Loss of canonical Wnt signaling is involved in the pathogenesis of Alzheimer’s disease.
Open accessAbstract
Alzheimer's disease (AD) is the most common form of dementia in the older population, however, the precise cause of the disease is unknown. The neuropathology is characterized by the presence of aggregates formed by amyloid-β (Aβ) peptide and phosphorylated tau; which is accompanied by progressive impairment of memory. Diverse signaling pathways are linked to AD, and among these the Wnt signaling pathway is becoming increasingly relevant, since it plays essential roles in the adult brain. Initially, Wnt signaling activation was proposed as a neuroprotective mechanism against Aβ toxicity. Later, it was reported that it participates in tau phosphorylation and processes of learning and memory. Interestingly, in the last years we demonstrated that Wnt signaling is fundamental in amyloid precursor protein (APP) processing and that Wnt dysfunction results in Aβ production and aggregation in vitro. Recent in vivo studies reported that loss of canonical Wnt signaling exacerbates amyloid deposition in a transgenic (Tg) mouse model of AD. Finally, we showed that inhibition of Wnt signaling in a Tg mouse previously at the appearance of AD signs, resulted in memory loss, tau phosphorylation and Aβ formation and aggregation; indicating that Wnt dysfunction accelerated the onset of AD. More importantly, Wnt signaling loss promoted cognitive impairment, tau phosphorylation and Aβ1–42 production in the hippocampus of wild-type (WT) mice, contributing to the development of an Alzheimer's-like neurophatology. Therefore, in this review we highlight the importance of Wnt/β-catenin signaling dysfunction in the onset of AD and propose that the loss of canonical Wnt signaling is a triggering factor of AD.
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Recent work in AD cerebral organoids has highlighted Wnt pathway dysregulation as a core feature of disease progression.
“Aberrant Wnt signaling has been implicated in Aβ production, tau phosphorylation, and synapse loss in multiple models, and recent work in AD cerebral organoids has highlighted Wnt pathway dysregulation as a core feature of disease progression (Kostes and Brafman, 2023; Tapia-Rojas and Inestrosa, 2018).”
From Isogenic human stem cell models reveal mutation-dependent protective mechanisms of APOE3 Christchurch (2026) · cites this paper as Tapia-Rojas and Inestrosa, 2018
The 'Role of Wnt Signaling in the Pathogenesis of AD' section links Wnt signaling loss to accelerated AD pathology, including Aβ production and tau phosphorylation. But it describes mouse models, not AD cerebral organoids, so it does not support the organoid-specific part of the claim. Page numbers were not available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAberrant Wnt signaling has been implicated in Aβ production, tau phosphorylation, and synapse loss in multiple models.
“Aberrant Wnt signaling has been implicated in Aβ production, tau phosphorylation, and synapse loss in multiple models, and recent work in AD cerebral organoids has highlighted Wnt pathway dysregulation as a core feature of disease progression (Kostes and Brafman, 2023; Tapia-Rojas and Inestrosa, 2018).”
From Isogenic human stem cell models reveal mutation-dependent protective mechanisms of APOE3 Christchurch (2026) · cites this paper as Tapia-Rojas and Inestrosa, 2018
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- Authors
- Inestrosa, N., & Tapia-Rojas, C.
- Affiliations
- Pontificia Universidad Católica de Chile (CL)
- Corresponding author
- Inestrosa, NibaldoC
- Venue
- Neural Regeneration Research
- Published
- 2018
- Volume
- 13
- Issue
- 10
- Pages
- 1705
- ISSN
- 1673-5374 (ISSN-L)
- PMC
- PMC6128062
- OpenAlex
- W2888246416
- Cited by
- 137
- References
- 74
- Citations by year
- 2026: 13 · 2025: 16 · 2024: 12 · 2023: 17 · 2022: 17 · 2021: 21 · 2020: 26 · 2019: 13 · 2018: 2
- FWCI
- 2.03
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-sa
- Locations
- Neural Regeneration Research (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, Wnt/β-catenin signaling, amyloid-beta, tau phosphorylation, APP processing, amyloid-beta aggregation, cognitive impairment, hippocampus, transgenic mouse model, neurodegeneration
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