Abstract
Cystatin C (CYS C, Cst3) is an endogenous cysteine protease inhibitor that plays neuroprotective roles in neurodegenerative diseases. We aimed to explore the association of CYS C with Parkinson’s disease (PD) models and investigate its involvement in the role of neurovascular units (NVUs) in PD neuro-pathogenesis. We used A53T α-synuclein (SNCA) transgenic mice and 6-hydroxydopamine-lesioned DAergic PC12 cells as experimental PD models to investigate the mechanisms behind this association. The injections of CYS C were administered to the right substantia nigra (SN) of A53T SNCA transgenic mice to measure the effects of CYS C in transgenic A53T SNCA mice. To explore the angiogenesis in vivo and in vitro, we used the chick embryo chorioallantoic membrane (CAM) assay and tube formation (TF) assay. We found that CYS C has a neuroprotective effect in this in vivo PD model. We observed increased VEGF, NURR1 and autophagy markers LC3B and decreased SNCA and apoptosis marker cleaved CASP3 in different brain regions of CYS C-treated A53T SNCA transgenic mice. In vitro, we observed that CYS C-induced VEGF, a secreted protein, attenuated 6-OHDA-lesioned DAergic PC12 cell degeneration by regulating p-PKC-α/p-ERK1/2-Nurr1 signaling and inducing autophagy. VEGF-mediated angiogenesis was markedly enhanced in the conditioned media of 6-OHDA-lesioned PC12 cells with CYS C-overexpression, whereas blockage of autophagy in CYS C-overexpressing PC12 cells significantly downregulated VEGF expression and the associated angiogenesis. Our data indicate that CYS C displays dual neuronal–vascular functions, promoting PC12 cell survival and angiogenesis via regulating the level of secreted VEGF in NVUs. Our study provides evidence that may aid in the development of an alternative approach for the treatment of PD through modulation of CYS C-mediated neuronal-vascular pathways.
Highlights
(NVUs), which regulate important pathological functions in neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s diseases (PD).[1,2] Several lines of evidence indicate that NVUs disruption, especially abnormal neuronal-vascular relationships, play an important role in PD pathogenesis.[3,4] In the NVUs, some secreted molecules such as vascular endothelial growth factors (VEGFs) are key components that mediate neuronal survival and maintain vascular homeostasis and promote angiogenesis.[5,6,7]
We observed that SQSTM1 decreased by 3.4-fold, 1.6-fold, 2.1-fold and 4.3-fold (SN) in Cystatin C (CYS C)-treated A53T SNCA mice compared to A53T SNCA mice (***Po0.001, CYS C-treated A53T versus A53T, n = 5; Figure 1A and B)
The current study shows that CYS C is a potential mediator functioning to induce angiogenesis and enhance cellular autophagy in the NVUs of PD models
Summary
(NVUs), which regulate important pathological functions in neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s diseases (PD).[1,2] Several lines of evidence indicate that NVUs disruption, especially abnormal neuronal-vascular relationships, play an important role in PD pathogenesis.[3,4] In the NVUs, some secreted molecules such as vascular endothelial growth factors (VEGFs) are key components that mediate neuronal survival and maintain vascular homeostasis and promote angiogenesis.[5,6,7]. In PD patients, increased VEGF in the CSF is associated with blood–brain barrier (BBB) dysfunction and neural degeneration.[8] Several lines of evidence have indicated that the secreted molecule VEGF could regulate angiogenesis and promote neuronal survival.[9,10,11] On the other hand, recent studies have shown that neuronal events such as autophagy could regulate the cerebral microenvironment, leading to disruption of the NVUs.[12] the neuronal–vascular relationship is critical for cerebral functions in aging-related diseases such as PD. We sought to determine: (1) how VEGF/NURR1 levels and autophagy change in the brain of CYS C-treated A53T α-synuclein (SNCA) mice, an in vivo PD model; (2) in an in vitro study, whether CYS C exerts neuronal–vascular dual functions in promoting DAergic PC12 cell survival and angiogenesis via regulating the secreted protein VEGF in NVUs; (3) how CYS C-mediated enhanced
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