Altered Expression of Glial Gap Junction Proteins Cx43, Cx30, and Cx47 in the 5XFAD Model of Alzheimer’s Disease

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 astrocyteoligodendrocyte 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 astrocyteastrocyte 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.

Glial Purinergic Signaling in Neurodegeneration

“…Also, the involvement of oligodendrocyte-specific connexins such as connexin-29 (CX29 or Gjc3), connexin-32 (CX32 or Gjb1) or connexin-47 (CX47 or Gjc2) in a manner similar to CX43 in astrocytes cannot be ruled out (179). A study showed a downregulation of oligodendrocytic CX47 in an AD model, contrasting with the increase of CX43 observed in astrocytes (180). The authors stipulate that such modification could favor astrocyte-astrocyte connection at the expense of astrocyte-oligodendrocyte communication, contributing to oligodendrocyte function impairment.…”

Astroglial Connexins in Neurodegenerative Diseases

“…Cx43 and Cx30 normally function as GJCs, as was repeatedly shown by experiments in acute brain slices from knockout mice, including the astrocytic Cx43 conditional knockout mice (hGFAP-cre:Cx43 f l/fl ), the Cx30 knockout mice (Dere et al, 2003;Theis et al, 2003), and the double KO mice (hGFAPcre:Cx43 f l/fl :Cx30 KO) (Wallraff et al, 2006;Rouach et al, 2008;Pannasch et al, 2011;Roux et al, 2011). The expression levels of these two Cxs in astrocytes varies in different brain regions (Batter et al, 1992;Nadarajah et al, 1996;Nagy et al, 1999), and can be changed in neurodegenerative diseases, such as AD (Mei et al, 2010;Yi et al, 2016;Angeli et al, 2020). Additionally, Cx26 has also been detected in certain astrocytes to a lesser extent (Altevogt and Paul, 2004;Lynn et al, 2011;Nagy et al, 2011).…”

“…Twenty years ago, Nagy and colleagues have firstly demonstrated that astrocyte Cx43 protein levels are increased in the brain tissue of AD patients, especially around the Aβ plaques (Nagy et al, 1995), which has been repeatedly confirmed (Kajiwara et al, 2018), and is also found in the APP/PS1 mouse model (Mei et al, 2010;Yi et al, 2016). However, a recent study showed that the mRNA level of Cx43 is decreased in the cortex and thalamus area of another mouse model of AD, 5xFAD mice, albeit the increased protein levels (Angeli et al, 2020). Treatment of Aβ 25−35 on primary astrocytes also results in a similar negative correlation between Cx43 mRNA and protein levels (Maulik et al, 2020).…”

Dysregulation of Astrocyte–Neuronal Communication in Alzheimer’s Disease

“…Several studies have proposed that connexin 43 (Cx43) in a hemichannel function mediates the Aβ peptide induction of ATP release from astrocytes. Thus, Cx43 is upregulated in AD mouse models and AD human brains [149][150][151][152]. Moreover, amyloid exposure triggers the increased expression of Cx43 both in vitro and in vivo AD models [82,153,154].…”