Previously we showed that that exogenous fibrillary (f)Aβ25-35, (a surrogate of Ab42),induces the cultured early passage cerebral normal adult human astrocytes (NAHAs) to make and accumulate Aβ42. Here, we investigated whether calcium-sensing receptor (CaSR) signaling plays any role in such Ab25-35-elicited effects in NAHAs and also in HCN-1A neurons. Methods - NAHAs and HCN1A neurons were treated with fibrillar Aβ25-35 plus/minus the CaSR inhibitor NPS2143 or the CaSR stimulator (“calcimimetic”), NPS R568. The Aβ42 synthesis and secretion were analyzed via immunoblot, and ELISA, and immunofluorescence microscopy. Results - Here, we show that in the NAHAs and in HCN-1A neurons, fAβ25-35 stimulates Aβ42 production and secretion through a CaSR-mediated control of Aβ42 accumulation. A CaSR inhibitor, the “calcilytic” NPS 2143, significantly prevented fAβ25-35 -treated NAHAs from accumulating and secreting Aβ42 . And in line with the CaSR controlling Aβ42 accumulation, the CaSR stimulator (“calcimimetic”), NPS R568, did not by itself stimulate the NAHAs’s basal Aβ42 accumulation, but it significantly, though relatively weakly, increased Aβ42 secretion. Finally, fAβ25-35 also stimulated Aβ42 accumulation in, and secretion from, HCN-1A neurons. These neuronal responses were also totally suppressed by NPS 2143. Conclusions - These observations suggest that Aβs released from either neurons or their cradling astrocytes can, by inducing initially uninfected cells to make and secrete Aβs, start or further drive an amyloid ‘contagion’ along astrocyte-neuron networks to produce full-blown Alzheimer’s disease. Furthermore they suggest that a CaSR inhibitor like NPS2143 might be a novel therapeutic drug for Alzheimer’s disease by blocking such a “contagion”.

CaSR INHIBITOR NPS2143 PREVENTS AMYLOID-β42 ACCUMULATION AND SECRETION IN NORMAL ADULT HUMAN ASTROCYTES AND POSTNATAL HUMAN NEURONS

CHIARINI, Anna Maria;R. Pacchiana;ARMATO, Ubaldo;DAL PRÀ, Ilaria Pierpaola
2013

Abstract

Previously we showed that that exogenous fibrillary (f)Aβ25-35, (a surrogate of Ab42),induces the cultured early passage cerebral normal adult human astrocytes (NAHAs) to make and accumulate Aβ42. Here, we investigated whether calcium-sensing receptor (CaSR) signaling plays any role in such Ab25-35-elicited effects in NAHAs and also in HCN-1A neurons. Methods - NAHAs and HCN1A neurons were treated with fibrillar Aβ25-35 plus/minus the CaSR inhibitor NPS2143 or the CaSR stimulator (“calcimimetic”), NPS R568. The Aβ42 synthesis and secretion were analyzed via immunoblot, and ELISA, and immunofluorescence microscopy. Results - Here, we show that in the NAHAs and in HCN-1A neurons, fAβ25-35 stimulates Aβ42 production and secretion through a CaSR-mediated control of Aβ42 accumulation. A CaSR inhibitor, the “calcilytic” NPS 2143, significantly prevented fAβ25-35 -treated NAHAs from accumulating and secreting Aβ42 . And in line with the CaSR controlling Aβ42 accumulation, the CaSR stimulator (“calcimimetic”), NPS R568, did not by itself stimulate the NAHAs’s basal Aβ42 accumulation, but it significantly, though relatively weakly, increased Aβ42 secretion. Finally, fAβ25-35 also stimulated Aβ42 accumulation in, and secretion from, HCN-1A neurons. These neuronal responses were also totally suppressed by NPS 2143. Conclusions - These observations suggest that Aβs released from either neurons or their cradling astrocytes can, by inducing initially uninfected cells to make and secrete Aβs, start or further drive an amyloid ‘contagion’ along astrocyte-neuron networks to produce full-blown Alzheimer’s disease. Furthermore they suggest that a CaSR inhibitor like NPS2143 might be a novel therapeutic drug for Alzheimer’s disease by blocking such a “contagion”.
amyloid-beta; Calcium-sensing receptor; Human Astrocytes; NPS 2143
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11562/589753
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