Objective: To evaluate cerebral hypoperfusion on cognitive dysfunction and related microvascular impairment in the MPTP mouse model.

Background: Vascular pathology and Parkinson’s disease (PD) pathology have been shown to coexist in the brains of dementia patients. However, the mechanisms underlying microvascular impairment and cognitive dysfunction remain poorly understood. In this study we aim to investigate how cognitive impairment could be exacerbated in a C57BL/6 mouse model of combined injury through the interaction of chronic cerebral hypoperfusion and MPTP toxicity.

Methods: PD mouse model was established by intraperitoneal injection of MPTP combined with probenecid. Further, chronic cerebral hypoperfusion was modeled by bilateral common carotid atrery stenesis (BCCAs) with piano wire. All animals were divided into 7 groups: control group, sham group, BCCAs group, PDCN group, PDMCI group, PDCN+BCCAs group and PDMCI+BCCAs group. A Morris water maze task, Open field test, and histological investigation were performed. Microvascular related pathology detection and transmission electron microscope were also performed. Last but not least, Western blot was used to investigate the underlying mechanisms of cerebral microvascular injury.

Results: Spatial memory impairment was synergistically exacerbated in the PDMCI+BCCAs group as compared to the BCCAs group or PDCN+BCCAs group. Either single MPTP treatment or BCCAs operation might induce increased vascular permeability, broken tight junctions of the vascular endothelial cells, decreased vasoganglion density and neovascularization, Moreover, when combined MPTP treatment with cerebral hypoperfusion, these observed injuries became worse, and we observed the most prominent microvascular structural damage in the PDMCI+BCCAs group then PDCN+BCCAs group. We further demonstrated that the mentioned microvascular injuries were related to the activation of AKT/MAPK signal pathways and subsequent reduced expression levels of tight junction protein ZO-1 and Occludin.

Conclusions: Our experimental results support a clinical hypothesis of the deleterious interaction between chronic cerebral hypoperfusion and MPTP injection. Chronic cerebral hypoperfusion induced perturbation in the equilibrium of PD-related pathology may exacerbate cognitive impairment in a mouse model of combined injury.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/chronic-cerebral-hypoperfusion-accelerates-cognitive-dysfunction-and-microvascular-impairment-in-the-mptp-mouse-model-of-parkinsons-disease/