Glial Gap Junction Pathology in the Spinal Cord of the 5xFAD Mouse Model of Early-Onset Alzheimer's Disease

Gap junctions (GJs) are specialized transmembrane channels assembled by two hemichannels of six connexin (Cx) proteins that facilitate neuroglial crosstalk in the central nervous system (CNS). Previous studies confirmed the crucial role of glial GJs in neurodegenerative disorders with dementia or motor dysfunction including Alzheimer's disease (AD). The aim of this study was to examine the alterations in astrocyte and related oligodendrocyte GJs in association with A beta plaques in the spinal cord of the 5xFAD mouse model of AD. Our analysis revealed abundant A beta plaque deposition, activated microglia, and astrogliosis in 12-month-old (12M) 5xFAD mice, with significant impairment of motor performance starting from 3-months (3M) of age. Additionally, 12M 5xFAD mice displayed increased immunoreactivity of astroglial Cx43 and Cx30 surrounding A beta plaques and higher protein levels, indicating upregulated astrocyte-to-astrocyte GJ connectivity. In addition, they demonstrated increased numbers of mature CC1-positive and precursor oligodendrocytes (OPCs) with higher immunoreactivity of Cx47-positive GJs in individual cells. Moreover, total Cx47 protein levels were significantly elevated in 12M 5xFAD, reflecting increased oligodendrocyte-tooligodendrocyte Cx47-Cx47 GJ connectivity. In contrast, we observed a marked reduction in Cx32 protein levels in 12M 5xFAD spinal cords compared with controls, while qRT-PCR analysis revealed a significant upregulation in Cx32 mRNA levels. Finally, myelin deficits were found focally in the areas occupied by A beta plaques, whereas axons themselves remained preserved. Overall, our data provide novel insights into the altered glial GJ expression in the spinal cord of the 5xFAD model of AD and the implicated role of GJ pathology in neurodegeneration. Further investigation to understand the functional consequences of these extensive alterations in oligodendrocyte-astrocyte (O/A) GJ connectivity is warranted.

Automated summary

This study examined the changes in glial gap junctions (GJs) in the spinal cord of the 5xFAD mouse model of Alzheimer's disease (AD). The results showed increased astrocyte-to-astrocyte GJ connectivity and oligodendrocyte-to-oligodendrocyte GJ connectivity. Additionally, Cx32 protein levels were reduced while mRNA levels were upregulated. The findings suggest the importance of GJ pathology in neurodegenerative disorders.