Table 3.

Harmful effects Aβ•CaSR signaling elicits in human neurons and astrocytes.

Cell type	Stimulus	Pathological effect	Effect of adding calcilytic to Aβs	Effect of calcimimetic alone
Neurons, astrocytes	Aβ42-os Aβ fibrils	Overproduction and diffuse intracellular accumulation of endogenous Aβ42 monomers and Aβ42-os due to an increased β-S and γ-S activity and (likely) to decreases in Aβ proteolysis	Total suppression of intracellular accumulation of Aβ42 monomers and Aβ42-os due to increased Aβ-os proteolysis (no effect on increased β-S and γ-S activities)	No apparent intracellular accumulation of Aβs
Neurons, astrocytes	Aβ42-os Aβ fibrils	Concurrent Aβ40-os intracellular accumulation	Modest decrease of Aβ40-os intracellular accumulation	n. d.*
Neurons, astrocytes	Aβ42-os Aβ fibrils	Surplus secretion of Aβ42-os, but not of Aβ40-os, along the Golgi/trans-Golgi pathway and axons ⇒ extracellular Aβ42/Aβ40 ratios values shift to the cytotoxic range	Total suppression of surplus release of Aβ42-os along the Golgi/trans-Golgi pathway and axons, but increased release of Aβ40-os⇒ extracellular Aβ42/Aβ40 ratios values remain in the normal range (NPS 2143 by itself exerts no effect on basal Aβ42-os secretion)	Significant surplus secretion of Aβ42-os
Neurons	Aβ42-os Aβ fibrils	Slow yet progressive death by apoptosis of the human cortical neurons (in vivo this is the cause of cognitive decline; Nelson et al., 2012).	Neurons remain alive and kicking	n. d.
Astrocytes	Aβ42-os Aβ fibrils	NAHAs survive and keep making and releasing neuron-harming compounds (see below)	No apparent effect on survival	n. d.
Astrocytes	Aβ fibrils	Increased activity of the glycogen synthase kinase (GSK)-3β, one of the main Tau kinases (Armato et al., 2013b).	Total suppression of the surge of GSK-3β activity (Armato et al., 2013b).	n. d.
Astrocytes	Aβ42-os Aβ fibrils	Stabilization and nuclear translocation of the HIF-1α•HIF-1β transcription factor ⇒ expression of VEGF-A, APP, and BACE1 genes ⇒ heightened synthesis/secretion of VEGF-A and Aβ42/Aβ42-os	HIF-1α destabilization ⇒ deep yet transient decrease of nuclear HIF-1α•HIF-1β transfer ⇒ no surplus production/release of VEGF-A, APP, and Aβ42/Aβ42-os	n. d.
Astrocytes	Aβ42-os, Aβ fibrils	Significant yet transient surge of total CASR protein	Downregulation of total CaSR protein: modest and transient with NPS 2143 alone but fast, intense and persistent with Aβs + NPS 2143	No change in total CaSR protein
Astrocytes	Aβ42-os Aβ fibrils	Induction and MEK/ERK-dependent activation of GTP cyclohydrolase-1 (GCH1) ⇒ production of BH4 (tetrahydrobiopterin) ⇒ dimerization and activation of the concomitantly induced NO synthase (NOS)-2 ⇒ excess release of NO	Inactivation of GCH1 ⇒ lack of BH4 ⇒ no dimerization and activation of the concomitantly induced NO synthase (NOS)-2 ⇒ no overproduction of NO	n. d.

^*n.d., not determined.