Calcium-sensing receptor antagonist (calcilytic) NPS 2143 prevents the increased secretion of endogenous Aβ42 prompted by exogenous Aβ25-35 in human cortical astrocytes and neurons

Previously we showed that adding fibrillar (f)Aβ25–35, a proxy retaining the main physical and biological features of Aβ42, stimulated untransformed astrocytes isolated from fragments of the adult human temporal lobe cerebral cortex to synthesize and accumulate large amounts of endogenous Aβ42 and its oligomers, while releasing excess amounts of nitric oxide (NO) and of vascular endothelial growth factor (VEGF-A) [1,2]. Here, we investigated the effects of fAβ25-35 and soluble (s)Aβ25-35 on Aβ42 and Aβ40 accumulation/secretion by human cortical astrocytes and HCN- 1A neurons. And since the calcium-sensing receptor (CaSR) binds Aβs, we studied whether calcium-CaSR signaling plays any role in such Aβ25-35-elicited effects and their modulation by NPS 2143, a CaSR allosteric antagonist (calcilytic). The fAβ25- 35-exposed astrocytes and neurons produced, accumulated, and secreted increased amounts of Aβ42, while Aβ40 also accrued but its secretion was unchanged. Accordingly, secreted Aβ42/Aβ40 ratio values rose for astrocytes and neurons but NPS 2143 addition specifically suppressed the fAβ25-35-elicited surges of endogenous Aβ42 secretion by both cell types. Therefore, NPS 2143 addition always kept Aβ42/Aβ40 values to baseline or lower levels. Compared to fAβ25-35, sAβ25-35 also stimulated Aβ42 secretion by astrocytes and neurons and NPS 2143 specifically and wholly suppressed this effect. Therefore, since NPS 2143 prevents any Aβ/CaSR-induced surplus secretion of endogenous Aβ42 and hence further vicious cycles of Aβ self-induction/secretion/ spreading, the CaSR antagonists like NPS 2143 might be novel therapeutic drugs for Alzheimer’s disease.