Apolipoprotein E protects against neuropathology induced by a high-fat diet and maintains the integrity of the blood-brain barrier during aging

Monique Mulder; Arjan Blokland; Dirk Jan Van Den Berg; Henny Schulten; Arjen H.F. Bakker; Dick Terwel; Wiel Honig; E. Ronald De Kloet; Louis M. Havekes; Harry W.M. Steinbusch; Elizabeth C.M. De Lange

doi:10.1038/labinvest.3780307

Apolipoprotein E protects against neuropathology induced by a high-fat diet and maintains the integrity of the blood-brain barrier during aging

Monique Mulder^*, Arjan Blokland, Dirk Jan Van Den Berg, Henny Schulten, Arjen H.F. Bakker, Dick Terwel, Wiel Honig, E. Ronald De Kloet, Louis M. Havekes, Harry W.M. Steinbusch, Elizabeth C.M. De Lange

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

63 Citations (Scopus)

Abstract

The present study provides evidence that chronic intake of a high-fat diet induces a dramatic extravasation of immunoglobulins, indicating alterations in blood-brain barrier (BBB) functioning, in the brains of apolipoprotein E (apoE)-knockout mice, but not of C57BI/6 control mice. Using sodium fluorescein as a marker for the permeability of the BBB, we found additional support for age-related disturbances of BBB function in apoE-knockout mice. Behavioral analysis of apoE-knockout mice compared with C57BI/6 mice indicated that they were also less efficient in acquiring the spatial Morris water maze task. Furthermore, apoE-knockout mice are known to develop severe atherosclerosis, which is exacerbated with a high-fat diet. We therefore compared the apoE-knockout mice with the apoE3-Leiden transgenic mice, which are known to develop atherosclerosis. However, apoE3-Leiden mice that were kept on a high-fat, high-cholesterol diet and that developed atherosclerosis to an extent similar to the apoE-knockout mice, showed no signs of BBB disturbances. These results indicate for the first time that apoE plays an essential role in the maintenance of the integrity of the BBB during aging and that it protects the brain from neuropathology induced by a high-fat diet. We therefore hypothesize that the role of apoE in the maintenance of the integrity of the BBB may be the mechanism by which apoE affects the progression of neurodegeneration, as seen in Alzheimer's disease.

Original language	English
Pages (from-to)	953-960
Number of pages	8
Journal	Laboratory Investigation
Volume	81
Issue number	7
DOIs	https://doi.org/10.1038/labinvest.3780307
Publication status	Published - 1 Jul 2001
Externally published	Yes

Bibliographical note

Funding Information:
This study was supported in part by grants from the Internationale Stichting Alzheimer Onderzoek (ISAO, Grant 98505) and the Hersenstichting Nederland (Grant H00.15). Address reprint requests to: Dr. Monique Mulder, Maastricht University, Department of Psychiatry and Neuropsychology, Universiteitssingel 50, P.O. Box 616, 6200 MD Maastricht, The Netherlands. E-mail: [email protected]

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Mulder, M., Blokland, A., Van Den Berg, D. J., Schulten, H., Bakker, A. H. F., Terwel, D., Honig, W., De Kloet, E. R., Havekes, L. M., Steinbusch, H. W. M., & De Lange, E. C. M. (2001). Apolipoprotein E protects against neuropathology induced by a high-fat diet and maintains the integrity of the blood-brain barrier during aging. Laboratory Investigation, 81(7), 953-960. https://doi.org/10.1038/labinvest.3780307

@article{ecd8250a8808465e803c834d329fe809,

title = "Apolipoprotein E protects against neuropathology induced by a high-fat diet and maintains the integrity of the blood-brain barrier during aging",

abstract = "The present study provides evidence that chronic intake of a high-fat diet induces a dramatic extravasation of immunoglobulins, indicating alterations in blood-brain barrier (BBB) functioning, in the brains of apolipoprotein E (apoE)-knockout mice, but not of C57BI/6 control mice. Using sodium fluorescein as a marker for the permeability of the BBB, we found additional support for age-related disturbances of BBB function in apoE-knockout mice. Behavioral analysis of apoE-knockout mice compared with C57BI/6 mice indicated that they were also less efficient in acquiring the spatial Morris water maze task. Furthermore, apoE-knockout mice are known to develop severe atherosclerosis, which is exacerbated with a high-fat diet. We therefore compared the apoE-knockout mice with the apoE3-Leiden transgenic mice, which are known to develop atherosclerosis. However, apoE3-Leiden mice that were kept on a high-fat, high-cholesterol diet and that developed atherosclerosis to an extent similar to the apoE-knockout mice, showed no signs of BBB disturbances. These results indicate for the first time that apoE plays an essential role in the maintenance of the integrity of the BBB during aging and that it protects the brain from neuropathology induced by a high-fat diet. We therefore hypothesize that the role of apoE in the maintenance of the integrity of the BBB may be the mechanism by which apoE affects the progression of neurodegeneration, as seen in Alzheimer's disease.",

author = "Monique Mulder and Arjan Blokland and {Van Den Berg}, {Dirk Jan} and Henny Schulten and Bakker, {Arjen H.F.} and Dick Terwel and Wiel Honig and {De Kloet}, {E. Ronald} and Havekes, {Louis M.} and Steinbusch, {Harry W.M.} and {De Lange}, {Elizabeth C.M.}",

note = "Funding Information: This study was supported in part by grants from the Internationale Stichting Alzheimer Onderzoek (ISAO, Grant 98505) and the Hersenstichting Nederland (Grant H00.15). Address reprint requests to: Dr. Monique Mulder, Maastricht University, Department of Psychiatry and Neuropsychology, Universiteitssingel 50, P.O. Box 616, 6200 MD Maastricht, The Netherlands. E-mail: [email protected]",

year = "2001",

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doi = "10.1038/labinvest.3780307",

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Mulder, M, Blokland, A, Van Den Berg, DJ, Schulten, H, Bakker, AHF, Terwel, D, Honig, W, De Kloet, ER, Havekes, LM, Steinbusch, HWM & De Lange, ECM 2001, 'Apolipoprotein E protects against neuropathology induced by a high-fat diet and maintains the integrity of the blood-brain barrier during aging', Laboratory Investigation, vol. 81, no. 7, pp. 953-960. https://doi.org/10.1038/labinvest.3780307

TY - JOUR

T1 - Apolipoprotein E protects against neuropathology induced by a high-fat diet and maintains the integrity of the blood-brain barrier during aging

AU - Mulder, Monique

AU - Blokland, Arjan

AU - Van Den Berg, Dirk Jan

AU - Schulten, Henny

AU - Bakker, Arjen H.F.

AU - Terwel, Dick

AU - Honig, Wiel

AU - De Kloet, E. Ronald

AU - Havekes, Louis M.

AU - Steinbusch, Harry W.M.

AU - De Lange, Elizabeth C.M.

N1 - Funding Information: This study was supported in part by grants from the Internationale Stichting Alzheimer Onderzoek (ISAO, Grant 98505) and the Hersenstichting Nederland (Grant H00.15). Address reprint requests to: Dr. Monique Mulder, Maastricht University, Department of Psychiatry and Neuropsychology, Universiteitssingel 50, P.O. Box 616, 6200 MD Maastricht, The Netherlands. E-mail: [email protected]

PY - 2001/7/1

Y1 - 2001/7/1

N2 - The present study provides evidence that chronic intake of a high-fat diet induces a dramatic extravasation of immunoglobulins, indicating alterations in blood-brain barrier (BBB) functioning, in the brains of apolipoprotein E (apoE)-knockout mice, but not of C57BI/6 control mice. Using sodium fluorescein as a marker for the permeability of the BBB, we found additional support for age-related disturbances of BBB function in apoE-knockout mice. Behavioral analysis of apoE-knockout mice compared with C57BI/6 mice indicated that they were also less efficient in acquiring the spatial Morris water maze task. Furthermore, apoE-knockout mice are known to develop severe atherosclerosis, which is exacerbated with a high-fat diet. We therefore compared the apoE-knockout mice with the apoE3-Leiden transgenic mice, which are known to develop atherosclerosis. However, apoE3-Leiden mice that were kept on a high-fat, high-cholesterol diet and that developed atherosclerosis to an extent similar to the apoE-knockout mice, showed no signs of BBB disturbances. These results indicate for the first time that apoE plays an essential role in the maintenance of the integrity of the BBB during aging and that it protects the brain from neuropathology induced by a high-fat diet. We therefore hypothesize that the role of apoE in the maintenance of the integrity of the BBB may be the mechanism by which apoE affects the progression of neurodegeneration, as seen in Alzheimer's disease.

AB - The present study provides evidence that chronic intake of a high-fat diet induces a dramatic extravasation of immunoglobulins, indicating alterations in blood-brain barrier (BBB) functioning, in the brains of apolipoprotein E (apoE)-knockout mice, but not of C57BI/6 control mice. Using sodium fluorescein as a marker for the permeability of the BBB, we found additional support for age-related disturbances of BBB function in apoE-knockout mice. Behavioral analysis of apoE-knockout mice compared with C57BI/6 mice indicated that they were also less efficient in acquiring the spatial Morris water maze task. Furthermore, apoE-knockout mice are known to develop severe atherosclerosis, which is exacerbated with a high-fat diet. We therefore compared the apoE-knockout mice with the apoE3-Leiden transgenic mice, which are known to develop atherosclerosis. However, apoE3-Leiden mice that were kept on a high-fat, high-cholesterol diet and that developed atherosclerosis to an extent similar to the apoE-knockout mice, showed no signs of BBB disturbances. These results indicate for the first time that apoE plays an essential role in the maintenance of the integrity of the BBB during aging and that it protects the brain from neuropathology induced by a high-fat diet. We therefore hypothesize that the role of apoE in the maintenance of the integrity of the BBB may be the mechanism by which apoE affects the progression of neurodegeneration, as seen in Alzheimer's disease.

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DO - 10.1038/labinvest.3780307

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Apolipoprotein E protects against neuropathology induced by a high-fat diet and maintains the integrity of the blood-brain barrier during aging

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