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Wnt signaling in Alzheimer's disease: up or down, that is the question.
Ageing Res Rev. 2009 Apr; 8(2):71-82.AR

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, neuropathologically characterized by amyloid-beta (Abeta) plaques and hyperphosphorylated tau accumulation. AD occurs sporadically (SAD), or is caused by hereditary missense mutations in the amyloid precursor protein (APP) or presenilin-1 and -2 (PSEN1 and PSEN2) genes, leading to early-onset familial AD (FAD). Accumulating evidence points towards a role for altered Wnt/beta-catenin-dependent signaling in the etiology of both forms of AD. Presenilins are involved in modulating beta-catenin stability; therefore FAD-linked PSEN-mediated effects can deregulate the Wnt pathway. Genetic variations in the low-density lipoprotein receptor-related protein 6 and apolipoprotein E in AD have been associated with reduced Wnt signaling. In addition, tau phosphorylation is mediated by glycogen synthase kinase-3 (GSK-3), a key antagonist of the Wnt pathway. In this review, we discuss Wnt/beta-catenin signaling in both SAD and FAD, and recapitulate which of its aberrant functions may be critical for (F)AD pathogenesis. We discuss the intriguing possibility that Abeta toxicity may downregulate the Wnt/beta-catenin pathway, thereby upregulating GSK-3 and consequent tau hyperphosphorylation, linking Abeta and tangle pathology. The currently available evidence implies that disruption of tightly regulated Wnt signaling may constitute a key pathological event in AD. In this context, drug targets aimed at rescuing Wnt signaling may prove to be a constructive therapeutic strategy for AD.

Authors+Show Affiliations

Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences & University Medical Centre Utrecht, Utrecht, The Netherlands.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Review

Language

eng

PubMed ID

19101658

Citation

Boonen, Rick A C M., et al. "Wnt Signaling in Alzheimer's Disease: Up or Down, That Is the Question." Ageing Research Reviews, vol. 8, no. 2, 2009, pp. 71-82.
Boonen RA, van Tijn P, Zivkovic D. Wnt signaling in Alzheimer's disease: up or down, that is the question. Ageing Res Rev. 2009;8(2):71-82.
Boonen, R. A., van Tijn, P., & Zivkovic, D. (2009). Wnt signaling in Alzheimer's disease: up or down, that is the question. Ageing Research Reviews, 8(2), 71-82. https://doi.org/10.1016/j.arr.2008.11.003
Boonen RA, van Tijn P, Zivkovic D. Wnt Signaling in Alzheimer's Disease: Up or Down, That Is the Question. Ageing Res Rev. 2009;8(2):71-82. PubMed PMID: 19101658.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Wnt signaling in Alzheimer's disease: up or down, that is the question. AU - Boonen,Rick A C M, AU - van Tijn,Paula, AU - Zivkovic,Danica, Y1 - 2008/12/03/ PY - 2008/10/03/received PY - 2008/11/26/revised PY - 2008/11/26/accepted PY - 2008/12/23/entrez PY - 2008/12/23/pubmed PY - 2009/6/6/medline SP - 71 EP - 82 JF - Ageing research reviews JO - Ageing Res Rev VL - 8 IS - 2 N2 - Alzheimer's disease (AD) is a progressive neurodegenerative disorder, neuropathologically characterized by amyloid-beta (Abeta) plaques and hyperphosphorylated tau accumulation. AD occurs sporadically (SAD), or is caused by hereditary missense mutations in the amyloid precursor protein (APP) or presenilin-1 and -2 (PSEN1 and PSEN2) genes, leading to early-onset familial AD (FAD). Accumulating evidence points towards a role for altered Wnt/beta-catenin-dependent signaling in the etiology of both forms of AD. Presenilins are involved in modulating beta-catenin stability; therefore FAD-linked PSEN-mediated effects can deregulate the Wnt pathway. Genetic variations in the low-density lipoprotein receptor-related protein 6 and apolipoprotein E in AD have been associated with reduced Wnt signaling. In addition, tau phosphorylation is mediated by glycogen synthase kinase-3 (GSK-3), a key antagonist of the Wnt pathway. In this review, we discuss Wnt/beta-catenin signaling in both SAD and FAD, and recapitulate which of its aberrant functions may be critical for (F)AD pathogenesis. We discuss the intriguing possibility that Abeta toxicity may downregulate the Wnt/beta-catenin pathway, thereby upregulating GSK-3 and consequent tau hyperphosphorylation, linking Abeta and tangle pathology. The currently available evidence implies that disruption of tightly regulated Wnt signaling may constitute a key pathological event in AD. In this context, drug targets aimed at rescuing Wnt signaling may prove to be a constructive therapeutic strategy for AD. SN - 1872-9649 UR - https://www.unboundmedicine.com/medline/citation/19101658/Wnt_signaling_in_Alzheimer's_disease:_up_or_down_that_is_the_question_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1568-1637(08)00056-1 DB - PRIME DP - Unbound Medicine ER -