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Impaired adult hippocampal neurogenesis in a mouse model of familial hypercholesterolemia: A role for the LDL receptor and cholesterol metabolism in adult neural precursor cells

OBJECTIVE: In familial hypercholesterolemia (FH), mutations in the low-density lipoprotein (LDL) receptor (LDLr) gene result in increased plasma LDL cholesterol. Clinical and preclinical studies have revealed an association between FH and hippocampus-related memory and mood impairment. We here asked...

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Autores principales: Engel, Daiane F., Grzyb, Anna N., de Oliveira, Jade, Pötzsch, Alexandra, Walker, Tara L., Brocardo, Patricia S., Kempermann, Gerd, de Bem, Andreza F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812372/
https://www.ncbi.nlm.nih.gov/pubmed/31767163
http://dx.doi.org/10.1016/j.molmet.2019.09.002
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author Engel, Daiane F.
Grzyb, Anna N.
de Oliveira, Jade
Pötzsch, Alexandra
Walker, Tara L.
Brocardo, Patricia S.
Kempermann, Gerd
de Bem, Andreza F.
author_facet Engel, Daiane F.
Grzyb, Anna N.
de Oliveira, Jade
Pötzsch, Alexandra
Walker, Tara L.
Brocardo, Patricia S.
Kempermann, Gerd
de Bem, Andreza F.
author_sort Engel, Daiane F.
collection PubMed
description OBJECTIVE: In familial hypercholesterolemia (FH), mutations in the low-density lipoprotein (LDL) receptor (LDLr) gene result in increased plasma LDL cholesterol. Clinical and preclinical studies have revealed an association between FH and hippocampus-related memory and mood impairment. We here asked whether hippocampal pathology in FH might be a consequence of compromised adult hippocampal neurogenesis. METHODS: We evaluated hippocampus-dependent behavior and neurogenesis in adult C57BL/6JRj and LDLr(−/−) mice. We investigated the effects of elevated cholesterol and the function of LDLr in neural precursor cells (NPC) isolated from adult C57BL/6JRj mice in vitro. RESULTS: Behavioral tests revealed that adult LDLr(−/−) mice showed reduced performance in a dentate gyrus (DG)-dependent metric change task. This phenotype was accompanied by a reduction in cell proliferation and adult neurogenesis in the DG of LDLr(−/−) mice, suggesting a potential direct impact of LDLr mutation on NPC. Exposure of NPC to LDL as well as LDLr gene knockdown reduced proliferation and disrupted transcriptional activity of genes involved in endogenous cholesterol synthesis and metabolism. The LDL treatment also induced an increase in intracellular lipid storage. Functional analysis of differentially expressed genes revealed parallel modulation of distinct regulatory networks upon LDL treatment and LDLr knockdown. CONCLUSIONS: Together, these results suggest that high LDL levels and a loss of LDLr function, which are characteristic to individuals with FH, might contribute to a disease-related impairment in adult hippocampal neurogenesis and, consequently, cognitive functions.
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spelling pubmed-68123722019-10-30 Impaired adult hippocampal neurogenesis in a mouse model of familial hypercholesterolemia: A role for the LDL receptor and cholesterol metabolism in adult neural precursor cells Engel, Daiane F. Grzyb, Anna N. de Oliveira, Jade Pötzsch, Alexandra Walker, Tara L. Brocardo, Patricia S. Kempermann, Gerd de Bem, Andreza F. Mol Metab Original Article OBJECTIVE: In familial hypercholesterolemia (FH), mutations in the low-density lipoprotein (LDL) receptor (LDLr) gene result in increased plasma LDL cholesterol. Clinical and preclinical studies have revealed an association between FH and hippocampus-related memory and mood impairment. We here asked whether hippocampal pathology in FH might be a consequence of compromised adult hippocampal neurogenesis. METHODS: We evaluated hippocampus-dependent behavior and neurogenesis in adult C57BL/6JRj and LDLr(−/−) mice. We investigated the effects of elevated cholesterol and the function of LDLr in neural precursor cells (NPC) isolated from adult C57BL/6JRj mice in vitro. RESULTS: Behavioral tests revealed that adult LDLr(−/−) mice showed reduced performance in a dentate gyrus (DG)-dependent metric change task. This phenotype was accompanied by a reduction in cell proliferation and adult neurogenesis in the DG of LDLr(−/−) mice, suggesting a potential direct impact of LDLr mutation on NPC. Exposure of NPC to LDL as well as LDLr gene knockdown reduced proliferation and disrupted transcriptional activity of genes involved in endogenous cholesterol synthesis and metabolism. The LDL treatment also induced an increase in intracellular lipid storage. Functional analysis of differentially expressed genes revealed parallel modulation of distinct regulatory networks upon LDL treatment and LDLr knockdown. CONCLUSIONS: Together, these results suggest that high LDL levels and a loss of LDLr function, which are characteristic to individuals with FH, might contribute to a disease-related impairment in adult hippocampal neurogenesis and, consequently, cognitive functions. Elsevier 2019-09-11 /pmc/articles/PMC6812372/ /pubmed/31767163 http://dx.doi.org/10.1016/j.molmet.2019.09.002 Text en © 2019 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Engel, Daiane F.
Grzyb, Anna N.
de Oliveira, Jade
Pötzsch, Alexandra
Walker, Tara L.
Brocardo, Patricia S.
Kempermann, Gerd
de Bem, Andreza F.
Impaired adult hippocampal neurogenesis in a mouse model of familial hypercholesterolemia: A role for the LDL receptor and cholesterol metabolism in adult neural precursor cells
title Impaired adult hippocampal neurogenesis in a mouse model of familial hypercholesterolemia: A role for the LDL receptor and cholesterol metabolism in adult neural precursor cells
title_full Impaired adult hippocampal neurogenesis in a mouse model of familial hypercholesterolemia: A role for the LDL receptor and cholesterol metabolism in adult neural precursor cells
title_fullStr Impaired adult hippocampal neurogenesis in a mouse model of familial hypercholesterolemia: A role for the LDL receptor and cholesterol metabolism in adult neural precursor cells
title_full_unstemmed Impaired adult hippocampal neurogenesis in a mouse model of familial hypercholesterolemia: A role for the LDL receptor and cholesterol metabolism in adult neural precursor cells
title_short Impaired adult hippocampal neurogenesis in a mouse model of familial hypercholesterolemia: A role for the LDL receptor and cholesterol metabolism in adult neural precursor cells
title_sort impaired adult hippocampal neurogenesis in a mouse model of familial hypercholesterolemia: a role for the ldl receptor and cholesterol metabolism in adult neural precursor cells
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812372/
https://www.ncbi.nlm.nih.gov/pubmed/31767163
http://dx.doi.org/10.1016/j.molmet.2019.09.002
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