Incidence of microvascular dysfunction is increased in hyperlipidemic mice, reducing cerebral blood flow and impairing remote memory
IntroductionThe development of cognitive dysfunction is not necessarily associated with diet-induced obesity. We hypothesized that cognitive dysfunction might require additional vascular damage, for example, in atherosclerotic mice.MethodsWe induced atherosclerosis in male C57BL/6N mice by injecting...
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Frontiers Media S.A.
2024-02-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2024.1338458/full |
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| author | Luis Daniel Hernandez Torres Flavia Rezende Flavia Rezende Eva Peschke Olga Will Jan-Bernd Hövener Frauke Spiecker Ümit Özorhan Josephine Lampe Ines Stölting Zouhair Aherrahrou Zouhair Aherrahrou Carsten Künne Kristina Kusche-Vihrog Kristina Kusche-Vihrog Urte Matschl Susanne Hille Susanne Hille Ralf P. Brandes Ralf P. Brandes Markus Schwaninger Markus Schwaninger Markus Schwaninger Oliver J. Müller Oliver J. Müller Walter Raasch Walter Raasch Walter Raasch |
| author_facet | Luis Daniel Hernandez Torres Flavia Rezende Flavia Rezende Eva Peschke Olga Will Jan-Bernd Hövener Frauke Spiecker Ümit Özorhan Josephine Lampe Ines Stölting Zouhair Aherrahrou Zouhair Aherrahrou Carsten Künne Kristina Kusche-Vihrog Kristina Kusche-Vihrog Urte Matschl Susanne Hille Susanne Hille Ralf P. Brandes Ralf P. Brandes Markus Schwaninger Markus Schwaninger Markus Schwaninger Oliver J. Müller Oliver J. Müller Walter Raasch Walter Raasch Walter Raasch |
| author_sort | Luis Daniel Hernandez Torres |
| collection | DOAJ |
| description | IntroductionThe development of cognitive dysfunction is not necessarily associated with diet-induced obesity. We hypothesized that cognitive dysfunction might require additional vascular damage, for example, in atherosclerotic mice.MethodsWe induced atherosclerosis in male C57BL/6N mice by injecting AAV-PCSK9DY (2x1011 VG) and feeding them a cholesterol-rich Western diet. After 3 months, mice were examined for cognition using Barnes maze procedure and for cerebral blood flow. Cerebral vascular morphology was examined by immunehistology.ResultsIn AAV-PCSK9DY-treated mice, plaque burden, plasma cholesterol, and triglycerides are elevated. RNAseq analyses followed by KEGG annotation show increased expression of genes linked to inflammatory processes in the aortas of these mice. In AAV-PCSK9DY-treated mice learning was delayed and long-term memory impaired. Blood flow was reduced in the cingulate cortex (-17%), caudate putamen (-15%), and hippocampus (-10%). Immunohistological studies also show an increased incidence of string vessels and pericytes (CD31/Col IV staining) in the hippocampus accompanied by patchy blood-brain barrier leaks (IgG staining) and increased macrophage infiltrations (CD68 staining).DiscussionWe conclude that the hyperlipidemic PCSK9DY mouse model can serve as an appropriate approach to induce microvascular dysfunction that leads to reduced blood flow in the hippocampus, which could explain the cognitive dysfunction in these mice. |
| first_indexed | 2024-03-07T21:42:55Z |
| format | Article |
| id | doaj.art-d4b6fd0e43c94446adef814c1470c76c |
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| language | English |
| last_indexed | 2024-03-07T21:42:55Z |
| publishDate | 2024-02-01 |
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| spelling | doaj.art-d4b6fd0e43c94446adef814c1470c76c2024-02-26T04:48:40ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922024-02-011510.3389/fendo.2024.13384581338458Incidence of microvascular dysfunction is increased in hyperlipidemic mice, reducing cerebral blood flow and impairing remote memoryLuis Daniel Hernandez Torres0Flavia Rezende1Flavia Rezende2Eva Peschke3Olga Will4Jan-Bernd Hövener5Frauke Spiecker6Ümit Özorhan7Josephine Lampe8Ines Stölting9Zouhair Aherrahrou10Zouhair Aherrahrou11Carsten Künne12Kristina Kusche-Vihrog13Kristina Kusche-Vihrog14Urte Matschl15Susanne Hille16Susanne Hille17Ralf P. Brandes18Ralf P. Brandes19Markus Schwaninger20Markus Schwaninger21Markus Schwaninger22Oliver J. Müller23Oliver J. Müller24Walter Raasch25Walter Raasch26Walter Raasch27Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, GermanyInstitute for Cardiovascular Physiology, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, GermanyDZHK (German Center for Cardiovascular Research) Partner Site Rhine-Main, GermanySection Biomedical Imaging, Molecular Imaging North Competence Center (MOIN CC), Department of Radiology and Neuroradiology, Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, Kiel, GermanySection Biomedical Imaging, Molecular Imaging North Competence Center (MOIN CC), Department of Radiology and Neuroradiology, Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, Kiel, GermanySection Biomedical Imaging, Molecular Imaging North Competence Center (MOIN CC), Department of Radiology and Neuroradiology, Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, Kiel, GermanyInstitute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, GermanyInstitute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, GermanyInstitute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, GermanyInstitute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, GermanyInstitute for Cardiogenetics, University Lübeck; University of Lübeck, Lübeck, GermanyDZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, GermanyDepartment of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, GermanyDZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, GermanyInstitute for Physiology, University Lübeck, Lübeck, GermanyDepartment Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, GermanyDZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Germany0Department of Internal Medicine III, University Hospital Schleswig-Holstein, Kiel, GermanyInstitute for Cardiovascular Physiology, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, GermanyDZHK (German Center for Cardiovascular Research) Partner Site Rhine-Main, GermanyInstitute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, GermanyDZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Germany1CBBM (Centre for Brain, Behavior and Metabolism), University of Lübeck, Lübeck, GermanyDZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Germany0Department of Internal Medicine III, University Hospital Schleswig-Holstein, Kiel, GermanyInstitute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, GermanyDZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Germany1CBBM (Centre for Brain, Behavior and Metabolism), University of Lübeck, Lübeck, GermanyIntroductionThe development of cognitive dysfunction is not necessarily associated with diet-induced obesity. We hypothesized that cognitive dysfunction might require additional vascular damage, for example, in atherosclerotic mice.MethodsWe induced atherosclerosis in male C57BL/6N mice by injecting AAV-PCSK9DY (2x1011 VG) and feeding them a cholesterol-rich Western diet. After 3 months, mice were examined for cognition using Barnes maze procedure and for cerebral blood flow. Cerebral vascular morphology was examined by immunehistology.ResultsIn AAV-PCSK9DY-treated mice, plaque burden, plasma cholesterol, and triglycerides are elevated. RNAseq analyses followed by KEGG annotation show increased expression of genes linked to inflammatory processes in the aortas of these mice. In AAV-PCSK9DY-treated mice learning was delayed and long-term memory impaired. Blood flow was reduced in the cingulate cortex (-17%), caudate putamen (-15%), and hippocampus (-10%). Immunohistological studies also show an increased incidence of string vessels and pericytes (CD31/Col IV staining) in the hippocampus accompanied by patchy blood-brain barrier leaks (IgG staining) and increased macrophage infiltrations (CD68 staining).DiscussionWe conclude that the hyperlipidemic PCSK9DY mouse model can serve as an appropriate approach to induce microvascular dysfunction that leads to reduced blood flow in the hippocampus, which could explain the cognitive dysfunction in these mice.https://www.frontiersin.org/articles/10.3389/fendo.2024.1338458/fullatherosclerosis AAV-PCSK9DY mouse modelcognitive dysfunctioncerebral blood flowhyperlipidemiapericytespatchy blood-brain barrier leaks |
| spellingShingle | Luis Daniel Hernandez Torres Flavia Rezende Flavia Rezende Eva Peschke Olga Will Jan-Bernd Hövener Frauke Spiecker Ümit Özorhan Josephine Lampe Ines Stölting Zouhair Aherrahrou Zouhair Aherrahrou Carsten Künne Kristina Kusche-Vihrog Kristina Kusche-Vihrog Urte Matschl Susanne Hille Susanne Hille Ralf P. Brandes Ralf P. Brandes Markus Schwaninger Markus Schwaninger Markus Schwaninger Oliver J. Müller Oliver J. Müller Walter Raasch Walter Raasch Walter Raasch Incidence of microvascular dysfunction is increased in hyperlipidemic mice, reducing cerebral blood flow and impairing remote memory Frontiers in Endocrinology atherosclerosis AAV-PCSK9DY mouse model cognitive dysfunction cerebral blood flow hyperlipidemia pericytes patchy blood-brain barrier leaks |
| title | Incidence of microvascular dysfunction is increased in hyperlipidemic mice, reducing cerebral blood flow and impairing remote memory |
| title_full | Incidence of microvascular dysfunction is increased in hyperlipidemic mice, reducing cerebral blood flow and impairing remote memory |
| title_fullStr | Incidence of microvascular dysfunction is increased in hyperlipidemic mice, reducing cerebral blood flow and impairing remote memory |
| title_full_unstemmed | Incidence of microvascular dysfunction is increased in hyperlipidemic mice, reducing cerebral blood flow and impairing remote memory |
| title_short | Incidence of microvascular dysfunction is increased in hyperlipidemic mice, reducing cerebral blood flow and impairing remote memory |
| title_sort | incidence of microvascular dysfunction is increased in hyperlipidemic mice reducing cerebral blood flow and impairing remote memory |
| topic | atherosclerosis AAV-PCSK9DY mouse model cognitive dysfunction cerebral blood flow hyperlipidemia pericytes patchy blood-brain barrier leaks |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2024.1338458/full |
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