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High-fat diet-induced diabetes leads to vascular alterations, pericyte reduction, and perivascular depletion of microglia in a 6-OHDA toxin model of Parkinson disease

Elabi, Osama F. LU ; Cunha, João Paulo M.C.M. ; Gaceb, Abderahim LU ; Fex, Malin LU and Paul, Gesine LU orcid (2021) In Journal of Neuroinflammation 18(1).
Abstract

Background: Diabetes has been recognized as a risk factor contributing to the incidence and progression of Parkinson’s disease (PD). Although several hypotheses suggest a number of different mechanisms underlying the aggravation of PD caused by diabetes, less attention has been paid to the fact that diabetes and PD share pathological microvascular alterations in the brain. The characteristics of the interaction of diabetes in combination with PD at the vascular interface are currently not known. Methods: We combined a high-fat diet (HFD) model of diabetes mellitus type 2 (DMT2) with the 6-OHDA lesion model of PD in male mice. We analyzed the association between insulin resistance and the achieved degree of dopaminergic nigrostriatal... (More)

Background: Diabetes has been recognized as a risk factor contributing to the incidence and progression of Parkinson’s disease (PD). Although several hypotheses suggest a number of different mechanisms underlying the aggravation of PD caused by diabetes, less attention has been paid to the fact that diabetes and PD share pathological microvascular alterations in the brain. The characteristics of the interaction of diabetes in combination with PD at the vascular interface are currently not known. Methods: We combined a high-fat diet (HFD) model of diabetes mellitus type 2 (DMT2) with the 6-OHDA lesion model of PD in male mice. We analyzed the association between insulin resistance and the achieved degree of dopaminergic nigrostriatal pathology. We further assessed the impact of the interaction of the two pathologies on motor deficits using a battery of behavioral tests and on microglial activation using immunohistochemistry. Vascular pathology was investigated histologically by analyzing vessel density and branching points, pericyte density, blood–brain barrier leakage, and the interaction between microvessels and microglia in the striatum. Results: Different degrees of PD lesion were obtained resulting in moderate and severe dopaminergic cell loss. Even though the HFD paradigm did not affect the degree of nigrostriatal lesion in the acute toxin-induced PD model used, we observed a partial aggravation of the motor performance of parkinsonian mice by the diet. Importantly, the combination of a moderate PD pathology and HFD resulted in a significant pericyte depletion, an absence of an angiogenic response, and a significant reduction in microglia/vascular interaction pointing to an aggravation of vascular pathology. Conclusion: This study provides the first evidence for an interaction of DMT2 and PD at the brain microvasculature involving changes in the interaction of microglia with microvessels. These pathological changes may contribute to the pathological mechanisms underlying the accelerated progression of PD when associated with diabetes.

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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Diabetes, Parkinson’s disease, Pericytes, Perivascular microglia, Vascular alterations
in
Journal of Neuroinflammation
volume
18
issue
1
article number
175
publisher
BioMed Central (BMC)
external identifiers
  • pmid:34376193
  • scopus:85112345124
ISSN
1742-2094
DOI
10.1186/s12974-021-02218-8
language
English
LU publication?
yes
additional info
Funding Information: The study was supported by the Swedish Parkinson Foundation. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
id
59deebba-bf8f-4de2-bd12-fed48b305ffe
date added to LUP
2021-08-26 10:15:06
date last changed
2025-03-10 20:24:57
@article{59deebba-bf8f-4de2-bd12-fed48b305ffe,
  abstract     = {{<p>Background: Diabetes has been recognized as a risk factor contributing to the incidence and progression of Parkinson’s disease (PD). Although several hypotheses suggest a number of different mechanisms underlying the aggravation of PD caused by diabetes, less attention has been paid to the fact that diabetes and PD share pathological microvascular alterations in the brain. The characteristics of the interaction of diabetes in combination with PD at the vascular interface are currently not known. Methods: We combined a high-fat diet (HFD) model of diabetes mellitus type 2 (DMT2) with the 6-OHDA lesion model of PD in male mice. We analyzed the association between insulin resistance and the achieved degree of dopaminergic nigrostriatal pathology. We further assessed the impact of the interaction of the two pathologies on motor deficits using a battery of behavioral tests and on microglial activation using immunohistochemistry. Vascular pathology was investigated histologically by analyzing vessel density and branching points, pericyte density, blood–brain barrier leakage, and the interaction between microvessels and microglia in the striatum. Results: Different degrees of PD lesion were obtained resulting in moderate and severe dopaminergic cell loss. Even though the HFD paradigm did not affect the degree of nigrostriatal lesion in the acute toxin-induced PD model used, we observed a partial aggravation of the motor performance of parkinsonian mice by the diet. Importantly, the combination of a moderate PD pathology and HFD resulted in a significant pericyte depletion, an absence of an angiogenic response, and a significant reduction in microglia/vascular interaction pointing to an aggravation of vascular pathology. Conclusion: This study provides the first evidence for an interaction of DMT2 and PD at the brain microvasculature involving changes in the interaction of microglia with microvessels. These pathological changes may contribute to the pathological mechanisms underlying the accelerated progression of PD when associated with diabetes.</p>}},
  author       = {{Elabi, Osama F. and Cunha, João Paulo M.C.M. and Gaceb, Abderahim and Fex, Malin and Paul, Gesine}},
  issn         = {{1742-2094}},
  keywords     = {{Diabetes; Parkinson’s disease; Pericytes; Perivascular microglia; Vascular alterations}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Journal of Neuroinflammation}},
  title        = {{High-fat diet-induced diabetes leads to vascular alterations, pericyte reduction, and perivascular depletion of microglia in a 6-OHDA toxin model of Parkinson disease}},
  url          = {{http://dx.doi.org/10.1186/s12974-021-02218-8}},
  doi          = {{10.1186/s12974-021-02218-8}},
  volume       = {{18}},
  year         = {{2021}},
}