CoChat
Sign Up
Cited by 245Alzheimer's disease research and treatmentsWnt/β-catenin signaling in development and cancerNeuroscience and Neuropharmacology Research

The DOI matches its Crossref record; 63 of the 63 references it cites were found in a registry or an index.

Wnt Signaling Deregulation in the Aging and Alzheimer’s Brain

Open access
Palomer, Ernest, Buechler, Johanna, Salinas, Patricia C.·2019·Frontiers in Cellular Neuroscience
DOI 10.3389/fncel.2019.00227PMC PMC6538920
Open this paper in CoChat — free accountOpen PDF

Abstract

Growing evidence suggests that synaptic signaling is compromised in the aging brain and in Alzheimer's disease (AD), contributing to synaptic decline. Wnt signaling is a prominent pathway at the synapse and is required for synaptic plasticity and maintenance in the adult brain. In this review, we summarize the current knowledge on deregulation of Wnt signaling in the context of aging and AD. Emerging studies suggest that enhancing Wnt signaling could boost synaptic function during aging, and ameliorate synaptic pathology in AD. Although further research is needed to determine the precise contribution of deficient Wnt signaling to AD pathogenesis, targeting Wnt signaling components may provide novel therapeutic avenues for synapse protection or restoration in the brain.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3389/fncel.2019.00227

Cites

63 of 63 references verified0 citation errors · 0 not checkable

Statistics

Figures

FIGURE 1 Wnt signaling pathways. (A) Canonical Wnt/ß-catenin pathway OFF: In the absence of Wnt binding to Frizzled (Fz) receptors and LRP5/6 co-receptors, ß-catenin interacts with the destruction complex (CK1, GSK3β, Axin1 and APC), resulting in its phosphorylation by Gsk3ß and CK1 and its subsequent degradation by the proteasome. (B) Canonical Wnt/ß-catenin pathway ON: When a Wnt ligand binds to LRP5/6 and Fz receptors, the scaffold protein Disheveled (Dvl) recruits Axin1 and the kinases CK1 and GSK3ß to the membrane, disrupting the destruction complex and impairing ß-catenin phosphorylation and degradation. ß-catenin accumulates in the cytoplasm and subsequently translocates to the nucleus, where it acts as an activator of TCF/LEF-mediated transcription of Wnt target genes. (C) The Planar Cell Polarity (PCP) pathway: The PCP does not require LRP5/6 and is ß-catenin-independent. When Wnts bind to Fz receptors, Dvl is activated, resulting in increased activation of ROCK and JNK through the small GTPases RhoA and Rac1, respectively. Changes in ROCK activity induce actin remodeling, and JNK activation can promote gene transcription via Jun phosphorylation. The palmitate group in Wnt ligands is indicated as a yellow tail. CK1, casein kinase 1; GSK3ß, glycogen synthase kinase 3β; Axin1, axis inhibition protein 1; APC, adenomatous polyposis coli; TCF, T-cell factor; LEF, lymphocyte-enhancer-binding factor; Rock, Rho associated coiled-coil-containing protein kinase 1; RhoA, RAS homolog gene-family member A; JNK, Jun N-terminal kinase.
FIGURE 1 Wnt signaling pathways. (A) Canonical Wnt/ß-catenin pathway OFF: In the absence of Wnt binding to Frizzled (Fz) receptors and LRP5/6 co-receptors, ß-catenin interacts with the destruction complex (CK1, GSK3β, Axin1 and APC), resulting in its phosphorylation by Gsk3ß and CK1 and its subsequent degradation by the proteasome. (B) Canonical Wnt/ß-catenin pathway ON: When a Wnt ligand binds to LRP5/6 and Fz receptors, the scaffold protein Disheveled (Dvl) recruits Axin1 and the kinases CK1 and GSK3ß to the membrane, disrupting the destruction complex and impairing ß-catenin phosphorylation and degradation. ß-catenin accumulates in the cytoplasm and subsequently translocates to the nucleus, where it acts as an activator of TCF/LEF-mediated transcription of Wnt target genes. (C) The Planar Cell Polarity (PCP) pathway: The PCP does not require LRP5/6 and is ß-catenin-independent. When Wnts bind to Fz receptors, Dvl is activated, resulting in increased activation of ROCK and JNK through the small GTPases RhoA and Rac1, respectively. Changes in ROCK activity induce actin remodeling, and JNK activation can promote gene transcription via Jun phosphorylation. The palmitate group in Wnt ligands is indicated as a yellow tail. CK1, casein kinase 1; GSK3ß, glycogen synthase kinase 3β; Axin1, axis inhibition protein 1; APC, adenomatous polyposis coli; TCF, T-cell factor; LEF, lymphocyte-enhancer-binding factor; Rock, Rho associated coiled-coil-containing protein kinase 1; RhoA, RAS homolog gene-family member A; JNK, Jun N-terminal kinase.CC BY · PubMed Central
FIGURE 2 Wnt signaling deregulation in the aging brain and in AD. (A) Wnt signaling components are deregulated in both the aging and AD brain. Notably, the Wnt antagonist Dkk1 is upregulated, whereas Wnt ligands, Dvl, ß-catenin, and TCF are downregulated, leading to decreased canonical Wnt signaling. (B) As Dkk1 mainly affects the canonical Wnt signaling pathway, we propose a model by which elevation of Dkk1 results in an imbalance between the Wnt/ß-catenin and PCP pathways, resulting in synaptic defects and synapse loss. (C) In the brain of AD subjects and AD mouse models, the Wnt antagonist Dkk1 is elevated, leading to increased activity of both Gsk3ß and ROCK, thus resulting in reduced Wnt/ß-catenin signaling and increased PCP signaling. The activation of these two kinases leads to synapse vulnerability but the precise mechanisms downstream remain to be defined. A possible mechanism is that tau phosphorylation and actin remodeling contribute to synaptic changes (gray arrows and diffuse red boxes in the scheme) and subsequent cognitive deficits. These results suggest that pharmacologically targeting Wnt signaling could be a promising therapeutic strategy for synapse protection in AD.
FIGURE 2 Wnt signaling deregulation in the aging brain and in AD. (A) Wnt signaling components are deregulated in both the aging and AD brain. Notably, the Wnt antagonist Dkk1 is upregulated, whereas Wnt ligands, Dvl, ß-catenin, and TCF are downregulated, leading to decreased canonical Wnt signaling. (B) As Dkk1 mainly affects the canonical Wnt signaling pathway, we propose a model by which elevation of Dkk1 results in an imbalance between the Wnt/ß-catenin and PCP pathways, resulting in synaptic defects and synapse loss. (C) In the brain of AD subjects and AD mouse models, the Wnt antagonist Dkk1 is elevated, leading to increased activity of both Gsk3ß and ROCK, thus resulting in reduced Wnt/ß-catenin signaling and increased PCP signaling. The activation of these two kinases leads to synapse vulnerability but the precise mechanisms downstream remain to be defined. A possible mechanism is that tau phosphorylation and actin remodeling contribute to synaptic changes (gray arrows and diffuse red boxes in the scheme) and subsequent cognitive deficits. These results suggest that pharmacologically targeting Wnt signaling could be a promising therapeutic strategy for synapse protection in AD.CC BY · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 63 references

Cited by

Sorted by citations

Related

See all

Metadata

Authors
Palomer, E., Buechler, J., & Salinas, P. C.
Affiliations
University College London (GB)
Corresponding author
  • Palomer, Ernest
  • Salinas, Patricia C.
ORCID
Venue
Frontiers in Cellular Neuroscience
Publisher
Frontiers Media SA
Published
2019-05-22
Volume
13
Pages
227-227
ISSN
1662-5102 (ISSN-L)
DOI
10.3389/fncel.2019.00227
PMC
PMC6538920
OpenAlex
W2945124452
Cited by
237
References
63
Citations by year
2026: 22 · 2025: 32 · 2024: 46 · 2023: 35 · 2022: 42 · 2021: 35 · 2020: 23 · 2019: 2
FWCI
3.08
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Cellular Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • Wellcome Trust (102267/Z/13/Z, 102267)
  • European Commission (HORIZON2020, H2020, 749209)
  • Horizon 2020 Framework Programme (MSCA-IF 749209)
  • Medical Research Council (MR/M024083, MR/M024083/1)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
Wnt signaling, Alzheimer's disease, brain aging, synaptic plasticity, synaptic dysfunction, therapeutic target

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review