Dataset Information

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.

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, Aβ_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 Aβ_25-35 exposure, but remain unchanged in cells pre-treated for 30-min with NPS 2143 before adding Aβ_25-35. 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.

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]

PMID: 28473749

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Project description:ImportanceAnnually in the United States, at least 3.5 million people seek medical attention for traumatic brain injury (TBI). The development of therapies for TBI is limited by the absence of diagnostic and prognostic biomarkers. Microtubule-associated protein tau is an axonal phosphoprotein. To date, the presence of the hypophosphorylated tau protein (P-tau) in plasma from patients with acute TBI and chronic TBI has not been investigated.ObjectiveTo examine the associations between plasma P-tau and total-tau (T-tau) levels and injury presence, severity, type of pathoanatomic lesion (neuroimaging), and patient outcomes in acute and chronic TBI.Design, setting, and participantsIn the TRACK-TBI Pilot study, plasma was collected at a single time point from 196 patients with acute TBI admitted to 3 level I trauma centers (<24 hours after injury) and 21 patients with TBI admitted to inpatient rehabilitation units (mean [SD], 176.4 [44.5] days after injury). Control samples were purchased from a commercial vendor. The TRACK-TBI Pilot study was conducted from April 1, 2010, to June 30, 2012. Data analysis for the current investigation was performed from August 1, 2015, to March 13, 2017.Main outcomes and measuresPlasma samples were assayed for P-tau (using an antibody that specifically recognizes phosphothreonine-231) and T-tau using ultra-high sensitivity laser-based immunoassay multi-arrayed fiberoptics conjugated with rolling circle amplification.ResultsIn the 217 patients with TBI, 161 (74.2%) were men; mean (SD) age was 42.5 (18.1) years. The P-tau and T-tau levels and P-tau-T-tau ratio in patients with acute TBI were higher than those in healthy controls. Receiver operating characteristic analysis for the 3 tau indices demonstrated accuracy with area under the curve (AUC) of 1.000, 0.916, and 1.000, respectively, for discriminating mild TBI (Glasgow Coma Scale [GCS] score, 13-15, n = 162) from healthy controls. The P-tau level and P-tau-T-tau ratio were higher in individuals with more severe TBI (GCS, ≤12 vs 13-15). The P-tau level and P-tau-T-tau ratio outperformed the T-tau level in distinguishing cranial computed tomography-positive from -negative cases (AUC = 0.921, 0.923, and 0.646, respectively). Acute P-tau levels and P-tau-T-tau ratio weakly distinguished patients with TBI who had good outcomes (Glasgow Outcome Scale-Extended GOS-E, 7-8) (AUC = 0.663 and 0.658, respectively) and identified those with poor outcomes (GOS-E, ≤4 vs >4) (AUC = 0.771 and 0.777, respectively). Plasma samples from patients with chronic TBI also showed elevated P-tau levels and a P-tau-T-tau ratio significantly higher than that of healthy controls, with both P-tau indices strongly discriminating patients with chronic TBI from healthy controls (AUC = 1.000 and 0.963, respectively).Conclusions and relevancePlasma P-tau levels and P-tau-T-tau ratio outperformed T-tau level as diagnostic and prognostic biomarkers for acute TBI. Compared with T-tau levels alone, P-tau levels and P-tau-T-tau ratios show more robust and sustained elevations among patients with chronic TBI.

Project description:Different tau biomarkers become abnormal at different stages of Alzheimer's disease, with CSF phospho-tau typically becoming elevated at subthreshold levels of tau-PET binding. To capitalize on the temporal order of tau biomarker-abnormality and capture the earliest changes of tau accumulation, we implemented an observational study design to examine longitudinal changes in tau-PET, cortical thickness and cognitive decline in amyloid-β-positive individuals with elevated CSF p-tau levels (P+) but subthreshold Tau-PET retention (T-). To this end, individuals without dementia (i.e. cognitively unimpaired or mild cognitive impairment, n = 231) were selected from the BioFINDER-2 study. Amyloid-β-positive (A+) individuals were categorized into biomarker groups based on cut-offs for abnormal CSF p-tau217 and 18F-RO948 (Tau) PET, yielding groups of tau-concordant-negative (A+P-T-; n = 30), tau-discordant (i.e. A+P+T-; n = 48) and tau-concordant-positive (A+P+T+; n = 18) individuals. In addition, 135 amyloid-β-negative, tau-negative, cognitively unimpaired individuals served as controls. Differences in annual change in regional tau-PET, cortical thickness and cognition between the groups were assessed using general linear models, adjusted for age, sex, clinical diagnosis and (for cognitive measures only) education. Mean follow-up time was ∼2 years. Longitudinal increase in tau-PET was faster in the A+P+T- group than in the control and A+P-T- groups across medial temporal and neocortical regions, with the highest accumulation rates in the medial temporal lobe. The A+P+T- group showed a slower rate of increase in tau-PET compared to the A+P+T+ group, primarily in neocortical regions. We did not detect differences in yearly change in cortical thickness or in cognitive decline between the A+P+T- and A+P-T- groups. The A+P+T+ group, however, showed faster cognitive decline compared to all other groups. Altogether, these findings suggest that the A+P+T- biomarker profile in persons without dementia is associated with an isolated effect on increased tau-PET accumulation rates but not on cortical thinning and cognitive decline. While this suggests that the tau-discordant biomarker profile is not strongly associated with short-term clinical decline, this group does represent an interesting population for monitoring the effects of interventions with disease-modifying agents on tau accumulation in early Alzheimer's disease, and for examining the emergence of tau aggregates in Alzheimer's disease. Further, we suggest updating the AT(N) criteria for Alzheimer's disease biomarker classification to APT(N).

Dataset Information

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.

Publications

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.

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