Calcium-Sensing Receptors of Human Astrocyte-Neuron Teams: Amyloid-β-Driven Mediators and Therapeutic Targets of Alzheimer’s Disease

Abstract

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 Ca2+-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

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

“…Under conditions of acute or chronic hypoxia, or during LOAD or when exposed to exogenous Aβs, APP levels and both β–S and γ–S activities raise significantly thereby increasing Aβs production and release (Perez et al, 2010 ; Dal Prà et al, 2011 , 2014a , b ; Takami and Funamoto, 2012 ). This might be due to Aβ 42 -os entering the nuclei and binding Aβ-interacting domains (AβIDs) in the APP and β– S genes promoters sequences causing their transcriptional activation (Bailey et al, 2011 ; Maloney and Lahiri, 2011 ; Barucker et al, 2014 ).…”

“…Yet, once bound to Aβs some of the receptors did undergo internalization and accumulated intracellularly (Kam et al, 2014 ; Jarosz-Griffiths et al, 2016 ). For example, highly specific soluble Aβ-os•CaSR complexes were shown to gather together and form patches at the plasma membrane of NAHAs prior to be internalized (Dal Prà et al, 2014a , b , 2015b ). Conversely, most of the fibrillar Aβ•CaSR complexes could not be internalized because of intrinsic mechanical hindrances and their persistent signaling likely altered crucial cellular functions with noxious and/or lethal consequences.…”

“…Besides upholding local ionic homeostasis, brain cells' CaSRs modulate the proliferation, differentiation, and migration of neurons and oligodendrocytes during development; axonal and dendritic growth; axons myelination; neurons' and glial membrane excitability; olfactory and gustatory signal integration; presynaptic external Ca 2+ signaling at neocortex nerve terminals; synaptic plasticity; and neurotransmission during perinatal and adult life. Importantly, an altered expression and/or dysfunction of the CaSR, as observed in CNS diseases like AD and ischemia/hypoxia/stroke, also deeply affects CaSR-dependent neurophysiological processes (Figure 2 ) (Chattopadhyay et al, 1999 ; Vizard et al, 2008 ; Bandyopadhyay et al, 2010 ; Chen et al, 2010 ; Armato et al, 2012 , 2013a ; Ruat and Traiffort, 2013 ; Kim et al, 2014 ; Dal Prà et al, 2014a , b , 2015a ; Bai et al, 2015 ; Noh et al, 2015 ; Tharmalingam et al, 2016 ).…”

“…Subsequently, the formation of Aβs•CaSR complexes and their endocytosis was shown to occur in NAHAs by using the highly specific in situ proximity ligation assay (Dal Prà et al, 2014a , b , 2015b ). As aforesaid, such Aβs•CaSR complexes elicited a surplus production and secretion of Aβ 42 and Aβ 42 -os from cortical NAHAs and HCN-1A neurons (Armato et al, 2013a ).…”

Calcium-dependent molecular fMRI using a magnetic nanosensor

“…Behaviorally-relevant extracellular calcium changes can last for tens of seconds, with activity-dependent fluctuations that push [Ca 2+ ] o to concentrations as low as 100 μM 6 ; even slower variations of [Ca 2+ ] o correlate to sleep-wake transitions 10 . Abnormal Ca 2+ signaling has been implicated in numerous brain disorders, such as epilepsy and Alzheimer’s disease 11 , but despite its significance in normal and pathological brain function, basic questions about the phenomenology and mechanisms associated with extracellular Ca 2+ remain.…”