Reactive Pericytes Lead to Microvascular Dysfunction and Cortical Neurodegeneration During Experimental Autoimmune Encephalomyelitis

YOUSEFI, M.; Özkan, A.; Kutay Özmen, K.; Uysalli, Y.; Mamipour, M.; Akkaya, N.; Dalal Amandi, A.-R.; Atbasi, A.; Heidarzadeh, M.; Evren Erdener, S.; Kawakami, N.; Kiraz, A.; Gürsoy Özdemir, Y.; Vural, A.

doi:10.1101/2025.02.17.638582

bioRxiv · 10.1101/2025.02.17.638582

Reactive Pericytes Lead to Microvascular Dysfunction and Cortical Neurodegeneration During Experimental Autoimmune Encephalomyelitis

YOUSEFI, M.·Özkan, A.·Kutay Özmen, K.·Uysalli, Y.·Mamipour, M.·Akkaya, N.·Dalal Amandi, A.-R.·Atbasi, A.·Heidarzadeh, M.·Evren Erdener, S.·Kawakami, N.·Kiraz, A.·Gürsoy Özdemir, Y.·Vural, A.

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Abstract

The mechanisms underlying neurodegeneration in multiple sclerosis remain incompletely understood. In this study, we aimed to investigate the role of vascular dysfunction in cortical neurodegeneration using a chronic cranial window model of experimental autoimmune encephalomyelitis in mice. After the induction of experimental autoimmune encephalomyelitis with myelin oligodendrocyte glycoprotein peptides in C57BL/6J mice, we assessed cerebrovascular reactivity though a chronic cranial window using laser speckle contrast imaging and intrinsic optical signal imaging in awake animals. We observed a significant reduction in cortical cerebrovascular reactivity during peak inflammation in the EAE group, as detected by laser speckle contrast imaging after 5% hypercapnia (p=0.04) and optical signal imaging after whisker stimulation (p=0.008). Histological analysis revealed a diffuse increase in CD13+ pericyte coverage (p=0.001), accompanied by focal IgG deposition within the microvascular lumen (p=0.04) and increased amount of CD45+ leukocytes stalled in microvessels (p=0.03) in the cortex of experimental autoimmune encephalomyelitis mice. Microglial activation was also present in the cortex of experimental autoimmune encephalomyelitis mice (p=0.04) and was particularly evident around microvessels with IgG deposition. Subpial and intracortical foci exhibiting loss of NeuN reactivity (p=0.03) and axonal loss (p=0.007) were detected in experimental autoimmune encephalomyelitis, but not in control mice. Altogether, these results demonstrate that microvascular function and neurovascular unit elements are globally affected in the cortex during autoimmune neuroinflammation and is related to neurodegeneration.

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YOUSEFI, M., Özkan, A., Kutay Özmen, K., Uysalli, Y., Mamipour, M., Akkaya, N., Dalal Amandi, A.-R., Atbasi, A., Heidarzadeh, M., Evren Erdener, S., Kawakami, N., Kiraz, A., Gürsoy Özdemir, Y., Vural, A.. 2025-02-20. Reactive Pericytes Lead to Microvascular Dysfunction and Cortical Neurodegeneration During Experimental Autoimmune Encephalomyelitis. https://doi.org/10.1101/2025.02.17.638582

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