Introduction: Astrocytes in Abeta42-hoarding human brains with Alzheimer’s disease (AD) upregulate vascular endothelial growth factor (VEGF)-A synthesis and accumulate Abeta42 intracellularly. Previously, we showed that fibrillary Abeta25-35 (a surrogate of Abeta42) induces VEGF-A synthesis and secretion and Abeta42 intracellular buildup in cultured early passage crebral normal adult astrocytes (NAHAs), both effects being mediated via the stabilization and nuclear translocation of HIF-1alpha/HIF-1beta complexes. Aims. Here, we investigated whether calcium-sensing receptor (CaSR) signaling plays any role in such Abeta25-35-elicited effects. Methods: NAHA cultures were treated with Abeta25-35 plus/minus the CaSR inhibitor NPS-89696 (a gift of Dr. E.F. Nemeth) and the Abeta42 contents of their protein extracts and HRE-DNA- HIF-1alpha/HIF-1beta complexes were analyzed via immunoblotting and EMSA, respectively. Results: trating NAHAs with Abeta25-35+NPS-89696 significantly reduced the de novo synthesis and accumulation of Abeta42 induced by Abeta25-35 alone. Exposure to Abeta25-35+NPS-89696 also hindered the stabilization and nuclear translocation of the HIF-1alpha/HIF-1beta complexes then elicited by Abeta25-35 itself. Conclusions: Our preliminary findings show that caSR signaling is importantly involved in Abeta42-production by Abeta25-35-exposed NAHAs. Previously, we showed that CaSR signaling is required also for nitric oxide synthase (NOS)-2 induction and NO hyperproduction by NAHAs treated with Abeta25-35 and/or combined proinflammatory cytokines. Therefore, the present results emphasize the notion that CaSR signaling plays a central role in the several trophic, proinflammatory and perhaps cytotoxic (release of produced Abeta42?) responses of the activated astrocytes in AD brains. Further, our findings suggest that administration CaSR inhibitors may be potentially beneficial in AD.
Abeta42 induction by its proxy, Abeta25-35, in cerebral normal human astrocytes requires calcium-sensing receptor (CaSR) signaling and nuclear translocation of HIF-1alpha/HIF-1beta complexes
DAL PRÀ, Ilaria Pierpaola;PACCHIANA, Raffaella;BONAFINI, Clara;ARMATO, Ubaldo;CHIARINI, Anna Maria
2011-01-01
Abstract
Introduction: Astrocytes in Abeta42-hoarding human brains with Alzheimer’s disease (AD) upregulate vascular endothelial growth factor (VEGF)-A synthesis and accumulate Abeta42 intracellularly. Previously, we showed that fibrillary Abeta25-35 (a surrogate of Abeta42) induces VEGF-A synthesis and secretion and Abeta42 intracellular buildup in cultured early passage crebral normal adult astrocytes (NAHAs), both effects being mediated via the stabilization and nuclear translocation of HIF-1alpha/HIF-1beta complexes. Aims. Here, we investigated whether calcium-sensing receptor (CaSR) signaling plays any role in such Abeta25-35-elicited effects. Methods: NAHA cultures were treated with Abeta25-35 plus/minus the CaSR inhibitor NPS-89696 (a gift of Dr. E.F. Nemeth) and the Abeta42 contents of their protein extracts and HRE-DNA- HIF-1alpha/HIF-1beta complexes were analyzed via immunoblotting and EMSA, respectively. Results: trating NAHAs with Abeta25-35+NPS-89696 significantly reduced the de novo synthesis and accumulation of Abeta42 induced by Abeta25-35 alone. Exposure to Abeta25-35+NPS-89696 also hindered the stabilization and nuclear translocation of the HIF-1alpha/HIF-1beta complexes then elicited by Abeta25-35 itself. Conclusions: Our preliminary findings show that caSR signaling is importantly involved in Abeta42-production by Abeta25-35-exposed NAHAs. Previously, we showed that CaSR signaling is required also for nitric oxide synthase (NOS)-2 induction and NO hyperproduction by NAHAs treated with Abeta25-35 and/or combined proinflammatory cytokines. Therefore, the present results emphasize the notion that CaSR signaling plays a central role in the several trophic, proinflammatory and perhaps cytotoxic (release of produced Abeta42?) responses of the activated astrocytes in AD brains. Further, our findings suggest that administration CaSR inhibitors may be potentially beneficial in AD.
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