Evidence map›Paper›PMID 21876249›Full record

ArticleJournal of Alzheimer's disease : JAD2011

Amyloid-β toxicity and tau hyperphosphorylation are linked via RCAN1 in Alzheimer's disease.

Ana Lloret, Mari-Carmen Badia, Esther Giraldo, Gennady Ermak, Maria-Dolores Alonso, Federico V Pallardó, Kelvin J A Davies, Jose Viña

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of Alzheimer's disease : JAD, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 77 papers.

0numbers the graph read from it
0cells of the map it votes in
77citing papers in PubMed
3.2field-weighted citation impact, top 8% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

77 citing papers in PubMed, 131 citations in OpenAlex.

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  7. Calcineurin inhibition may prevent Alzheimer disease in people with Down syndrome.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025
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17 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors at 3 institutions in 2 countries.

Ana LloretDepartment of Physiology, Faculty of Medicine, University of Valencia, INCLIVA, Valencia, Spain.
Mari-Carmen Badia
Esther Giraldo
Gennady Ermak
Maria-Dolores Alonso
Federico V Pallardó
Kelvin J A Davies
Jose Viña
Universitat de València · ESHospital Clínico Universitario de Valencia · ESUniversity of Southern California · US

Funding

OXYGEN RADICAL TOXICITY AND RED CELL PROTEIN DEGRADATIONR01ES003598 · NIEHS · UNIVERSITY OF SOUTHERN CALIFORNIA · PI DAVIES, KELVIN J. A. · 1988 to 2017
$5.7M
ADAPT 78 IN OXIDANT STRESS, AGING AND NEURODEGENERATIONR01AG016256 · NIA · UNIVERSITY OF SOUTHERN CALIFORNIA · PI DAVIES, KELVIN J. A. · 2000 to 2004
$1.6M
Oxygen Radical Toxicity and Protein DegradationR56ES003598 · NIEHS · UNIVERSITY OF SOUTHERN CALIFORNIA · PI DAVIES, KELVIN J. A. · 2012 to 2012
$138k
NIA NIH HHS R01 AG016256NIEHS NIH HHS 3R01-ES003598-22S2NIEHS NIH HHS R01 ES003598NIEHS NIH HHS R01-ES003598NIEHS NIH HHS R56 ES003598
6 · The paper itself

Abstract

Amyloid-β peptide (Aβ) toxicity and tau hyperphosphorylation are hallmarks of Alzheimer's disease (AD). How their molecular relationships may affect the etiology, progression, and severity of the disease, however, has not been elucidated. We now report that incubation of fetal rat cortical neurons with Aβ upregulates expression of the Regulator of Calcineurin gene RCAN1, and this is mediated by Aβ-induced oxidative stress. Calcineurin (PPP3CA) is a serine-threonine phosphatase that dephosphorylates tau. RCAN1 proteins inhibit this phosphatase activity of calcineurin. Increased expression of RCAN1 also causes upregulation of glycogen synthase kinase-3β (GSK3β), a tau kinase. Thus, increased RCAN1 expression might be expected to decrease phospho-tau dephosphorylation (via calcineurin inhibition) and increase tau phosphorylation (via increased GSK3β activity). Indeed, we find that incubation of primary cortical neurons with Aβ results in increased phosphorylation of tau, unless RCAN1 gene expression is silenced, or antioxidants are added. Thus we propose a mechanism to link Aβ toxicity and tau hyperphosphorylation in AD: In our hypothesis, Aβ causes mitochondrial oxidative stress and increases production of reactive oxygen species, which result in an upregulation of RCAN1 gene expression. RCAN1 proteins then both inhibit calcineurin and induce expression of GSK3β. Both mechanisms shift tau to a hyperphosphorylated state. We also find that lymphocytes from persons whose ApoE genotype is ε4/ε4 (with high risk of developing AD) show higher levels of RCAN1 and phospho-tau than those carrying the ApoE ε3/ε3 or ε3/ε4 genotypes. Thus upregulation of RCAN1 may be a valuable biomarker for AD risk.

Indexed as

Alzheimer DiseaseAdultAmyloid beta-PeptidesAnimalsCalcineurinCells, CulturedCerebral CortexChromatography, High Pressure LiquidDNA-Binding ProteinsEmbryo, MammalianFemaleGene Expression RegulationGlutathioneGlycogen Synthase Kinase 3Glycogen Synthase Kinase 3 betaHumansAmyloid beta-Peptidesamyloid beta-protein (1-40)amyloid beta-protein (1-42)CalcineurinDNA-Binding ProteinsGlutathioneGlycogen Synthase Kinase 3Glycogen Synthase Kinase 3 betaGSK3B protein, humanGsk3b protein, ratIntracellular Signaling Peptides and ProteinsMuscle ProteinsPeptide FragmentsRCAN1 protein, humanRNA, Small Interferingtau Proteins

Identifiers

PMID21876249
PMCPMC3690537
OpenAlexW1697463694

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.