Evidence map›Paper›PMID 28374012›Full record

ArticleeNeuro

Activation of Ras-ERK Signaling and GSK-3 by Amyloid Precursor Protein and Amyloid Beta Facilitates Neurodegeneration in Alzheimer's Disease.

Lisa Kirouac, Alexander J Rajic, David H Cribbs, Jaya Padmanabhan

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

Article in eNeuro. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 111 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
111citing papers in PubMed, 2 pooled it
12.1field-weighted citation impact, top 1% 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

111 citing papers in PubMed, 2 syntheses or guidelines pooled it, 207 citations in OpenAlex.

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51 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

4 authors at 2 institutions in 1 country.

Lisa KirouacDepartment of Molecular Medicine, USF Health Byrd Alzheimer's Institute, Morsani College of Medicine, University of South Florida , Tampa, FL 33613.ORCID 0000-0002-4948-4451
Alexander J RajicInstitute for Memory Impairment and Neurological Disorders, Department of Neurology, University of California, Irvine , Irvine, CA 92697-4540.
David H CribbsInstitute for Memory Impairment and Neurological Disorders, Department of Neurology, University of California, Irvine , Irvine, CA 92697-4540.
Jaya PadmanabhanDepartment of Molecular Medicine, USF Health Byrd Alzheimer's Institute, Morsani College of Medicine, University of South Florida , Tampa, FL 33613.ORCID 0000-0003-2019-5135
University of California, Irvine · USUniversity of South Florida · US

Funding

UC Irvine Alzheimer's Disease Research Center Induced Pluripotent Stem Cell CoreP50AG016573 · NIA · UNIVERSITY OF CALIFORNIA-IRVINE · PI LAFERLA, FRANK M · 2000 to 2019
$37.0M
Regulatory functions of alpha 1-antichymotrypsin in inflammation and Alzheimer'sR21AG031429 · NIA · UNIVERSITY OF SOUTH FLORIDA · PI PADMANABHAN, JAYA · 2010 to 2011
$326k
NIA NIH HHS P50 AG016573NIA NIH HHS R21 AG031429
6 · The paper itself

Abstract

It is widely accepted that amyloid β (Aβ) generated from amyloid precursor protein (APP) oligomerizes and fibrillizes to form neuritic plaques in Alzheimer's disease (AD), yet little is known about the contribution of APP to intracellular signaling events preceding AD pathogenesis. The data presented here demonstrate that APP expression and neuronal exposure to oligomeric Aβ42 enhance Ras/ERK signaling cascade and glycogen synthase kinase 3 (GSK-3) activation. We find that RNA interference (RNAi)-directed knockdown of APP in B103 rat neuroblastoma cells expressing APP inhibits Ras-ERK signaling and GSK-3 activation, indicating that APP acts upstream of these signal transduction events. Both ERK and GSK-3 are known to induce hyperphosphorylation of tau and APP at Thr668, and our findings suggest that aberrant signaling by APP facilitates these events. Supporting this notion, analysis of human AD brain samples showed increased expression of Ras, activation of GSK-3, and phosphorylation of APP and tau, which correlated with Aβ levels in the AD brains. Furthermore, treatment of primary rat neurons with Aβ recapitulated these events and showed enhanced Ras-ERK signaling, GSK-3 activation, upregulation of cyclin D1, and phosphorylation of APP and tau. The finding that Aβ induces Thr668 phosphorylation on APP, which enhances APP proteolysis and Aβ generation, denotes a vicious feedforward mechanism by which APP and Aβ promote tau hyperphosphorylation and neurodegeneration in AD. Based on these results, we hypothesize that aberrant proliferative signaling by APP plays a fundamental role in AD neurodegeneration and that inhibition of this would impede cell cycle deregulation and neurodegeneration observed in AD.

Indexed as

AgedAged, 80 and overAlzheimer DiseaseAmyloid beta-PeptidesAmyloid beta-Protein PrecursorAnimalsBrainCell Line, TumorCyclin D1Extracellular Signal-Regulated MAP KinasesFemaleGlycogen Synthase Kinase 3HumansMaleMAP Kinase Signaling SystemNerve DegenerationAmyloid beta-Peptidesamyloid beta-protein (1-42)Amyloid beta-Protein PrecursorCyclin D1Extracellular Signal-Regulated MAP KinasesGlycogen Synthase Kinase 3MAPT protein, humanMapt protein, ratPeptide Fragmentsras Proteinstau ProteinsA-betaAlzheimer’s diseaseamyloid precursor proteinGSK3protein phosphorylationRas-MAPK signaling

Identifiers

PMID28374012
PMCPMC5367084
OpenAlexW2596555436

What OpenQuestion holds

Textmetadata
LicenceCC BY
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.