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

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-β(x-42) (Aβ(42)) and later hyperphosphorylated (hp)-Tau oligomeric “infectious seeds”. Hitherto, only neurons were held to m...

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Detalles Bibliográficos
Autores principales: Dal Prà, I, Chiarini, A, Pacchiana, R, Gardenal, E, Chakravarthy, B, Whitfield, J. F, Armato, U
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Bentham Science Publishers 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207075/
https://www.ncbi.nlm.nih.gov/pubmed/25342943
http://dx.doi.org/10.2174/1570159X12666140828214701
Descripción
Sumario: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-β(x-42) (Aβ(42)) 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 Aβ(42). While the Aβ-exposed neurons start dying, astrocytes survive and keep oversecreting Aβ(42), 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 Aβ(42) oligomers interacting with the CaSRs of swelling numbers of astrocyte-neuron teams thereby recruiting them to overrelease additional Aβ(42) 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