Loss of Astrocyte Polarization in the Tg-ArcSwe Mouse Model of Alzheimer's Disease

Abstract

Aquaporin-4 (AQP4) is the predominant water channel in brain and is selectively expressed in astrocytes. Astrocytic endfoot membranes exhibit tenfold higher densities of AQP4 than non-endfoot membranes, making AQP4 an excellent marker of astrocyte polarization. Loss of astrocyte polarization is known to compromise astrocytic function and to be associated with impaired water and K+ homeostasis. Here we investigate by a combination of light and electron microscopic immunocytochemistry whether amyloid deposition is associated with a loss of astrocyte polarization, using AQP4 as a marker. We used the tg-ArcSwe mouse model of Alzheimer's disease, as this model displays perivascular plaques as well as plaques confined to the neuropil. 3D reconstructions were done to establish the spatial relation between plaques and astrocytic endfeet, the latter known to contain the perivascular pool of AQP4. Changes in AQP4 expression emerge just after the appearance of the first plaques. Typically, there is a loss of AQP4 from endfoot membranes at sites of perivascular amyloid deposits, combined with an upregulation of AQP4 in the neuropil surrounding plaques. By electron microscopy it could be verified that the upregulation reflects an increased concentration of AQP4 in those delicate astrocytic processes that abound in synaptic regions. Thus, astrocytes exhibit a redistribution of AQP4 from endfoot membranes to non-endfoot membrane domains. The present data suggest that the development of amyloid deposits is associated with a loss of astrocyte polarization. The possible perturbation of water and K+ homeostasis could contribute to cognitive decline and seizure propensity in patients with Alzheimer's disease.

Cytoprotective effects of growth factors: BDNF more potent than GDNF in an organotypic culture model of Parkinson's disease

“…In line with our findings in paper IV, AQP4 upregulation has been found to be strong in the neuropil in AD (342,346). Further, AQP4 expression is largely studied in relation to senile plaques, where AQP4 is reported to be lost in vessels associated with such plaques in a mouse model of AD (346) and in the dense core of plaque bodies in human neocortex but enhanced at the borders of the plaque (342), whilst another study shows that AQP4-ir corresponds to plaques and is increased in perivascular membranes (343). 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).…”

“…In patients with AD, upregulation of AQP4 and GFAP has been reported in cortical astrocytes, along with increased Aqp4 mRNA in a mouse model of AD (343,345,364). In line with our findings in paper IV, AQP4 upregulation has been found to be strong in the neuropil in AD (342,346). Further, AQP4 expression is largely studied in relation to senile plaques, where AQP4 is reported to be lost in vessels associated with such plaques in a mouse model of AD (346) and in the dense core of plaque bodies in human neocortex but enhanced at the borders of the plaque (342), whilst another study shows that AQP4-ir corresponds to plaques and is increased in perivascular membranes (343).…”

“…This contradiction can possibly be explained by a study showing upregulation of AQP4 in the neuropil surrounding plaques and loss of AQP4 from endfoot membranes at sites of perivascular amyloid deposits (346), indicating a redistribution of AQP4 from endfoot membranes to non-endoot domains. Furthermore, low concentration of amyloid-β induced AQP4-expression in astrocytic cell cultures, whereas higher concentrations reduced the expression (347).…”

“…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.…”

Glial-conditional deletion of aquaporin-4 ( Aqp4 ) reduces blood–brain water uptake and confers barrier function on perivascular astrocyte endfeet

“…In other words, astrocytes may acquire barrier function and restrict water exchange between brain and blood, dependent on their complement of AQP4. This finding has direct implications for a number of experimental and clinical conditions that are characterized by a loss of perivascular AQP4, including mesial temporal lobe epilepsy (16), experimental stroke (17), and a model of Alzheimer's disease (18).…”