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Wnt-5a occludes Abeta oligomer-induced depression of glutamatergic transmission in hippocampal neurons.

Cerpa W, Farías GG, Godoy JA, Fuenzalida M, Bonansco C, Inestrosa NC - Mol Neurodegener (2010)

Bottom Line: Conversely, in the presence of Abeta oligomers the fEPSP and EPSCs amplitude decreased without modification of the PPF, while the postsynaptic scaffold protein (PSD-95) decreased as well.Co-perfusion of hippocampal slices with Wnt-5a and Abeta oligomers occludes against the synaptic depression of EPSCs as well as the reduction of PSD-95 clusters induced by Abeta oligomers in neuronal cultures.Taken together these results indicate that Wnt-5a and Abeta oligomers inversely modulate postsynaptic components.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centro de Envejecimiento y Regeneración (CARE), Centro de Regulación Celular y Patología "Joaquín V, Luco" (CRCP), MIFAB, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile. ninestrosa@bio.puc.cl.

ABSTRACT

Background: Soluble amyloid-beta (Abeta;) oligomers have been recognized to be early and key intermediates in Alzheimer's disease (AD)-related synaptic dysfunction. Abeta oligomers block hippocampal long-term potentiation (LTP) and impair rodent spatial memory. Wnt signaling plays an important role in neural development, including synaptic differentiation.

Results: We report here that the Wnt signaling activation prevents the synaptic damage triggered by Abeta oligomers. Electrophysiological analysis of Schaffer collaterals-CA1 glutamatergic synaptic transmission in hippocampal slices indicates that Wnt-5a increases the amplitude of field excitatory postsynaptic potentials (fEPSP) and both AMPA and NMDA components of the excitatory postsynaptic currents (EPSCs), without modifying the paired pulse facilitation (PPF). Conversely, in the presence of Abeta oligomers the fEPSP and EPSCs amplitude decreased without modification of the PPF, while the postsynaptic scaffold protein (PSD-95) decreased as well. Co-perfusion of hippocampal slices with Wnt-5a and Abeta oligomers occludes against the synaptic depression of EPSCs as well as the reduction of PSD-95 clusters induced by Abeta oligomers in neuronal cultures. Taken together these results indicate that Wnt-5a and Abeta oligomers inversely modulate postsynaptic components.

Conclusion: These results indicate that post-synaptic damage induced by Abeta oligomers in hippocampal neurons is prevented by non-canonical Wnt pathway activation.

No MeSH data available.


Related in: MedlinePlus

Aβ oligomers but not Aβ fibrils reduce the amplitude of fEPSP without affect the PPF. (A, left), Superimposed, average (10 sweeps) of fEPSPs before (a) and after 40 min of Aβ oligomers perfusion (b). (A, right), Superimposed, normalized (to R1), averaged (10 sweeps) fEPSPs evoked by paired pulse stimulation (100 ms delay) in control and in presence of Aβ oligomers (a+b), and time course of Aβ oligomer effects on fEPSPs. a) baseline, b) effect of Aβ oligomers and c) washout with ACSF. (B) Summary data of fEPSPs amplitude (left) and facilitation index in control and after Aβ oligomers treatment. (n = 5). (C) Superimposed, average (10 sweeps) of EPSCs evoked by single and paired pulse protocol, before (control, gray trace) and after 40 min of continued perfusion with Aβ oligomers (black trace). (D) Summary date of EPSCs amplitude (right) and facilitation index (left) in control and after Aβ oligomers treatment, respectively. (n = 5). (E) Superimposed, normalized (to R1), averaged (10 sweeps) fEPSPs evoked by paired pulse stimulation in control and in presence of Aβ fibrils. (F), Summary date of fEPSPs amplitude (left) and facilitation index (right) in control and after Aβ fibrils treatment (n = 4). Bar represents the mean ± SEM (*p < 0.05 Student's t test).
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Figure 2: Aβ oligomers but not Aβ fibrils reduce the amplitude of fEPSP without affect the PPF. (A, left), Superimposed, average (10 sweeps) of fEPSPs before (a) and after 40 min of Aβ oligomers perfusion (b). (A, right), Superimposed, normalized (to R1), averaged (10 sweeps) fEPSPs evoked by paired pulse stimulation (100 ms delay) in control and in presence of Aβ oligomers (a+b), and time course of Aβ oligomer effects on fEPSPs. a) baseline, b) effect of Aβ oligomers and c) washout with ACSF. (B) Summary data of fEPSPs amplitude (left) and facilitation index in control and after Aβ oligomers treatment. (n = 5). (C) Superimposed, average (10 sweeps) of EPSCs evoked by single and paired pulse protocol, before (control, gray trace) and after 40 min of continued perfusion with Aβ oligomers (black trace). (D) Summary date of EPSCs amplitude (right) and facilitation index (left) in control and after Aβ oligomers treatment, respectively. (n = 5). (E) Superimposed, normalized (to R1), averaged (10 sweeps) fEPSPs evoked by paired pulse stimulation in control and in presence of Aβ fibrils. (F), Summary date of fEPSPs amplitude (left) and facilitation index (right) in control and after Aβ fibrils treatment (n = 4). Bar represents the mean ± SEM (*p < 0.05 Student's t test).

Mentions: The current hypothesis on AD suggests that the neurotoxic Aβ specifically affects central synapses, in the form of Aβ oligomers [13,20]. Aβ oligomers associate with regions enriched in PSD-95 [20] and reduce the PSD-95 content in both hippocampal neurons [21] and APP transgenic animals [26]. We confirmed such studies and asked whether the Wnt-5a activation of the non-canonical pathway is able to overcome the neurotoxic effect of Aβ oligomers. To examine the effects of Aβ oligomers on excitatory glutamatergic transmission in the CA3-CA1 synapses, we recorded fEPSP. The fEPSP amplitude decreased after 20 min of adding 500 nM Aβ to the ACSF perfusion media (Figure 2A), without changing either the fV amplitude (data non-shown) or PPF (Figure 2A). This effect was partially reversible after 20 min of washout (Figure 2A). On average, Aβ induces a decrease of 47% ± 10 of fEPSP amplitude (p < 0.05; n = 5), (Figure 2B, left graph), without affecting facilitation. In fact, mean values of the PPF did not change significantly with respect to their controls in any of these conditions (Figure 2B, right graph). The hippocampal slices treated with Aβ fibrils (500 nM) showed no effects on either the amplitude or facilitation (Figure 2E and 2F). Additional file 1A shows an additional control, using reverse peptide Aβ42-1 amplitude of fEPSP. No changes with respect to the baseline were observed.


Wnt-5a occludes Abeta oligomer-induced depression of glutamatergic transmission in hippocampal neurons.

Cerpa W, Farías GG, Godoy JA, Fuenzalida M, Bonansco C, Inestrosa NC - Mol Neurodegener (2010)

Aβ oligomers but not Aβ fibrils reduce the amplitude of fEPSP without affect the PPF. (A, left), Superimposed, average (10 sweeps) of fEPSPs before (a) and after 40 min of Aβ oligomers perfusion (b). (A, right), Superimposed, normalized (to R1), averaged (10 sweeps) fEPSPs evoked by paired pulse stimulation (100 ms delay) in control and in presence of Aβ oligomers (a+b), and time course of Aβ oligomer effects on fEPSPs. a) baseline, b) effect of Aβ oligomers and c) washout with ACSF. (B) Summary data of fEPSPs amplitude (left) and facilitation index in control and after Aβ oligomers treatment. (n = 5). (C) Superimposed, average (10 sweeps) of EPSCs evoked by single and paired pulse protocol, before (control, gray trace) and after 40 min of continued perfusion with Aβ oligomers (black trace). (D) Summary date of EPSCs amplitude (right) and facilitation index (left) in control and after Aβ oligomers treatment, respectively. (n = 5). (E) Superimposed, normalized (to R1), averaged (10 sweeps) fEPSPs evoked by paired pulse stimulation in control and in presence of Aβ fibrils. (F), Summary date of fEPSPs amplitude (left) and facilitation index (right) in control and after Aβ fibrils treatment (n = 4). Bar represents the mean ± SEM (*p < 0.05 Student's t test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2823745&req=5

Figure 2: Aβ oligomers but not Aβ fibrils reduce the amplitude of fEPSP without affect the PPF. (A, left), Superimposed, average (10 sweeps) of fEPSPs before (a) and after 40 min of Aβ oligomers perfusion (b). (A, right), Superimposed, normalized (to R1), averaged (10 sweeps) fEPSPs evoked by paired pulse stimulation (100 ms delay) in control and in presence of Aβ oligomers (a+b), and time course of Aβ oligomer effects on fEPSPs. a) baseline, b) effect of Aβ oligomers and c) washout with ACSF. (B) Summary data of fEPSPs amplitude (left) and facilitation index in control and after Aβ oligomers treatment. (n = 5). (C) Superimposed, average (10 sweeps) of EPSCs evoked by single and paired pulse protocol, before (control, gray trace) and after 40 min of continued perfusion with Aβ oligomers (black trace). (D) Summary date of EPSCs amplitude (right) and facilitation index (left) in control and after Aβ oligomers treatment, respectively. (n = 5). (E) Superimposed, normalized (to R1), averaged (10 sweeps) fEPSPs evoked by paired pulse stimulation in control and in presence of Aβ fibrils. (F), Summary date of fEPSPs amplitude (left) and facilitation index (right) in control and after Aβ fibrils treatment (n = 4). Bar represents the mean ± SEM (*p < 0.05 Student's t test).
Mentions: The current hypothesis on AD suggests that the neurotoxic Aβ specifically affects central synapses, in the form of Aβ oligomers [13,20]. Aβ oligomers associate with regions enriched in PSD-95 [20] and reduce the PSD-95 content in both hippocampal neurons [21] and APP transgenic animals [26]. We confirmed such studies and asked whether the Wnt-5a activation of the non-canonical pathway is able to overcome the neurotoxic effect of Aβ oligomers. To examine the effects of Aβ oligomers on excitatory glutamatergic transmission in the CA3-CA1 synapses, we recorded fEPSP. The fEPSP amplitude decreased after 20 min of adding 500 nM Aβ to the ACSF perfusion media (Figure 2A), without changing either the fV amplitude (data non-shown) or PPF (Figure 2A). This effect was partially reversible after 20 min of washout (Figure 2A). On average, Aβ induces a decrease of 47% ± 10 of fEPSP amplitude (p < 0.05; n = 5), (Figure 2B, left graph), without affecting facilitation. In fact, mean values of the PPF did not change significantly with respect to their controls in any of these conditions (Figure 2B, right graph). The hippocampal slices treated with Aβ fibrils (500 nM) showed no effects on either the amplitude or facilitation (Figure 2E and 2F). Additional file 1A shows an additional control, using reverse peptide Aβ42-1 amplitude of fEPSP. No changes with respect to the baseline were observed.

Bottom Line: Conversely, in the presence of Abeta oligomers the fEPSP and EPSCs amplitude decreased without modification of the PPF, while the postsynaptic scaffold protein (PSD-95) decreased as well.Co-perfusion of hippocampal slices with Wnt-5a and Abeta oligomers occludes against the synaptic depression of EPSCs as well as the reduction of PSD-95 clusters induced by Abeta oligomers in neuronal cultures.Taken together these results indicate that Wnt-5a and Abeta oligomers inversely modulate postsynaptic components.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centro de Envejecimiento y Regeneración (CARE), Centro de Regulación Celular y Patología "Joaquín V, Luco" (CRCP), MIFAB, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile. ninestrosa@bio.puc.cl.

ABSTRACT

Background: Soluble amyloid-beta (Abeta;) oligomers have been recognized to be early and key intermediates in Alzheimer's disease (AD)-related synaptic dysfunction. Abeta oligomers block hippocampal long-term potentiation (LTP) and impair rodent spatial memory. Wnt signaling plays an important role in neural development, including synaptic differentiation.

Results: We report here that the Wnt signaling activation prevents the synaptic damage triggered by Abeta oligomers. Electrophysiological analysis of Schaffer collaterals-CA1 glutamatergic synaptic transmission in hippocampal slices indicates that Wnt-5a increases the amplitude of field excitatory postsynaptic potentials (fEPSP) and both AMPA and NMDA components of the excitatory postsynaptic currents (EPSCs), without modifying the paired pulse facilitation (PPF). Conversely, in the presence of Abeta oligomers the fEPSP and EPSCs amplitude decreased without modification of the PPF, while the postsynaptic scaffold protein (PSD-95) decreased as well. Co-perfusion of hippocampal slices with Wnt-5a and Abeta oligomers occludes against the synaptic depression of EPSCs as well as the reduction of PSD-95 clusters induced by Abeta oligomers in neuronal cultures. Taken together these results indicate that Wnt-5a and Abeta oligomers inversely modulate postsynaptic components.

Conclusion: These results indicate that post-synaptic damage induced by Abeta oligomers in hippocampal neurons is prevented by non-canonical Wnt pathway activation.

No MeSH data available.


Related in: MedlinePlus