Calcium-Sensing Receptor Antagonist NPS 2143 Restores Amyloid Precursor Protein Physiological Non-Amyloidogenic...

Physiological non-amyloidogenic processing (NAP) of amyloid precursor holoprotein (hAPP) by α-secretases (e.g., ADAM10) extracellularly sheds neurotrophic/neuroprotective soluble (s)APPα and precludes amyloid-β peptides (Aβs) production via β-secretase amyloidogenic processing (AP). Evidence exists that Aβs interact with calcium-sensing receptors (CaSRs) in human astrocytes and neurons, driving the overrelease of toxic Aβ₄₂/Aβ₄₂-os (oligomers), which is completely blocked by CaSR antagonist (calcilytic) NPS 2143. Here, we investigated the mechanisms underlying NPS 2143 beneficial effects in human astrocytes. Moreover, because Alzheimer's disease (AD) involves neuroinflammation, we examined whether NPS 2143 remained beneficial when both fibrillary (f)Aβ_25-35 and a microglial cytokine mixture (CMT) were present. Thus, hAPP NAP prevailed over AP in untreated astrocytes, which extracellularly shed all synthesized sAPPα while secreting basal Aβ_40/42 amounts. Conversely, fAβ_25-35 alone dramatically reduced sAPPα extracellular shedding while driving Aβ₄₂/Aβ₄₂-os oversecretion that CMT accelerated but not increased, despite a concurring hAPP overexpression. NPS 2143 promoted hAPP and ADAM10 translocation to the plasma membrane, thereby restoring sAPPα extracellular shedding and fully suppressing any Aβ₄₂/Aβ₄₂-os oversecretion, but left hAPP expression unaffected. Therefore, as anti-AD therapeutics calcilytics support neuronal viability by safeguarding astrocytes neurotrophic/neuroprotective sAPPα shedding, suppressing neurons and astrocytes Aβ₄₂/Aβ₄₂-os build-up/secretion, and remaining effective even under AD-typical neuroinflammatory conditions.