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.