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.
Subject(s)
Alzheimer Disease/genetics , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Astrocytes/physiology , Cell Polarity/genetics , Amyloid beta-Protein Precursor/genetics , Animals , Aquaporin 4/metabolism , Astrocytes/ultrastructure , Diagnosis, Computer-Assisted , Disease Models, Animal , Glial Fibrillary Acidic Protein/metabolism , Humans , Mice , Mice, Transgenic , Microscopy, Immunoelectron , Mutation/genetics , Platelet Endothelial Cell Adhesion Molecule-1/metabolismABSTRACT
Little is known about how amyloid-beta (Abeta) is deposited in relation to the complex ultrastructure of the brain. Here we combined serial section immunoelectron microscopy with 3D reconstruction to elucidate the spatial relationship between Abeta deposits and ultrastructurally identified cellular compartments. The analysis was performed in a transgenic mouse model with mutant presenilin-1, and mutant amyloid-beta protein precursor (AbetaPP) and tau transgenes (3xTg-AD mice) and in aged dogs that develop Abeta plaques spontaneously. Reconstructions based on serial ultrathin sections of hippocampus (mice) or neocortex (dogs) that had been immunolabeled with Abeta (Abeta(1-42)) antibodies showed that the organization of extracellular Abeta deposits is more complex than anticipated from light microscopic analyses. In both species, deposits were tightly associated with plasma membranes of pyramidal cell bodies and major dendrites. The deposits typically consisted of thin sheets as well as slender tendrils that climbed along the large caliber dendritic stems of pyramidal neurons. No preferential association was observed between Abeta deposits and thin dendritic branches or spines, nor was there any evidence of preferential accumulation of Abeta around synaptic contacts or glial processes. Our data suggest that plaque formation is a precisely orchestrated process that involves specialized domains of dendrosomatic plasma membranes.
