Nogo-A/S1PR2 Signaling Pathway Inactivation Decreases Microvascular Damage and Enhances Microvascular Regeneration in PDMCI Mice

The incidence of mild cognitive impairment in Parkinson's disease (PDMCI) is as high as 18-55%. However, the pathological mechanism of PDMCI is not yet clear. Our previous research showed that microvascular pathology and chronic cerebral hypoperfusion participated in the occurrence and development of PDMCI. Nogo-A has been suggested to be a negative regulator of microvascular regeneration in the central nervous system. Moreover, few insights have illuminated the mechanisms of Nogo-A and microvascular pathology in PDMCI. Therefore, we hypothesized that Nogo-A might be involved in the negative regulation of PDMCI angiogenesis. In this study, C57BL/6J mice were injected with Nogo-A-specific short hairpin RNA (shRNA-Nogo-A) in the lateral ventricle and intraperitoneally injected with a combination of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and probenecid. Subjects were classified into the following five groups for the Morris water maze test: control (CON), CON + shRNA-GFP, CON + shRNA-Nogo-A, PDMCI, and PDMCI + shRNA-Nogo-A. Furthermore, blood-brain barrier (BBB) permeability, fluorescein isothiocyanate (FITC)-conjugated dextran, transmission electron microscopy (TEM), immunofluorescence and Western blot analyses were performed. The results showed that MPTP could cause spatial memory and behavioral impairment, significant microvascular impairment and increased Nogo-A expression. When Nogo-A expression was downregulated, the cognitive and microvascular impairments were alleviated, and the expression of sphingosine-1-phosphate receptor 2 (S1PR2) and the RhoA/ROCK signaling pathway were inhibited. These findings suggested that Nogo-A could bind to S1PR2, activate related signaling pathways, and lead to the inhibition of vascular remodeling in PDMCI mice. This study indicated that Nogo-A downregulation could mediate microvascular remodeling and provide further insights into the pathogenesis of PDMCI.