Evidence map›Paper›PMID 23164821›Full record

ArticleMolecular psychiatry2014

Clusterin regulates β-amyloid toxicity via Dickkopf-1-driven induction of the wnt-PCP-JNK pathway.

R Killick, E M Ribe, R Al-Shawi, B Malik, C Hooper, C Fernandes, R Dobson, P M Nolan, A Lourdusamy, S Furney and 19 more

Registry-linked trialOpen access · bronzeAbstract readMulticenter Study
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular psychiatry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT06362707 (A Placebo Controlled Randomized Double-blind Parallel Group 12-month Trial of Fasudil for the Treatment of Early Alzheimer's Disease), which is not on this map. Cited by 139 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
139citing papers in PubMed, 2 pooled it
6.2field-weighted citation impact, top 3% 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.

NCT06362707 phase2recruitingnot on this mapstarted 2024, after this paper: background citation

A Placebo Controlled Randomized Double-blind Parallel Group 12-month Trial of Fasudil for the Treatment of Early Alzheimer's Disease (FEAD)

TypeinterventionalSponsorHelse Stavanger HFRan2024 to 2028Enrolled200ConditionsCognitive Decline, Mild, Alzheimer DiseaseArmsFasudil, Placebo
3 · Its place in the literature

Who cites it

139 citing papers in PubMed, 2 syntheses or guidelines pooled it, 231 citations in OpenAlex.

  1. Pooled it
  2. Pooled it
  3. Article
  4. DKK2 contributes to context discrimination and adult hippocampal neurogenesis by suppressing Wnt/PCP signaling.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2026
    Article
  5. Review
  6. Article
  7. Article
  8. Review
  9. Contextualizing molecular and structural aging across human organs.medRxiv : the preprint server for health sciences · 2025
    Article
  10. Article
  11. Article
  12. Wnt/β-catenin Signaling in Central Nervous System Regeneration.Advances in experimental medicine and biology · 2025
    Review
  13. Review
  14. Article
  15. Article
  16. Article
  17. Review
  18. Article
  19. New Insights into the Role of KLF10 in Tissue Fibrosis.International journal of molecular sciences · 2024
    Review
  20. Review

79 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

29 authors at 5 institutions in 3 countries.

R KillickKing's College London, Institute of Psychiatry, London, UK.
E M RibeKing's College London, Institute of Psychiatry, London, UK.
R Al-ShawiDivision of Medicine and Centre for Biomedical Science, University College London, London, UK.
B MalikKing's College London, Institute of Psychiatry, London, UK.
C HooperKing's College London, Institute of Psychiatry, London, UK.
C FernandesKing's College London, Institute of Psychiatry, London, UK.
R DobsonKing's College London, Institute of Psychiatry, London, UK.
P M NolanMRC Harwell, Mammalian Genetics Unit, Harwell Science and Innovation Campus, Oxfordshire, UK.
A LourdusamyKing's College London, Institute of Psychiatry, London, UK.
S FurneyKing's College London, Institute of Psychiatry, London, UK.
K LinKing's College London, Institute of Psychiatry, London, UK.
G BreenKing's College London, Institute of Psychiatry, London, UK.
R WroeKing's College London, Institute of Psychiatry, London, UK.
A W M ToKing's College London, Institute of Psychiatry, London, UK.
K LeroyUniversité Libre de Bruxelles, Faculté de Médecine, Brussels, Belgium.
M CausevicKing's College London, Institute of Psychiatry, London, UK.
A UsardiKing's College London, Institute of Psychiatry, London, UK.
M RobinsonKing's College London, Institute of Psychiatry, London, UK.
W NobleKing's College London, Institute of Psychiatry, London, UK.
R WilliamsonKing's College London, Institute of Psychiatry, London, UK.
K LunnonDivision of Medicine and Centre for Biomedical Science, University College London, London, UK.
S KellieUniversity of Queensland, School of Chemistry and Molecular Biosciences, Brisbane, Queensland, Australia.
C H ReynoldsKing's College London, Institute of Psychiatry, London, UK.
C BazenetKing's College London, Institute of Psychiatry, London, UK.
A HodgesKing's College London, Institute of Psychiatry, London, UK.
J-P BrionUniversité Libre de Bruxelles, Faculté de Médecine, Brussels, Belgium.
J StephensonKing's College London, Institute of Psychiatry, London, UK.
J Paul SimonsDivision of Medicine and Centre for Biomedical Science, University College London, London, UK.
Simon LovestoneKing's College London, Institute of Psychiatry, London, UK.
King's College London · GBUniversity College London · GBUniversité Libre de Bruxelles · BEMary Lyon Centre at MRC Harwell · GBThe University of Queensland · AU

Funding

Medical Research Council MC_U142684173Wellcome Trust
6 · The paper itself

Abstract

Although the mechanism of Aβ action in the pathogenesis of Alzheimer's disease (AD) has remained elusive, it is known to increase the expression of the antagonist of canonical wnt signalling, Dickkopf-1 (Dkk1), whereas the silencing of Dkk1 blocks Aβ neurotoxicity. We asked if clusterin, known to be regulated by wnt, is part of an Aβ/Dkk1 neurotoxic pathway. Knockdown of clusterin in primary neurons reduced Aβ toxicity and DKK1 upregulation and, conversely, Aβ increased intracellular clusterin and decreased clusterin protein secretion, resulting in the p53-dependent induction of DKK1. To further elucidate how the clusterin-dependent induction of Dkk1 by Aβ mediates neurotoxicity, we measured the effects of Aβ and Dkk1 protein on whole-genome expression in primary neurons, finding a common pathway suggestive of activation of wnt-planar cell polarity (PCP)-c-Jun N-terminal kinase (JNK) signalling leading to the induction of genes including EGR1 (early growth response-1), NAB2 (Ngfi-A-binding protein-2) and KLF10 (Krüppel-like factor-10) that, when individually silenced, protected against Aβ neurotoxicity and/or tau phosphorylation. Neuronal overexpression of Dkk1 in transgenic mice mimicked this Aβ-induced pathway and resulted in age-dependent increases in tau phosphorylation in hippocampus and cognitive impairment. Furthermore, we show that this Dkk1/wnt-PCP-JNK pathway is active in an Aβ-based mouse model of AD and in AD brain, but not in a tau-based mouse model or in frontotemporal dementia brain. Thus, we have identified a pathway whereby Aβ induces a clusterin/p53/Dkk1/wnt-PCP-JNK pathway, which drives the upregulation of several genes that mediate the development of AD-like neuropathologies, thereby providing new mechanistic insights into the action of Aβ in neurodegenerative diseases.

Indexed as

AgedAlzheimer DiseaseAmyloid beta-PeptidesAnimalsCells, CulturedClusterinEmbryo, MammalianEnzyme InhibitorsFemaleGene Expression RegulationHumansIntercellular Signaling Peptides and ProteinsMaleMAP Kinase Signaling SystemMiceMice, Inbred C57BLAmyloid beta-PeptidesClusterinDKK1 protein, humanEnzyme InhibitorsIntercellular Signaling Peptides and ProteinsWnt Proteins

Identifiers

PMID23164821
PMCPMC3873038
OpenAlexW2046422248

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

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.