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

Abstract

Gap junctions (GJs) are specialized transmembrane channels assembled by two hemi-channels 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 Aβ plaques in the spinal cord of the 5xFAD mouse model of AD. Our analysis revealed abundant Aβ 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 Aβ 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-to-oligodendrocyte 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 Aβ 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.

Bayesian genome-wide TWAS with reference transcriptomic data of brain and blood tissues identified 93 risk genes for Alzheimer’s disease dementia

“…First, due to the computation burden of running BGW-TWAS tool, we only applied BGW-TWAS to reference GTEx V8 data of three tissues (prefrontal cortex, cortex, and whole blood). Other tissues such as hippocampus, muscle, and spinal cord, are also known to play crucial roles in the biological mechanisms of AD dementia [57,58,59]. Failing to consider all available tissues in GTEx V8 data may fail to capture a full spectrum of genetically regulated gene expression associated with AD dementia.…”

Modification of astrocytic Cx43 hemichannel activity in animal models of AD: modulation by adenosine A2A receptors

“…Astrocytic hemichannels are mainly composed of hexamers of Cx43 and Cx30, which accumulate in astrocyte processes allowing the release of gliotransmitter and ion fluxes that can regulate hippocampal synaptic transmission and plasticity, and consequently memory [ 12 , 13 ]. Astrocytic Cx43 levels are upregulated in animal models of AD, namely in transgenic APP/PS1 and 5xFAD mice [ 14 – 16 ]. Moreover, there are evidences of dysfunctional astrocytic hemichannels in animal models of AD that do not exhibit alterations on gap junction astrocytic communication [ 17 – 19 ].…”