Aquaporin‐4 Overexpression in Rat ALS Model

Abstract

Onset of motoneuron death characterizing amyotrophic lateral sclerosis (ALS) is closely linked to modified astrocytic and glial environments. Here, we show that in the spinal cord from transgenic rat overexpressing mutated human SOD1, aquaporin-4 mRNA and protein are specifically overexpressed in the gray matter at end stage of disease. Immunohistochemistry and double immunofluorescence allowed to detect, in the spinal cord gray matter of the ALS rat, increased aquaporin-4 surrounding both vessel and motoneuron perikarya. The use of pre-embedding immunohistochemistry at electron microscopic level confirmed such localization associated with swollen astrocytic processes surrounding the vessels. The AQP4 immunohistochemical labeling surrounding several motoneuron perikarya was only seen in ALS rats. Identification of this AQP4-positive cellular type remains unclear.

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“…In contrast, we find an increased expression of AQP4 in perivascular as well as perineural membranes, in addition to the neuropil, accompanied by elevated expression of GFAP, following neurotoxic treatment. This pattern is in line with several disease models, including ischemic stroke (449) (348,365) and spongiform encephalopathy (349). As these chronic neurodegenerative diseases share similarities with PD, they provide an indication of AQP4 expression in relation to regional, progressive cell death.…”

“…Potentially, a PD model including LBs would have painted a different picture on AQP4 distribution in PD than our models, as astrocytes are known to accumulate α-synuclein (452). Further, in models of ALS, a slight upregulation of perivascular AQP4 and GFAP has been described in mice (365), whereas vast upregulation of AQP4 mRNA and protein has been shown in rats, where expression was increased around vessels together with GFAP, and in motoneuron perikaya (348). These results also indicate that differences between species may be present, which has also been found between bovine and mice in spongiform encephalopathy, with more pronounced expression and earlier upregulation of AQP4 in bovine (349).…”

“…It has been demonstrated that the expression of astrocytes is particularly low in the SNpc (182), although their role in the pathogenesis of PD remains largely unexplored. AQP4 is shown to play a role in several chronic neurodegenerative diseases, where its expression is upregulated and potentially linked to neuroinflammatory processes (335,342,348,350). However, its expression in PD requires further support, and it remains to be elucidated whether it plays a beneficial or detrimental role.…”

“…However, evidence for changes in the number or astrocyte reactivity in postmortem brains of PD patients is inconsistent (185,187), and gliosis has been shown to be more prominent in models of PD than in patients (186). Notably, upregulation of AQP4 is not necessarily co-localized with GFAP expression, as shown in a mouse model of ALS (348), and GFAP upregulation is not automatically accompanied by an increase in AQP4, evident in a model of cerebral malaria (341). This indicates that AQP4 expression is not linearly related to GFAP.…”

“…It is demonstrated that the number of astrocytes in the SNpc is particularly low (182), although the phenotypic expression of these astrocytes is not well described, including the expression of AQP4. This aquaporin has been shown to be implicated in several chronic neurodegenerative diseases, where up-and downregulation as well as loss of endfoot polarization have been described (342,343,345,346,(348)(349)(350). The expression pattern of AQP4 in PD remains largely unexplored, however.…”