Amyloid β-Exposed Human Astrocytes Overproduce Phospho-Tau and Overrelease It within Exosomes, Effects Suppressed by Calcilytic NPS 2143-Further Implications for Alzheimer's Therapy

The two main drivers of Alzheimer's disease (AD), amyloid-beta (4) and hyperphosphorylated Tau (p-Tau) oligomers, cooperatively accelerate AD progression, but a hot debate is still ongoing about which of the two appears first. Here we present preliminary evidence showing that Tau and p-Tau are expressed by untransformed cortical adult human astrocytes in culture and that exposure of such cells to an 442 proxy, A beta(25-35), which binds the calcium sensing receptor (CaSR) and activates its signaling, significantly increases intracellular p-Tau levels, an effect CaSR antagonist (calcilytic) NPS 2143 wholly hinders. The astrocytes also release both Tau and p-Tau by means of exosomes into the extracellular medium, an activity that could mediate p-Tau diffusion within the brain. Preliminary data also indicate that exosomal levels of p-Tau increase after A beta(25-35) exposure, but remain unchanged in cells pre-treated for 30-min with NPS 2143 before adding A beta(25-35). Thus, our previous and present findings raise the unifying prospect that A beta.CaSR signaling plays a crucial role in AD development and progression by simultaneously activating (i) the amyloidogenic processing of amyloid precursor holoprotein, whose upshot is a surplus production and secretion of 442 oligomers, and (ii) the GSK-3 beta-mediated increased production of p-Tau oligomers which are next released extracellularly inside exosomes. Therefore, as calcilytics suppress both effects on A beta(42) and p-Tau metabolic handling, these highly selective antagonists of pathological A beta.CaSR signaling would effectively