Curr Neuropharmacol. 2014 12(4):353-364. doi: 10.2174/1570159X12666140828214701.

Calcium-sensing receptors of human astrocyte-neuron teams: amyloid-β-driven mediators and therapeutic targets of Alzheimer’s disease.

Dal Prà I1, Chiarini A1, Pachiana R1, Gardenal E1, Chakravarthy B2, Whitfield JF2, Armato U1.

1Histology & Embryology Section, Department of Life & Reproduction Sciences, University of Verona Medical School, Verona, Venetia, Italy. 2National Research Council of Canada, Ottawa, Ontario, Canada.



It is generally assumed that the neuropathology of sporadic (late-onset or nonfamilial) Alzheimer’s disease (AD) is driven by the overproduction and spreading of first Amyloid-βx-42 (Aβ42) and later hyperphosphorylated (hp)-Tau oligomeric “infectious seeds”. Hitherto, only neurons were held to make and spread both oligomer types; astrocytes would just remove debris. However, we have recently shown that exogenous fibrillar or soluble Aβ peptides specifically bind and activate the Ca(2+)-sensing receptors (CaSRs) of untransformed human cortical adult astrocytes and postnatal neurons cultured in vitro driving them to produce, accrue, and secrete surplus endogenous Aβ42. While the Aβ-exposed neurons start dying, astrocytes survive and keep oversecreting Aβ42, nitric oxide (NO), and vascular endothelial growth factor (VEGF)-A. Thus astrocytes help neurons’ demise. Moreover, we have found that a highly selective allosteric CaSR agonist (“calcimimetic“), NPS R-568, mimics the just mentioned neurotoxic actions triggered by Aβ●CaSR signaling. Contrariwise, and most important, NPS 2143, a highly selective allosteric CaSR antagonist (“calcilytic“), fully suppresses all the Aβ●CaSR signaling-driven noxious actions. Altogether our findings suggest that the progression of AD neuropathology is promoted by unceasingly repeating cycles of accruing exogenous Aβ42 oligomers interacting with the CaSRs of swelling numbers of astrocyte-neuron teams thereby recruiting them to overrelease additional Aβ42 oligomers, VEGF-A, and NO. Calcilytics would beneficially break such Aβ●CaSR-driven vicious cycles and hence halt or at least slow the otherwise unstoppable spreading of AD neuropathology.

PMID: 25342943



The human brain is the most complex and functionally marvellous machine in our close galactic neighbourhood. It contains several intertwined networks of distinct elements, i.e. neurones interconnected via synapses; astrocytes linked via gap junctions; and vessels wrapped by astrocytic branches that locally dilate when neurones fire. Other cell types are scattered within such networks, i.e. oligodendrocytes producing axons swaddling myelin sheaths; microglia acting as immunological supervisors, debris scavengers, and sources of cytokines; and ependymal cells in part functioning as stem cells. Here we won’t even address the extremely complex connections among neurones, the ion-regulated action potentials mediating neurotransmitters release at synapses, and the metabolic modulation by astrocytes forming with groups of “client” neurones the so called “astrocyte-neuron teams (ANTs)”, that associate with vessels in neuro-vascular units (NVUs) (Fig. 1A). This sketchy view of human brain complexity, whose inner workings are still little known, underlies the mental functions of “cognition” and “conscience”, and justifies why the mechanisms underlying central nervous system (CNS) diseases, particularly the neurodegenerative ailments, Alzheimer’s disease (AD) included, have hitherto remained the object of hot controversies.

AD is the most common type of senile dementia affecting more than 60 million people worldwide, half of which in the Western world. Early onset familial AD (EOFAD), due to mutated genes (APP, PS1, PS2), is relatively rare (1-3% of all cases). Sporadic or late onset AD (LOAD) has a debated aetiology. EOFAD’s neuropathology starts diffusely in the brain and its clinical manifestations occur earlier. LOAD’s neuropathology begins focally in the lateral entorhinal cortex (LEC) of the temporal lobe and thence spreads to cognition-linked upper cerebral cortical areas (Fig. 1B). AD’s preclinical stage is asymptomatic and lasts from 20 to 45 years. AD’s second stage, the amnestic minor cognitive impairment or aMCI presents with worsening amnesias. After 2-6 years, AD’s clinical stage (6-12 years) is typified by progressive losses of cognition and coping capacity, and ends up in death. AD’s incidence has kept growing during last decades just as if it were an epidemic, but there is no evidence of a prion-like truly infectious agent causing it. Daunting AD features are an inexorable course and the present lack of any therapy that would alter, slow or stop human AD progression. Also daunting is the emotional stress endured by the family members and the healthcare costs. Concerning aetiology, in EOFAD cases, the autosomally dominant transmitted mutations cause the overproduction of amyloid-beta (Aβx-42) peptides, which form oligomers (Aβ-os) and fibrils that accumulate within the brain causing cytotoxic and inflammatory repercussions. At length, Aβ-os induce the accumulation of hyper-phosphorylated (p-)Tau oligomers (p-Tau-os), the second toxic AD drivers. Next, Aβ-os and p-Tau-os concur to destroy synapses, to elicit metabolic alterations, and ultimately to cause the “incommunicado” demise. This is the “amyloid cascade hypothesis” that applies well to EOFAD cases but, according to some, does not to LOAD patients, to which should instead apply the “Tau-first hypothesis”. The latter indicates as the first AD toxic driver p-Tau-os, whose spread causes neurotoxicity and Aβ-os accumulation too. However, according to others, ageing-linked dysmetabolism, diabetes, and cerebral angiopathy prejudice Aβx-42 brain clearance thereby inducing its accumulation, Aβ-os formation, etc. This view applies the “amyloid cascade hypothesis” even to LOAD cases. Obviously, there is no shortage of theories concerning LOAD aetiopathogenesis: here we mentioned only the main ones. Notably, these are neuronocentric views assigning a major role to neurones, while considering astroglial cells as bystanders or debris scavengers.

However, brain evolution has seen in mammals an astounding development of astroglia climaxing in the human brain cerebral cortex. Human astrocytes are multirole players, i.e. neurones’ metabolic “nurses”, synapses’ guardians, neurotransmitters’ recyclers, calcium signallers, tissue harm reactors, gliotransmitters’, proinflammatory cytokines’, vascular endothelial growth factor (VEGF-A)’s, and nitric oxide (NO)’s secretors, and NVUs’ intermediaries (Fig. 1A). Our AD-relevant findings have shown that, once exposed to pathological levels of exogenous Aβ-os, cortical nontumorigenic adult human astrocytes share with human cortical postnatal neurones the capability to synthesise and secrete (besides NO and VEGF-A) neurotoxic amounts of Aβ-os. Soon thereafter, neurones start dying. These effects happen because Aβ-os specifically bind the astrocytes and neurones’ Ca(2+)-sensing receptors (CaSRs) and activate their manifold signalling pathways. Therefore, given their high numbers, human astrocytes can significantly increase brain’s Aβ-os burden and hence concur as co-primary partners to AD pathogenesis. In fact, the Aβ-os/CaSR-elicited surplus release of newly synthesised (endogenous) Aβ-os causes the latter to spread, bind, and activate the CaSRs of adjacent neurones and astrocytes. Thus, Aβ-os can self-induce themselves by interacting with the CaSRs of both astrocytes and neurones—a feature that could sustain the escalating spread of AD neuropathology in humans. Hence, our findings harbour a therapeutic potential. Notably, we showed that adding a calcilytic, i.e. a highly selective and specific CaSR antagonist, can stop the Aβ-osCaSR-triggered surplus secretion of de novo synthesised Aβ-os by cortical human astrocytes and neurones. In addition, the calcilytic does prevent human neurones’ demise caused by pathological Aβ-os levels. Hence, based on findings gained from experimentally exploiting (with prior Bioethical Committee approval) untransformed human cortical astrocytes and neurones, we surmise that calcilytics entertain the potential to halt the slow spread of AD neuropathology and hence AD clinical progression in vivo. Previously, calcilytics were studied as anti-osteoporosis agents but failed because they induced a lengthy secretion of parathyroid hormone (PTH) that co-stimulated bone production and bone lysis. Now, we propose that novel PTH-short-stimulating calcilytics be employed as AD-halting agents to be administered at an early stage (e.g., aMCI) when cognitive abilities are mostly preserved. Clearly, further studies are required to validate our proposal. Thus, dysfunctional hyperactivities of the CaSRs may underlie the parallel increases, already noted in previous decades, in the incidence of osteoporosis and neurodegenerative disorders, AD included, in humans.


Armato Fig. 1 for alzher

Fig. 1. (A) Schematic representation of a neurovascular unit (NVU) showing an astrocyte (astro) acting as a bridge between a neurone and a cerebral vessel. Astrocytes also enwrap and protect synapses (not shown). Their closeness to neurones justifying the concept of “astrocyte-neurons teams (ANTs)” allows the Aβ-os released from neurones to bind and activate astrocytes’ CaSRs thereby triggering the release of newly produced Aβ-os from astrocytes that interact with the CaSRs of adjacent neurones and astrocytes. This self-inducing and self-sustaining mechanism would promote the spread of AD neuropathology and AD progression. Part of a second astrocyte (astro), a microglial cell (micro), and an oligodendrocyte (olig) are also depicted. (B) Illustration of the progressive spreading (in darker grey colour) of AD neuropathology from the temporal lobe’s LEC to upper cerebral cortex areas related to cognition. In each instance, the medial face of a right hemisphere is shown, with its frontal pole on the left side.



  1. Armato U, Chiarini A, Chakravarthy B, Chioffi F, Pacchiana R, Colarusso E, Whitfield JF, Dal Prà I. Calcium-sensing receptor antagonist (calcilytic) NPS 2143 specifically blocks the increased secretion of endogenous Aβ42 prompted by exogenous fibrillary or soluble Aβ25-35 in human cortical astrocytes and neurons-therapeutic relevance to Alzheimer’s disease. Biochim Biophys Acta. 2013 Oct; 1832(10):1634-52. doi: 10.1016/j.bbadis. 2013.04.020. PMID: 23628734.
  2. Dal Prà I, Chiarini A, Gui L, Chakravarthy B, Pacchiana R, Gardenal E, Whitfield JF, Armato U. Do astrocytes collaborate with neurons in spreading the “infectious” aβ and Tau drivers of Alzheimer’s disease? Neuroscientist. 2015 Feb; 21(1):9-29. doi: 10.1177/1073858414529828. PMID: 24740577.



Ubaldo Armato, MD

Professor & Senior Investigator Scientist, University of Verona Medical School, 8 Strada Le Grazie, 37134 Verona, Venetia, Italy.

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