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Activation of Wnt signaling by lithium and rosiglitazone reduced spatial memory impairment and neurodegeneration in brains of an APPswe/PSEN1ΔE9 mouse model of Alzheimer's disease

Molecular Psychiatry volume 15, pages 272–285 (2010)Cite this article

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, accumulation of the amyloid-β-peptide (Aβ) and synaptic alterations. Treatment with lithium has been shown to provide neuroprotection against several insults, including protection against Aβ neurotoxicity in vitro. Rosiglitazone, a peroxisome proliferator activated receptor-γ agonist, has been shown to attenuate Aβ-peptide neurotoxic effects, including the inflammatory response of microglia and astrocytes. Both types of drugs activate Wnt signaling, a pathway that has been shown to be related to AD. In this study, a double transgenic mouse model, which coexpresses APPswe and the exon 9 deletion of the presenilin 1 (PSEN1) gene, was used to examine, in vivo, the effect of lithium and rosiglitazone on Aβ neurotoxicity. Mice were tested for spatial memory, and their brain samples were used for histochemical and biochemical analysis. In this study, we report that both drugs significantly reduced (1) spatial memory impairment induced by amyloid burden; (2) Aβ aggregates and Aβ oligomers; and (3) astrocytic and microglia activation. They also prevented changes in presynaptic and postsynaptic marker proteins. Finally, both drugs activate Wnt signaling shown by the increase in β-catenin and by the inhibition of the glycogen synthase kinase-3β. We conclude that lithium and rosiglitazone, possibly by the activation of the Wnt signaling pathway, reduce various AD neuropathological markers and may be considered as potential therapeutic agents against the disease.

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Acknowledgements

This research was supported by grants from FONDAP (No. 13980001), the Millennium Institute for Fundamental and Basic Biology (MIFAB) and a grant from DIPUC to EMT. We thank Sebastian Belmar for his help with biochemical assays. This work is a partial account to fulfill the requirements of a PhD degree in Cell and Molecular Biology, presented by EMT at the Department of Cell and Molecular Biology, Faculty of Biological Sciences, PUC.

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  1. Centro de Envejecimiento y Regeneración (CARE), Centro de Regulación Celular y Patología ‘Joaquín V. Luco’ (CRCP), MIFAB, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chille

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Toledo, E., Inestrosa, N. Activation of Wnt signaling by lithium and rosiglitazone reduced spatial memory impairment and neurodegeneration in brains of an APPswe/PSEN1ΔE9 mouse model of Alzheimer's disease. Mol Psychiatry 15, 272–285 (2010). https://doi.org/10.1038/mp.2009.72

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