Abstract
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.
Highlights
Diabetes has been recognized as a risk factor contributing to the incidence and progression of Parkinson’s disease (PD)
high-fat diet (HFD) does not affect the degree of the nigrostriatal lesion in a 6‐OHDA PD model In order to induce insulin resistance and mimic diabetes mellitus type 2 (DMT2), we fed mice a HFD or control diet (CTRL) diet for 7 weeks before inducing a nigrostriatal lesion by administration of 6-OHDA into the medial forebrain bundle (MFB)
We determined whether all animals in the HFD group had developed insulin resistance and if there was a correlation between insulin resistance and the degree of nigral dopaminergic neuron loss
Summary
Diabetes has been recognized as a risk factor contributing to the incidence and progression of Parkinson’s disease (PD). 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. Elucidation of factors that contribute to disease progression may help to reveal the underlying mechanisms aggravating the disease and identify targets that can be addressed to slow disease progression. Numerous studies suggest an association between neurodegeneration and metabolic diseases. Additional evidence supporting the link between metabolic dysfunction and neurodegeneration comes from clinical and preclinical studies demonstrating a beneficial effect of anti-diabetic medication in PD [11] and PD models reviewed in [12]
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