Restoring Wnt/β-catenin signaling is a promising therapeutic strategy for Alzheimer’s disease

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Abstract

Alzheimer’s disease (AD) is an aging-related neurological disorder characterized by synaptic loss and dementia. Wnt/β-catenin signaling is an essential signal transduction pathway that regulates numerous cellular processes including cell survival. In brain, Wnt/β-catenin signaling is not only crucial for neuronal survival and neurogenesis, but it plays important roles in regulating synaptic plasticity and blood-brain barrier integrity and function. Moreover, activation of Wnt/β-catenin signaling inhibits amyloid-β production and tau protein hyperphosphorylation in the brain. Critically, Wnt/β-catenin signaling is greatly suppressed in AD brain via multiple pathogenic mechanisms. As such, restoring Wnt/β-catenin signaling represents a unique opportunity for the rational design of novel AD therapies.

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WNT signaling in bone homeostasis and disease: from human mutations to treatments.

Roland Baron, Michaela Kneissel (2013)

Low bone mass and strength lead to fragility fractures, for example, in elderly individuals affected by osteoporosis or children with osteogenesis imperfecta. A decade ago, rare human mutations affecting bone negatively (osteoporosis-pseudoglioma syndrome) or positively (high-bone mass phenotype, sclerosteosis and Van Buchem disease) have been identified and found to all reside in components of the canonical WNT signaling machinery. Mouse genetics confirmed the importance of canonical Wnt signaling in the regulation of bone homeostasis, with activation of the pathway leading to increased, and inhibition leading to decreased, bone mass and strength. The importance of WNT signaling for bone has also been highlighted since then in the general population in numerous genome-wide association studies. The pathway is now the target for therapeutic intervention to restore bone strength in millions of patients at risk for fracture. This paper reviews our current understanding of the mechanisms by which WNT signalng regulates bone homeostasis.

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The role of brain vasculature in neurodegenerative disorders

Melanie D Sweeney, Kassandra Kisler, Axel Montagne … (2018)

Adequate supply of blood and structural and functional integrity of blood vessels is key to normal brain functioning. On the other hand, cerebral blood flow (CBF) shortfalls and blood-brain barrier (BBB) dysfunction are early findings in neurodegenerative disorders in humans and animal models. Here, we first examine molecular definition of cerebral blood vessels, and pathways regulating CBF and BBB integrity. Then, we examine the role of CBF and BBB in the pathogenesis of Alzheimer’s disease (AD), Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis and multiple sclerosis. We focus on AD as a platform of our analysis because more is known about neurovascular dysfunction in this disease than in other neurodegenerative disorders. Finally, we propose a hypothetical model of AD biomarkers to include brain vasculature as a factor contributing to the disease onset and progression, and suggest a common pathway linking brain vascular contributions to neurodegeneration in multiple neurodegenerative disorders.

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Emerging roles of Wnts in the adult nervous system.

Nibaldo Inestrosa, Ernest Arenas (2010)

The roles of the Wnt signalling pathway in several developmental processes, including synaptic differentiation, are well characterized. The expression of Wnt ligands and Wnt signalling components in the mature mammalian CNS suggests that this pathway might also play a part in synaptic maintenance and function. In fact, Wnts have a crucial role in synaptic physiology, as they modulate the synaptic vesicle cycle, the trafficking of neurotransmitter receptors and the interaction of these receptors with scaffold proteins in postsynaptic regions. In addition, Wnts participate in adult neurogenesis and protect excitatory synaptic terminals from amyloid-beta oligomer toxicity. Here, the latest insights into the function of Wnt signalling in the adult nervous system and therapeutic opportunities for neurodegenerative diseases such as Alzheimer's and Parkinson's disease are discussed.

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Author and article information

Contributors

Yonghe Li:

ORCID: http://orcid.org/0000-0003-3489-6362

Li.Yonghe@mayo.edu

Journal

Journal ID (nlm-ta): Mol Brain

Journal ID (iso-abbrev): Mol Brain

Title: Molecular Brain

Publisher: BioMed Central (London )

ISSN (Electronic): 1756-6606

Publication date (Electronic): 4 December 2019

Publication date PMC-release: 4 December 2019

Publication date Collection: 2019

Volume: 12

Electronic Location Identifier: 104

Affiliations

[1 ]ISNI 0000 0004 0443 9942, GRID grid.417467.7, Department of Neuroscience, , Mayo Clinic, ; Jacksonville, FL 32224 USA

[2 ]ISNI 0000 0001 2264 7233, GRID grid.12955.3a, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, , Institute of Neuroscience, Medical College, Xiamen University, ; Xiamen, 361102 China

[3 ]ISNI 0000 0001 0163 8573, GRID grid.479509.6, Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, ; La Jolla, CA 92037 USA

Author information

Yonghe Li http://orcid.org/0000-0003-3489-6362

Article

Publisher ID: 525

DOI: 10.1186/s13041-019-0525-5

PMC ID: 6894260

PubMed ID: 31801553

SO-VID: 318efc56-1c8d-48dd-aa1c-315e79f5b064

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 30 October 2019

Date accepted : 26 November 2019

Funding

Funded by: The Ed and Ethel Moore Alzheimer’s Disease Research Program Pilot Grant from the Florida Department of Health

Award ID: 9AZ09

Award Recipient : Yonghe Li

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ScienceOpen disciplines: Neurosciences

Keywords: wnt,alzheimer’s disease,neuronal survival,neurogenesis,synaptic plasticity,drug target

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ScienceOpen disciplines: Neurosciences

Keywords: wnt, alzheimer’s disease, neuronal survival, neurogenesis, synaptic plasticity, drug target

Restoring Wnt/β-catenin signaling is a promising therapeutic strategy for Alzheimer’s disease

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Neuronal Signaling

Most cited references 116

WNT signaling in bone homeostasis and disease: from human mutations to treatments.

The role of brain vasculature in neurodegenerative disorders

Emerging roles of Wnts in the adult nervous system.

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