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

Journal of Neuroinflammation

Osama F. Elabi¹  Abderahim Gaceb¹  Gesine Paul²  João Paulo M. C. M. Cunha³  Malin Fex³ 

[1] Translational Neurology Group, Department of Clinical Science, Wallenberg Neuroscience Center and Wallenberg Center for Molecular Medicine, Lund University, 22184, Lund, Sweden;Translational Neurology Group, Department of Clinical Science, Wallenberg Neuroscience Center and Wallenberg Center for Molecular Medicine, Lund University, 22184, Lund, Sweden;Department of Neurology, Scania University Hospital, 22185, Lund, Sweden;Unit of Molecular Metabolism, Lund University Diabetes Centre, Box 50332, Jan Waldenströms gata 35, 202 13, Malmö, Sweden;

关键词: Diabetes;    Parkinson’s disease;    Vascular alterations;    Pericytes;    Perivascular microglia;   

DOI  :  10.1186/s12974-021-02218-8

来源: Springer

【 摘 要 】

BackgroundDiabetes 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.MethodsWe 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.ResultsDifferent 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.ConclusionThis 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.

【 授权许可】

CC BY