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Impaired Wnt Signaling in the Prefrontal Cortex of Alzheimer’s Disease

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Abstract

Wnt pathway is involved in synaptic plasticity and neuronal survival, and alterations in Wnt signaling have previously been reported both in aging and neurodegenerative diseases, including Alzheimer’s disease (AD). This study sought to evaluate Wnt signaling pathway interplay integrity across prefrontal lobe structures in AD patients compared to normal aging. Using the open-access BrainCloud™ database, 84 gene expression profiles and clustering effect were analyzed in the dorsomedial prefrontal cortex (PFC) across a time span of 21–78 years of age. Next, expression levels of the selected genes were investigated in post-mortem brain tissue from 30 AD patients and 30 age-matched controls in three interdependent brain areas of the PFC. Results were assessed in relation to Braak stage and cognitive impairment of the patients. We found a general age-related factor in Wnt pathway genes with a group of genes being closely interrelated in their expression across the time span investigated in healthy individuals. This interrelation was altered in the AD brains studied, as several genes presented aberrant transcription, even though not always being altered at protein levels. Noteworthy, beta(β)-catenin and glycogen synthase kinase 3-beta (GSK3β) showed a dynamic switch in protein levels and activity, especially in the orbitofrontal cortex and the medial frontal gyrus. A significant decrease in β-catenin protein levels were inversely associated with increased GSK3β tyrosine activating phosphorylation, in addition to downstream effects associated with disease progression and cognitive decline. This study is the first that comprehensively evaluates Wnt signaling pathway in the prefrontal cortical lobe structures of AD brains, in relation to age-related coordinated Wnt signaling changes. Our findings further support that increased kinase activity of GSK3β is associated with AD pathology in the PFC.

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Abbreviations

AD :

Alzheimer’s disease patients

PFC :

prefrontal cortex

CNS :

central nervous system

M :

male

F :

female

NCBI :

National Center for Biotechnology

OFC :

orbitofrontal cortex

MFG :

medial frontal gyrus

SFG :

superior frontal gyrus

PMI :

post-mortem interval

RT-qPCR :

reverse transcription quantitative real-time polymerase chain reaction

MIQE :

the minimum information for publication of quantitative real-time experiments

RIN :

RNA integrity number

ND :

non-demented controls

FC :

fold-change

kDa :

kilodalton

p:

phosphorylation

Ser :

serine

Tyr :

tyrosine

MMSE :

Mini-Mental State Examination

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Acknowledgements

The authors are grateful to Hans-Jørgen Jensen and Rasmus Rydbirk for technical assistance.

Availability of Data and Materials

The data analyzed during the current study is available from the corresponding author on reasonable request.

Funding

This work was supported by the Dagmar Marshalls Foundation and Familien Hede Nielsens Foundation.

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Authors and Affiliations

  1. Research Laboratory for Stereology and Neuroscience, Bispebjerg-Frederiksberg Hospital, University Hospital of Copenhagen, Nielsine Nielsens Vej 6B, Building 11B, 2nd floor, DK-2400, Copenhagen, Denmark

    Jonas Folke, Bente Pakkenberg & Tomasz Brudek

  2. Institute of Clinical Medicine, Faculty of Health, University of Copenhagen, Blegdamsvej 3B, DK-2200, Copenhagen, Denmark

    Bente Pakkenberg

Authors
  1. Jonas Folke
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  2. Bente Pakkenberg
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  3. Tomasz Brudek
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Contributions

J.F. helped design the study, performed the experiments, analyzed and interpreted the data, and wrote the manuscript. T.B. designed the study, supervised the study and assisted with experimental design, data interpretation, and manuscript preparation. B.P supervised the project and assisted with manuscript preparations. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Jonas Folke.

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Ethics Approval

The Ethics Committee for the Copenhagen Regional Area approved this study (H-16031730).

Conflict of Interests

The authors declare that there is no conflict of interest.

Electronic Supplementary Material

Additional file 1

Figures S1, S2, Tables S1, S2, and S3: Figure S1 presents non-significant RT-qPCR validation results. Figure S2 shows a schematic presentation of the western blot setup and workflow including calculations. Table S1 presents genes related to the Wnt signaling pathway included in the study, including their chromosomal location. Table S2 presents the primer date for each primer pair used in this study, including the PCR efficiency, R2, and acquisition temperatures. Table S3 presents the basic demographic of brain samples. Table S4 presents the correlation of genes with close chromosomal proximity during aging. (DOCX 708 kb)

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Folke, J., Pakkenberg, B. & Brudek, T. Impaired Wnt Signaling in the Prefrontal Cortex of Alzheimer’s Disease. Mol Neurobiol 56, 873–891 (2019). https://doi.org/10.1007/s12035-018-1103-z

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  • DOI: https://doi.org/10.1007/s12035-018-1103-z

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