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Simvastatin rescues memory and granule cell maturation through the Wnt/β-catenin signaling pathway in a mouse model of Alzheimer’s disease

We previously showed that simvastatin (SV) restored memory in a mouse model of Alzheimer disease (AD) concomitantly with normalization in protein levels of memory-related immediate early genes in hippocampal CA1 neurons. Here, we investigated age-related changes in the hippocampal memory pathway, an...

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Autores principales: Tong, Xin-Kang, Royea, Jessika, Hamel, Edith
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8994768/
https://www.ncbi.nlm.nih.gov/pubmed/35397630
http://dx.doi.org/10.1038/s41419-022-04784-y
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author Tong, Xin-Kang
Royea, Jessika
Hamel, Edith
author_facet Tong, Xin-Kang
Royea, Jessika
Hamel, Edith
author_sort Tong, Xin-Kang
collection PubMed
description We previously showed that simvastatin (SV) restored memory in a mouse model of Alzheimer disease (AD) concomitantly with normalization in protein levels of memory-related immediate early genes in hippocampal CA1 neurons. Here, we investigated age-related changes in the hippocampal memory pathway, and whether the beneficial effects of SV could be related to enhanced neurogenesis and signaling in the Wnt/β-catenin pathway. APP mice and wild-type (WT) littermate controls showed comparable number of proliferating (Ki67-positive nuclei) and immature (doublecortin (DCX)-positive) granule cells in the dentate gyrus until 3 months of age. At 4 months, Ki67 or DCX positive cells decreased sharply and remained less numerous until the endpoint (6 months) in both SV-treated and untreated APP mice. In 6 month-old APP mice, dendritic extensions of DCX immature neurons in the molecular layer were shorter, a deficit fully normalized by SV. Similarly, whereas mature granule cells (calbindin-immunopositive) were decreased in APP mice and not restored by SV, their dendritic arborizations were normalized to control levels by SV treatment. SV increased Prox1 protein levels (↑67.7%, p < 0.01), a Wnt/β-catenin signaling target, while significantly decreasing (↓61.2%, p < 0.05) the upregulated levels of the β-catenin-dependent Wnt pathway inhibitor DKK1 seen in APP mice. In APP mice, SV benefits were recapitulated by treatment with the Wnt/β-catenin specific agonist WAY-262611, whereas they were fully abolished in mice that received the Wnt/β-catenin pathway inhibitor XAV939 during the last month of SV treatment. Our results indicate that activation of the Wnt-β-catenin pathway through downregulation of DKK1 underlies SV neuronal and cognitive benefits.
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spelling pubmed-89947682022-04-27 Simvastatin rescues memory and granule cell maturation through the Wnt/β-catenin signaling pathway in a mouse model of Alzheimer’s disease Tong, Xin-Kang Royea, Jessika Hamel, Edith Cell Death Dis Article We previously showed that simvastatin (SV) restored memory in a mouse model of Alzheimer disease (AD) concomitantly with normalization in protein levels of memory-related immediate early genes in hippocampal CA1 neurons. Here, we investigated age-related changes in the hippocampal memory pathway, and whether the beneficial effects of SV could be related to enhanced neurogenesis and signaling in the Wnt/β-catenin pathway. APP mice and wild-type (WT) littermate controls showed comparable number of proliferating (Ki67-positive nuclei) and immature (doublecortin (DCX)-positive) granule cells in the dentate gyrus until 3 months of age. At 4 months, Ki67 or DCX positive cells decreased sharply and remained less numerous until the endpoint (6 months) in both SV-treated and untreated APP mice. In 6 month-old APP mice, dendritic extensions of DCX immature neurons in the molecular layer were shorter, a deficit fully normalized by SV. Similarly, whereas mature granule cells (calbindin-immunopositive) were decreased in APP mice and not restored by SV, their dendritic arborizations were normalized to control levels by SV treatment. SV increased Prox1 protein levels (↑67.7%, p < 0.01), a Wnt/β-catenin signaling target, while significantly decreasing (↓61.2%, p < 0.05) the upregulated levels of the β-catenin-dependent Wnt pathway inhibitor DKK1 seen in APP mice. In APP mice, SV benefits were recapitulated by treatment with the Wnt/β-catenin specific agonist WAY-262611, whereas they were fully abolished in mice that received the Wnt/β-catenin pathway inhibitor XAV939 during the last month of SV treatment. Our results indicate that activation of the Wnt-β-catenin pathway through downregulation of DKK1 underlies SV neuronal and cognitive benefits. Nature Publishing Group UK 2022-04-09 /pmc/articles/PMC8994768/ /pubmed/35397630 http://dx.doi.org/10.1038/s41419-022-04784-y Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Tong, Xin-Kang
Royea, Jessika
Hamel, Edith
Simvastatin rescues memory and granule cell maturation through the Wnt/β-catenin signaling pathway in a mouse model of Alzheimer’s disease
title Simvastatin rescues memory and granule cell maturation through the Wnt/β-catenin signaling pathway in a mouse model of Alzheimer’s disease
title_full Simvastatin rescues memory and granule cell maturation through the Wnt/β-catenin signaling pathway in a mouse model of Alzheimer’s disease
title_fullStr Simvastatin rescues memory and granule cell maturation through the Wnt/β-catenin signaling pathway in a mouse model of Alzheimer’s disease
title_full_unstemmed Simvastatin rescues memory and granule cell maturation through the Wnt/β-catenin signaling pathway in a mouse model of Alzheimer’s disease
title_short Simvastatin rescues memory and granule cell maturation through the Wnt/β-catenin signaling pathway in a mouse model of Alzheimer’s disease
title_sort simvastatin rescues memory and granule cell maturation through the wnt/β-catenin signaling pathway in a mouse model of alzheimer’s disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8994768/
https://www.ncbi.nlm.nih.gov/pubmed/35397630
http://dx.doi.org/10.1038/s41419-022-04784-y
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