Abstract
Glial gap junction proteins, called connexins (Cxs), form gap junctions in the central nervous system (CNS) to allow the bidirectional cytosolic exchange of molecules between adjacent cells. Their involvement in inheritable diseases and the use of experimental animal models that closely mimic such diseases revealed the critical role of glial GJs in myelination and homeostasis. Cxs are also implicated in acquired demyelinating disorders, such as Multiple Sclerosis (MS) and Alzheimer’s disease (AD). Animal and human studies have revealed a role of the astrocytic Cx43 in the progression of AD but the role of Cx47, which is the main partner of Cx43 in the astrocyte-oligodendrocyte GJs is still unknown. The aim of this study was to investigate the astrocytic connexins, Cx43 and Cx30 in relation to oligodendrocytic Cx47 in the cortex and thalamus of the 5XFAD mouse model of AD. The model was characterized by increased Aβ deposition, gliosis, neuronal loss, and memory impairment. Compared to wild-type mice, Cx43 and Cx30 showed increased immunoreactivity in older 5XFAD mice, reflecting astrogliosis, while Cx47 immunoreactivity was reduced. Moreover, Cx47 GJ plaques showed reduced colocalization with Cx43 plaques. Oligodendrocyte precursor cells (OPCs) and mature oligodendrocyte populations were also depleted, and myelin deficits were observed. Our findings indicate reduced astrocyte-oligodendrocyte gap junction connectivity and possibly a shift in Cx43 expression toward astrocyte-astrocyte gap junctions and/or hemichannels, that could impair oligodendrocyte homeostasis and myelination. However, other factors, such as Aβ toxicity, could directly affect oligodendrocyte survival in AD. Our study provides evidence that Cxs might have implications in the progression of AD, although the role of oligodendrocyte Cxs in AD requires further investigation.
Highlights
Alzheimer’s disease (AD) is the most common form of irreversible dementia and is characterized by the loss of cognitive function (Skaper, 2012)
Aβ deposition gradually increased with age and larger deposits were observed in 9- months-old 5XFAD mice compared to 3- and 6-months-old animals (Figures 1A,B)
Since reactive astrocytes are involved in inflammatory responses, surrounding Aβ plaques in AD (Perez-Nievas and SerranoPozo, 2018) we further investigated the expression of the major astrocytic Cxs (Cx43 and Cx30) which compose the gap junctions (GJs) or HCs in 5XFAD mice
Summary
Alzheimer’s disease (AD) is the most common form of irreversible dementia and is characterized by the loss of cognitive function (Skaper, 2012). Familial AD mutations in the APP and PSEN1 genes affect the proteolytic processing of the amyloid precursor protein (APP), with increased accumulation of Aβ peptides (especially Aβ42) causing neuronal toxicity (Hardy and Selkoe, 2002; Haass and Selkoe, 2007; Reiss et al, 2018). Tissue damage caused by Aβ accumulation was confirmed in 5XFAD mice, a transgenic mouse model of familial AD, by showing elevated levels of nitrotyrosine (NT), a toxic product of superoxide reaction with nitric oxide (NO) (Modi et al, 2015). INOS gene expression levels in 5XFAD and control mice were found to be similar, indicating that iNOS is not excessively produced by glial cells of this mouse model (Griñán-Ferré et al, 2016)
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