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Aberrant Wnt signaling pathway in medial temporal lobe structures of Alzheimer’s disease

  • Neurology and Preclinical Neurological Studies - Original Article
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Abstract

Cognitive decline is a cardinal feature of Alzheimer’s disease (AD) predominantly linked to synaptic failure, disrupted network connectivity and neurodegeneration. A large body of evidence associates the Wnt pathway with synaptic modulation and cognitive processes, suggesting a potential role for aberrant Wnt signaling in cognitive impairment. In fact, altered expression of key Wnt pathway components has been found in brains of AD patients as well as AD animal models supporting a deregulated pathway in AD. The evidence for deregulated Wnt signaling in AD, however, remains sparse and focused on isolated Wnt pathway components. Here, we provide the first comprehensive pathway-focused evaluation of the Wnt pathway in the entorhinal cortex and hippocampus of AD brains. Our data demonstrate altered Wnt pathway gene expression at all levels of the pathway in both medial temporal lobe regions with the hippocampus exhibiting most pronounced changes. Furthermore, the Wnt pathway constituents Wnt7b and Tcf7l1/Tcf3 showed overlapping gene expression alterations across both medial temporal lobe structures, while β-catenin was inversely expressed between brain regions. We also identified total protein alterations of the intracellular Wnt pathway signaling components β-catenin, Gsk3β and Tcf7l1/Tcf3 and the phosphorylation state of β-catenin and Gsk3β in the hippocampus suggestive of a link between AD and aberrant canonical activity. Alterations in Gsk3β co-appeared with hippocampal kinase-targeted hyperphosphorylation at specific tau epitope in soluble pretangles and prominent tau aggregation exclusively in insoluble neurofibrillary tangles of AD subjects. The Wnt pathway-focused approach confirms altered Wnt signaling in the neurodegenerative AD brain and highlights the potential role of the pathway as a therapeutic target for the treatment of patients.

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Acknowledgments

We would like to thank Kate Pedersen and Anette Bredal Christiansen for technical expertise and the Netherland Brain Bank for the kind tissue donation. Financial support was granted by the Copenhagen Graduate School of Health Science, University of Copenhagen.

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We declare no conflict of interest.

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Authors and Affiliations

  1. Synaptic Transmission, H. Lundbeck A/S, Valby, Denmark

    Jesper Riise, Niels Plath & Anna Parachikova

  2. Research Laboratory for Stereology and Neuroscience, Bispebjerg University Hospital, Copenhagen, Denmark

    Jesper Riise & Bente Pakkenberg

  3. Institute for Neuroscience and Pharmacology, Copenhagen University, Copenhagen, Denmark

    Jesper Riise

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  1. Jesper Riise
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Correspondence to Jesper Riise.

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Riise, J., Plath, N., Pakkenberg, B. et al. Aberrant Wnt signaling pathway in medial temporal lobe structures of Alzheimer’s disease. J Neural Transm 122, 1303–1318 (2015). https://doi.org/10.1007/s00702-015-1375-7

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