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


ABSTRACT: The two main drivers of Alzheimer's disease (AD), amyloid-? (A?) 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 A?42 proxy, A?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?25-35 exposure, but remain unchanged in cells pre-treated for 30-min with NPS 2143 before adding A?25-35. Thus, our previous and present findings raise the unifying prospect that A?•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 A?42 oligomers, and (ii) the GSK-3?-mediated increased production of p-Tau oligomers which are next released extracellularly inside exosomes. Therefore, as calcilytics suppress both effects on A?42 and p-Tau metabolic handling, these highly selective antagonists of pathological A?•CaSR signaling would effectively halt AD's progressive spread preserving patients' cognition and life quality.

SUBMITTER: Chiarini A 

PROVIDER: S-EPMC5397492 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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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.

Chiarini Anna A   Armato Ubaldo U   Gardenal Emanuela E   Gui Li L   Dal Prà Ilaria I  

Frontiers in neuroscience 20170420


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 Aβ<sub>42</sub> proxy, Aβ<sub>25-35</sub>, which binds the calcium-sensing receptor (CaSR) and acti  ...[more]

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