Objective: The aim of this study was to investigate the role of microvascular pathology between abnormal αSyn aggregation and PD cognitive dysfunction.

Background: Higher plasma alpha-synuclein (αSyn) levels are associated with cognitive impairment in Parkinson’s disease (PD); nevertheless, whether the pathologic αSyn affects cerebral microvascular system (CMS) and the intrinsic relationship between this effect and cognitive dysfunction still remains unknown.Mouse models of αSyn induced-PD pathology and cell model of αSyn aggregation were used to explore it.

Method: The relationship between cerebral microangiopathy and cognitive impairment was investigated in mouse models of αSyn injecting induced-PD pathology in vivo. We also studied the effects of αSyn aggregation on cerebral microvascular endothelium in vitro.

Results: Modeling αSyn induced-PD pathology in mice led to the impairment of CMS, neurovascular unit (NVU) coupling and blood-brain barrier (BBB), correspondingly exacerbating cognitive dysfunction. Significantly, in the early stage of post-injection, αSyn preformed fibril(s) (PFFs) triggered relatively mild tyrosine hydroxylase (TH)-positive cell loss, but led to more serious cerebral microvascular injury and cognitive decline.  In this stage of PFFs-induced αSyn pathology, a dissociation of TH⁺ neuronal damage and microvascular injury occurred, and compared with the degree of TH⁺ neuronal damage, the degree of cognitive decline was more consistent with the cerebral microvascular injury. In addition, primary cultured brain microvascular endothelial cells (BMVECs) in vitro and BMVECs in vivo were involved in the spreading of αSyn fibrils. Then, αSyn aggregation and the “activation of αSyn nucleation” could be initiated in brain microvascular endothelium cell line by PFFs, it caused endothelial dysfunction, decreased the expression of its structure and function associated proteins, and induced PARP-1 dependent cell death, which in turn interpreted why PFFs induced αSyn spreading and pathological damage in CMS to some extent.

Conclusion: This study demonstrated that cerebral microvascular injury provoked by the form of αSyn fibril may independently exacerbate cognitive impairment in PD, revealing experimental evidence for targeted blocking of αSyn fibrils transmission to BMVECs and inhibiting cerebral microvascular apoptosis for preventing PD cognitive impairment.

« Back to MDS Virtual Congress 2020

MDS Abstracts - https://www.mdsabstracts.org/abstract/cerebral-microvascular-injury-provoked-by-alpha-synuclein-preformed-fibrils-exacerbates-cognitive-dysfunction-in-parkinsons-disease/