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- W2609957407 abstract "Abstract 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 Aβ 42 /Aβ 42 -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 Aβ 42 /Aβ 42 -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 Aβ 42 /Aβ 42 -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 Aβ 42 /Aβ 42 -os build-up/secretion, and remaining effective even under AD-typical neuroinflammatory conditions." @default.
- W2609957407 created "2017-05-05" @default.
- W2609957407 creator A5010830340 @default.
- W2609957407 creator A5041652591 @default.
- W2609957407 creator A5052407008 @default.
- W2609957407 creator A5061275176 @default.
- W2609957407 date "2017-04-28" @default.
- W2609957407 modified "2023-10-18" @default.
- W2609957407 title "Calcium-Sensing Receptor Antagonist NPS 2143 Restores Amyloid Precursor Protein Physiological Non-Amyloidogenic Processing in Aβ-Exposed Adult Human Astrocytes" @default.
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- W2609957407 doi "https://doi.org/10.1038/s41598-017-01215-3" @default.
- W2609957407 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/5430644" @default.
- W2609957407 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/28455519" @default.
- W2609957407 hasPublicationYear "2017" @default.
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