Calcium-Sensing Receptors of Human Neural Cells Play Crucial Roles in Alzheimer's Disease

Abstract

In aged subjects, late-onset Alzheimer's disease (LOAD) starts in the lateral entorhinal allocortex where a failure of clearance mechanisms triggers an accumulation of neurotoxic amyloid-β42 oligomers (Aβ42-os). In neurons and astrocytes, Aβ42-os enhance the transcription of Aβ precursor protein (APP) and β-secretase/BACE1 genes. Thus, by acting together with γ-secretase, the surpluses of APP and BACE1 amplify the endogenous production of Aβ42-os which pile up, damage mitochondria, and are oversecreted. At the plasmalemma, exogenous Aβ42-os bind neurons' and astrocytes' calcium-sensing receptors (CaSRs) activating a set of intracellular signaling pathways which upkeep Aβ42-os intracellular accumulation and oversecretion by hindering Aβ42-os proteolysis. In addition, Aβ42-os accumulating in the extracellular milieu spread and reach mounting numbers of adjacent and remoter teams of neurons and astrocytes which in turn are recruited, again via Aβ42-os•CaSR-governed mechanisms, to produce and release additional Aβ42-os amounts. This relentless self-sustaining mechanism drives AD progression toward upper cortical areas. Later on accumulating Aβ42-os elicit the advent of hyperphosphorylated (p)-Tau oligomers which acting together with Aβ42-os and other glial neurotoxins cooperatively destroy wider and wider cognition-related cortical areas. In parallel, Aβ42-os•CaSR signals also elicit an excess production and secretion of nitric oxide and vascular endothelial growth factor-A from astrocytes, of Aβ42-os and myelin basic protein from oligodendrocytes, and of proinflammatory cytokines, nitric oxide and (likely) Aβ42-os from microglia. Activated astrocytes and microglia survive the toxic onslaught, whereas neurons and oligodendrocytes increasingly die. However, we have shown that highly selective allosteric CaSR antagonists (calcilytics), like NPS 2143 and NPS 89626, efficiently suppress all the neurotoxic effects Aβ42-os•CaSR signaling drives in cultured cortical untransformed human neurons and astrocytes. In fact, calcilytics increase Aβ42 proteolysis and discontinue the oversecretion of Aβ42-os, nitric oxide, and vascular endothelial growth factor-A from both astrocytes and neurons. Seemingly, calcilytics would also benefit the other types of glial cells and cerebrovascular cells otherwise damaged by the effects of Aβ42-os•CaSR signaling. Thus, given at amnestic minor cognitive impairment (aMCI) or initial symptomatic stages, calcilytics could prevent or terminate the propagation of LOAD neuropathology and preserve human neurons' viability and hence patients' cognitive abilities.

Amyloid β‐induced astrogliosis is mediated by β1‐integrin via NADPH oxidase 2 in Alzheimer's disease

“…The primary goal of the current study was to unmask the molecular players that contribute to the dysregulation of astrocyte physiology during AD progression. It is well known in these cells that Aβ promotes calcium imbalance by mechanisms that involve endoplasmic reticulum activation and stress (Alberdi et al ., ), regulation of L‐type calcium channel expression (Daschil et al ., ), and calcium‐sensing receptor activation (Chiarini et al ., ). In addition to these activities, the glial cellular stress generated via NOX enzyme activities may contribute to leading glia‐mediated neurotoxicity in AD (Angelova & Abramov, ).…”

Calcilytic NPS 2143 Reduces Amyloid Secretion and Increases sAβPPα Release from PSEN1 Mutant iPSC-Derived Neurons

“…In this regard, reports indicated the calcium sensing receptor (CaSR) as a potential key player in AD [24][25][26]. CaSR is a G-protein coupled receptor (GPCR) mainly expressed in the parathyroid glands where it exerts its primary role in sensing extracellular Ca 2+ levels and in regulating parathyroid hormone secretion accordingly [27].…”

Platelet‐derived growth factor up‐regulates Ca 2+ ‐sensing receptors in idiopathic pulmonary arterial hypertension

“…The PDGF-mediated activation of STAT1/3 has been demonstrated to up-regulate the gene expression of c-Jun and AP1 transcription activators, which are involved in PASMC growth. On the other hand, previous studies reported that CaSR expression is regulated by STAT1/3 in addition to proinflammatory cytokines such as IL-1b and IL-6 (19,24). STAT1/3 modulate the P1 activity of CaSR via the STAT element in exon 1A (19).…”