the input–output protocol treated with ANDRO (black circle) or with vehicle solution (ACSF, white circles). (d) Fiber volley (FV) amplitude induced by the input–output protocol treated with ANDRO (black circle) or with vehicle solution (white circles). (e) Hippocampal slices were exposed to ANDRO, and LTP was induced. The arrow indicates LTP induction by TBS, and the plot shows the fEPSP slope at different times. (f) Hippocampal slices were exposed to Aβ oligomers (1 μM); arrow indicates the time of TBS and the plot show the fEPSP slope at different times. (g) Hippocampal slices were exposed to ANDRO (10 μM) in the presences of Aβ oligomers (1 μM), arrow indicates the time of TBS and the plot show the fEPSP slope at different times. (h) Plot of fEPSP slope changes, in the presence or absence of ANDRO plus Aβ oligomers. The inset shows representative recordings. The dots and bars represent the mean ± SE from 7 different slices, *p < 0.05. Three animals were used per experimental group. Data are presented as mean ± SEM. Statistical differences were calculated by Student’s t test, followed by Dunnett’s post hoc test. Asterisks indicate statistically significant differences (*p < 0.05). Statistical significant differences in in vitro experiments of ANDRO and Aβ oligomers were calculated by one-way ANOVA, followed by Bonferroni’s post hoc test.
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Fig5: ANDRO increases the synaptic transmission and protect the LTP against the Aβ oligomers in vitro. (a) fEPSP recordings in the presence of 10 μM ANDRO. (b) Plot of paired pulse facilitation (PPF) in the presence or absence of ANDRO. Inset shows representative recordings. Bars represent the mean ± SE from 7 different slices, *p < 0.05. (c) fEPSP amplitude induced by the input–output protocol treated with ANDRO (black circle) or with vehicle solution (ACSF, white circles). (d) Fiber volley (FV) amplitude induced by the input–output protocol treated with ANDRO (black circle) or with vehicle solution (white circles). (e) Hippocampal slices were exposed to ANDRO, and LTP was induced. The arrow indicates LTP induction by TBS, and the plot shows the fEPSP slope at different times. (f) Hippocampal slices were exposed to Aβ oligomers (1 μM); arrow indicates the time of TBS and the plot show the fEPSP slope at different times. (g) Hippocampal slices were exposed to ANDRO (10 μM) in the presences of Aβ oligomers (1 μM), arrow indicates the time of TBS and the plot show the fEPSP slope at different times. (h) Plot of fEPSP slope changes, in the presence or absence of ANDRO plus Aβ oligomers. The inset shows representative recordings. The dots and bars represent the mean ± SE from 7 different slices, *p < 0.05. Three animals were used per experimental group. Data are presented as mean ± SEM. Statistical differences were calculated by Student’s t test, followed by Dunnett’s post hoc test. Asterisks indicate statistically significant differences (*p < 0.05). Statistical significant differences in in vitro experiments of ANDRO and Aβ oligomers were calculated by one-way ANOVA, followed by Bonferroni’s post hoc test.

Mentions: We decided to evaluate the role of ANDRO in synaptic transmission in vitro. For this evaluation, we incubated hippocampal slices from WT mice from 2 month with 10 μM ANDRO for 30 min and observed an increase in the slope of fEPSP (Figure 5a) [F(3,5) = 49.39, p < 0,05]. To investigate whether this effect corresponded to a pre- or postsynaptic effect, the PPF index was determined [39]. The results indicated that ANDRO did not change the facilitation index (Figure 5b) [F(4,4) = 35.15, p = NS], indicating that the response did not depend on presynaptic modulation and is most likely mediated by a postsynaptic effect. Interestingly, we performed input–output experiments to analyze synaptic strength; however, we did not observe any effects on the basal transmission when the samples were exposed to ANDRO (Figure 5c and d).Figure 5


Andrographolide reduces cognitive impairment in young and mature AβPPswe/PS-1 mice.

Serrano FG, Tapia-Rojas C, Carvajal FJ, Hancke J, Cerpa W, Inestrosa NC - Mol Neurodegener (2014)

ANDRO increases the synaptic transmission and protect the LTP against the Aβ oligomers in vitro. (a) fEPSP recordings in the presence of 10 μM ANDRO. (b) Plot of paired pulse facilitation (PPF) in the presence or absence of ANDRO. Inset shows representative recordings. Bars represent the mean ± SE from 7 different slices, *p < 0.05. (c) fEPSP amplitude induced by the input–output protocol treated with ANDRO (black circle) or with vehicle solution (ACSF, white circles). (d) Fiber volley (FV) amplitude induced by the input–output protocol treated with ANDRO (black circle) or with vehicle solution (white circles). (e) Hippocampal slices were exposed to ANDRO, and LTP was induced. The arrow indicates LTP induction by TBS, and the plot shows the fEPSP slope at different times. (f) Hippocampal slices were exposed to Aβ oligomers (1 μM); arrow indicates the time of TBS and the plot show the fEPSP slope at different times. (g) Hippocampal slices were exposed to ANDRO (10 μM) in the presences of Aβ oligomers (1 μM), arrow indicates the time of TBS and the plot show the fEPSP slope at different times. (h) Plot of fEPSP slope changes, in the presence or absence of ANDRO plus Aβ oligomers. The inset shows representative recordings. The dots and bars represent the mean ± SE from 7 different slices, *p < 0.05. Three animals were used per experimental group. Data are presented as mean ± SEM. Statistical differences were calculated by Student’s t test, followed by Dunnett’s post hoc test. Asterisks indicate statistically significant differences (*p < 0.05). Statistical significant differences in in vitro experiments of ANDRO and Aβ oligomers were calculated by one-way ANOVA, followed by Bonferroni’s post hoc test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Fig5: ANDRO increases the synaptic transmission and protect the LTP against the Aβ oligomers in vitro. (a) fEPSP recordings in the presence of 10 μM ANDRO. (b) Plot of paired pulse facilitation (PPF) in the presence or absence of ANDRO. Inset shows representative recordings. Bars represent the mean ± SE from 7 different slices, *p < 0.05. (c) fEPSP amplitude induced by the input–output protocol treated with ANDRO (black circle) or with vehicle solution (ACSF, white circles). (d) Fiber volley (FV) amplitude induced by the input–output protocol treated with ANDRO (black circle) or with vehicle solution (white circles). (e) Hippocampal slices were exposed to ANDRO, and LTP was induced. The arrow indicates LTP induction by TBS, and the plot shows the fEPSP slope at different times. (f) Hippocampal slices were exposed to Aβ oligomers (1 μM); arrow indicates the time of TBS and the plot show the fEPSP slope at different times. (g) Hippocampal slices were exposed to ANDRO (10 μM) in the presences of Aβ oligomers (1 μM), arrow indicates the time of TBS and the plot show the fEPSP slope at different times. (h) Plot of fEPSP slope changes, in the presence or absence of ANDRO plus Aβ oligomers. The inset shows representative recordings. The dots and bars represent the mean ± SE from 7 different slices, *p < 0.05. Three animals were used per experimental group. Data are presented as mean ± SEM. Statistical differences were calculated by Student’s t test, followed by Dunnett’s post hoc test. Asterisks indicate statistically significant differences (*p < 0.05). Statistical significant differences in in vitro experiments of ANDRO and Aβ oligomers were calculated by one-way ANOVA, followed by Bonferroni’s post hoc test.
Mentions: We decided to evaluate the role of ANDRO in synaptic transmission in vitro. For this evaluation, we incubated hippocampal slices from WT mice from 2 month with 10 μM ANDRO for 30 min and observed an increase in the slope of fEPSP (Figure 5a) [F(3,5) = 49.39, p < 0,05]. To investigate whether this effect corresponded to a pre- or postsynaptic effect, the PPF index was determined [39]. The results indicated that ANDRO did not change the facilitation index (Figure 5b) [F(4,4) = 35.15, p = NS], indicating that the response did not depend on presynaptic modulation and is most likely mediated by a postsynaptic effect. Interestingly, we performed input–output experiments to analyze synaptic strength; however, we did not observe any effects on the basal transmission when the samples were exposed to ANDRO (Figure 5c and d).Figure 5

Bottom Line: This impairment includes synaptic failure associated with the loss of synaptic proteins that contribute to AD progression.Additionally, we observed that ANDRO recovers spatial memory functions that correlate with protecting synaptic plasticity and synaptic proteins in two different age groups.Our results suggest that ANDRO could be used in a potential preventive therapy during AD progression.

View Article: PubMed Central - PubMed

Affiliation: Centro de Envejecimiento y Regeneración (CARE), Santiago, Chile. faserran@uc.cl.

ABSTRACT
Alzheimer's disease (AD) is a neurodegenerative disorder in which the amyloid-β (Aβ) oligomers are a key factor in synaptic impairment and in spatial memory decline associated with neuronal dysfunction. This impairment includes synaptic failure associated with the loss of synaptic proteins that contribute to AD progression. Interestingly, the use of natural compounds is an emergent conceptual strategy in the search for drugs with therapeutic potentials for treating neurodegenerative disorders. In the present study, we report that andrographolide (ANDRO), which is a labdane diterpene extracted from Andrographis paniculata, increases slope of field excitatory postsynaptic potentials (fEPSP) in the CA1 region of hippocampal slices and inhibits long-term depression (LTD), protecting the long-term potentiation (LTP) against the damage induced by Aβ oligomers in vitro, most likely by inhibiting glycogen synthase kinase-3β (GSK-3β). Additionally, ANDRO prevents changes in neuropathology in two different age groups (7- and 12-month-old mice) of an AβPPswe/PS-1 Alzheimer's model. ANDRO reduces the Aβ levels, changing the ontogeny of amyloid plaques in hippocampi and cortices in 7-month-old mice, and reduces tau phosphorylation around the Aβ oligomeric species in both age groups. Additionally, we observed that ANDRO recovers spatial memory functions that correlate with protecting synaptic plasticity and synaptic proteins in two different age groups. Our results suggest that ANDRO could be used in a potential preventive therapy during AD progression.

No MeSH data available.


Related in: MedlinePlus