Abstract
The two main drivers of Alzheimer's disease (AD), amyloid-β (Aβ) 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 Aβ42 proxy, Aβ25−35, 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 Aβ25−35 exposure, but remain unchanged in cells pre-treated for 30-min with NPS 2143 before adding Aβ25−35. Thus, our previous and present findings raise the unifying prospect that Aβ•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 Aβ42 oligomers, and (ii) the GSK-3β-mediated increased production of p-Tau oligomers which are next released extracellularly inside exosomes. Therefore, as calcilytics suppress both effects on Aβ42 and p-Tau metabolic handling, these highly selective antagonists of pathological Aβ•CaSR signaling would effectively halt AD's progressive spread preserving patients' cognition and life quality.
Highlights
Late onset Alzheimer’s disease (LOAD) is the most common dementia afflicting millions of people worldwide
The p-Tyr216/p-Ser9 ratio values and glycogen synthase kinase (GSK)-3β activity increase up to 8-fold in fAβ25−35-exposed astrocytes (Figure 1D) as the latter does in hippocampal neurons (Takashima et al, 1998)
A 30 min pre-treatment with calcilytic NPS 2143 totally quells the raise in fAβ25−35-induced p-Tyr216GSK-3β levels; contrariwise, the p-Tyr216GSK-3β/total GSK-3 ratio values fall below control values (Figures 1A,B)
Summary
Late onset (non-familial) Alzheimer’s disease (LOAD) is the most common dementia afflicting millions of people worldwide It is characterized by extracellular deposits of fibrillar Aβ42 peptides (neuritic or senile plaques) and by intracellular pre-tangles and neurofibrillary tangles (NFTs) of phosphorylated Tau (p-Tau) protein (Selkoe, 2008a,b; Grinberg et al, 2009; Braak et al, 2011; Attems et al, 2012; Elobeid et al, 2012; Braak and Del Tredici, 2013). Neurons uptake exogenous Tau proteins via endocytosis into the somatodentritic compartments or axon termini from which they are conveyed to various cell sites (Wu et al, 2013) These data indicated the urgent need to reassess the relationship between Aβ peptides exposure and p-Tau production and release in adult human astrocytes and neurons. Details on materials and methods we used are in Supplementary Materials
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