Aquaporin-4 reduces neuropathology in a mouse model of Alzheimer’s disease by remodeling peri-plaque astrocyte structure

Abstract

Redistribution of the water channel aquaporin-4 (AQP4) away from astrocyte endfeet and into parenchymal processes is a striking histological feature in mouse models of Alzheimer’s disease (AD) and other neurological conditions with prominent astrogliosis. AQP4 redistribution has been proposed to impair bulk Aβ clearance in AD, resulting in increased amyloid deposition in the brain; however, this finding is controversial. Here, we provide evidence in support of a different and novel role of AQP4 in AD. We found that Aqp4 deletion significantly increased amyloid deposition in cerebral cortex of 5xFAD mice, with an increase in the relative number of fibrillar vs. dense core plaques. AQP4 deficient 5xFAD mice also showed a significant reduction in the density of GFAP labeled peri-plaque astrocyte processes. Microglial plaque coverage was also significantly reduced, suggesting astrocyte involvement in organizing the peri-plaque glial response. The alterations in peri-plaque glial structure were accompanied by increased neuronal uptake of Aβ and an increase in the number of dystrophic neurites surrounding plaques. On the basis of these findings, we propose that redistribution of AQP4 into the parenchymal processes facilitates astrocyte structural plasticity and the formation of a reactive glial net around plaques that protects neurons from the deleterious effects of Aβ aggregates. AQP4 redistribution may thus facilitate plaque containment and reduce neuropathology in AD.

Microglia prevent beta-amyloid plaque formation in the early stage of an Alzheimer’s disease mouse model with suppression of glymphatic clearance

“…An early study from our laboratory has reported that AQP4 deficiency decreases Aβ uptake in cultured astrocytes, and in turn attenuates changes in MAPK signaling pathways, finally reducing astrocyte activity [46]. Similarly, reduced reactive astroglosis is likewise 13 observed in 7-9-month-old AQP4 -/-/5xTg-AD mouse brains [47]. These data together indicate that long-term loss of AQP4 not only damages glymphatic clearance of Aβ, but also decreases astrocyte phagocytosis of Aβ, in turn exacerbating the pathological progression of AD.…”

Microglia prevent beta-amyloid plaque formation in the early stage of an Alzheimer’s disease mouse model with suppression of glymphatic clearance

“…An early study from our laboratory has reported that AQP4 deficiency decreases Aβ uptake in cultured astrocytes, and in turn attenuates changes in mitogen-activated protein kinase pathways, finally reducing astrocyte activity [48]. Similarly, reduced reactive astroglosis is likewise observed in 7-9-monthold AQP4 -/-/5xTg-AD mouse brains [49]. These data together indicate that long-term loss of AQP4 not only damages glymphatic clearance of Aβ, but also decreases astrocyte phagocytosis of Aβ, in turn exacerbating the pathological progression of AD.…”

Synaptic Loss, ER Stress and Neuro-Inflammation Emerge Late in the Lateral Temporal Cortex and Associate with Progressive Tau Pathology in Alzheimer’s Disease

“…Despite the fact that GFAP and thus astrogliosis can be considered a robust indicator of the disease, we failed to observe any significant overt change in the water channel AQP4, thought to be involved in the glymphatic clearance of Aβ [82,83] and proposed to be disrupted in AD [36]. Nevertheless, our measurements of AQP4 were either sampled at random within the temporal lobe via histology or represented total tissue levels in immunoblots and thus were not localised to the site of plaques, where greatest changes have been identified [84,85]. We similarly detected no changes in the expression levels for Iba1, a general marker of microglia.…”