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Peripheral Inflammation, Apolipoprotein E4, and Amyloid-β Interact to Induce Cognitive and Cerebrovascular Dysfunction
Cerebrovascular dysfunction is rapidly reemerging as a major process of Alzheimer’s disease (AD). It is, therefore, crucial to delineate the roles of AD risk factors in cerebrovascular dysfunction. While apolipoprotein E4 (APOE4), Amyloid-β (Aβ), and peripheral inflammation independently induce cere...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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SAGE Publications
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5521356/ https://www.ncbi.nlm.nih.gov/pubmed/28707482 http://dx.doi.org/10.1177/1759091417719201 |
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author | Marottoli, Felecia M. Katsumata, Yuriko Koster, Kevin P. Thomas, Riya Fardo, David W. Tai, Leon M. |
author_facet | Marottoli, Felecia M. Katsumata, Yuriko Koster, Kevin P. Thomas, Riya Fardo, David W. Tai, Leon M. |
author_sort | Marottoli, Felecia M. |
collection | PubMed |
description | Cerebrovascular dysfunction is rapidly reemerging as a major process of Alzheimer’s disease (AD). It is, therefore, crucial to delineate the roles of AD risk factors in cerebrovascular dysfunction. While apolipoprotein E4 (APOE4), Amyloid-β (Aβ), and peripheral inflammation independently induce cerebrovascular damage, their collective effects remain to be elucidated. The goal of this study was to determine the interactive effect of APOE4, Aβ, and chronic repeated peripheral inflammation on cerebrovascular and cognitive dysfunction in vivo. EFAD mice are a well-characterized mouse model that express human APOE3 (E3FAD) or APOE4 (E4FAD) and overproduce human Aβ42 via expression of 5 Familial Alzheimer’s disease (5xFAD) mutations. Here, we utilized EFAD carriers [5xFAD(+/−)/APOE(+/+) (EFAD+)] and noncarriers [5xFAD(−/−)/APOE(+/+) (EFAD−)] to compare the effects of peripheral inflammation in the presence or absence of human Aβ overproduction. Low-level, chronic repeated peripheral inflammation was induced in EFAD mice via systemic administration of lipopolysaccharide (LPS; 0.5 mg/kg/wk i.p.) from 4 to 6 months of age. In E4FAD+ mice, peripheral inflammation caused cognitive deficits and lowered post-synaptic protein levels. Importantly, cerebrovascular deficits were observed in LPS-challenged E4FAD+ mice, including cerebrovascular leakiness, lower vessel coverage, and cerebral amyloid angiopathy-like Aβ deposition. Thus, APOE4, Aβ, and peripheral inflammation interact to induce cerebrovascular damage and cognitive deficits. |
format | Online Article Text |
id | pubmed-5521356 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | SAGE Publications |
record_format | MEDLINE/PubMed |
spelling | pubmed-55213562017-08-07 Peripheral Inflammation, Apolipoprotein E4, and Amyloid-β Interact to Induce Cognitive and Cerebrovascular Dysfunction Marottoli, Felecia M. Katsumata, Yuriko Koster, Kevin P. Thomas, Riya Fardo, David W. Tai, Leon M. ASN Neuro Original Paper Cerebrovascular dysfunction is rapidly reemerging as a major process of Alzheimer’s disease (AD). It is, therefore, crucial to delineate the roles of AD risk factors in cerebrovascular dysfunction. While apolipoprotein E4 (APOE4), Amyloid-β (Aβ), and peripheral inflammation independently induce cerebrovascular damage, their collective effects remain to be elucidated. The goal of this study was to determine the interactive effect of APOE4, Aβ, and chronic repeated peripheral inflammation on cerebrovascular and cognitive dysfunction in vivo. EFAD mice are a well-characterized mouse model that express human APOE3 (E3FAD) or APOE4 (E4FAD) and overproduce human Aβ42 via expression of 5 Familial Alzheimer’s disease (5xFAD) mutations. Here, we utilized EFAD carriers [5xFAD(+/−)/APOE(+/+) (EFAD+)] and noncarriers [5xFAD(−/−)/APOE(+/+) (EFAD−)] to compare the effects of peripheral inflammation in the presence or absence of human Aβ overproduction. Low-level, chronic repeated peripheral inflammation was induced in EFAD mice via systemic administration of lipopolysaccharide (LPS; 0.5 mg/kg/wk i.p.) from 4 to 6 months of age. In E4FAD+ mice, peripheral inflammation caused cognitive deficits and lowered post-synaptic protein levels. Importantly, cerebrovascular deficits were observed in LPS-challenged E4FAD+ mice, including cerebrovascular leakiness, lower vessel coverage, and cerebral amyloid angiopathy-like Aβ deposition. Thus, APOE4, Aβ, and peripheral inflammation interact to induce cerebrovascular damage and cognitive deficits. SAGE Publications 2017-07-14 /pmc/articles/PMC5521356/ /pubmed/28707482 http://dx.doi.org/10.1177/1759091417719201 Text en © The Author(s) 2017 http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). |
spellingShingle | Original Paper Marottoli, Felecia M. Katsumata, Yuriko Koster, Kevin P. Thomas, Riya Fardo, David W. Tai, Leon M. Peripheral Inflammation, Apolipoprotein E4, and Amyloid-β Interact to Induce Cognitive and Cerebrovascular Dysfunction |
title | Peripheral Inflammation, Apolipoprotein E4, and Amyloid-β Interact to Induce Cognitive and Cerebrovascular Dysfunction |
title_full | Peripheral Inflammation, Apolipoprotein E4, and Amyloid-β Interact to Induce Cognitive and Cerebrovascular Dysfunction |
title_fullStr | Peripheral Inflammation, Apolipoprotein E4, and Amyloid-β Interact to Induce Cognitive and Cerebrovascular Dysfunction |
title_full_unstemmed | Peripheral Inflammation, Apolipoprotein E4, and Amyloid-β Interact to Induce Cognitive and Cerebrovascular Dysfunction |
title_short | Peripheral Inflammation, Apolipoprotein E4, and Amyloid-β Interact to Induce Cognitive and Cerebrovascular Dysfunction |
title_sort | peripheral inflammation, apolipoprotein e4, and amyloid-β interact to induce cognitive and cerebrovascular dysfunction |
topic | Original Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5521356/ https://www.ncbi.nlm.nih.gov/pubmed/28707482 http://dx.doi.org/10.1177/1759091417719201 |
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