Palazzo, C. | bioRxiv Science

bioRxiv2024

Aquaporin-4 expression levels and mis-localization are inversely linked to peritumoral edema in gliomas of varying aggressiveness

Aquaporin-4 (AQP4) and its extended isoform, AQP4ex, are crucial for regulating brain water homeostasis. Mis-localization of these isoforms is implicated in various brain tumors, including glioblastoma multiforme (GBM). This study explores AQP4 isoform expression and localization in Pilocytic Astrocytomas (PA), a circumscribed astrocytic low-grade glioma, compared to GBM, an adult-type diffuse high grade glioma. We found significant upregulation of AQP4 and AQP4ex in PA, with notable mis-localization deviating from the typical perivascular localization seen in healthy tissue. This mis-localization mirrors the phenotype observed in AQP4ex knockout models, where impaired AQP4 localization is linked to disrupted water homeostasis and reduced waste clearance, despite overall increased AQP4 levels. Interestingly, PA shows minimal peritumoral edema and a relatively intact blood-brain barrier (BBB), with elevated phosphorylated AQP4ex (pAQP4ex) suggesting a role in stabilizing AQP4 function. In contrast, GBM exhibits reduced AQP4/AQP4ex expression, significant peritumoral edema, and BBB disruption. GFAP isoforms, GFAP{kappa} and GFAP{delta}, are upregulated in PA, associated with Rosenthal fibers, indicating a stabilizing astrocytic response. GBM, however, shows generalized GFAP increase, reflecting aggressive gliosis and disrupted water homeostasis. In conclusion, both AQP4 expression levels and mis-localization are important factors influencing peritumoral edema and tumor aggressiveness in gliomas. This study positions AQP4 as a potential biomarker for glioma progression, offering insights into astrocytic function and paving the way for targeted therapies.

cancer biology↗

bioRxiv2024

The Aquaporin-4 expression and localization in the olfactory epithelium modulate the odorant-evoked responses and olfactory driven behavior

Aquaporin-4 (AQP4) is a water-selective channel expressed in glial cells throughout the central nervous system. It serves as the main water channel in the neuropil, and is involved in various physiological functions, ranging from regulating water homeostasis by adjusting cell volume to modulating neuronal activity. Different isoforms of AQP4 are expressed in glial-like cells known as sustentacular cells (SUSs) of the olfactory epithelium (OE). Interestingly, mice lacking all AQP4 isoforms exhibit impaired olfactory abilities. Hence, we aim to uncover the physiological role of two AQP4 isoforms, the perivascular AQP4ex isoform and the Orthogonal Array of Particle (OAP)-forming isoform (AQP4M23) in the OE. Primarily, we investigated the impact of AQP4 isoforms on OE protein expression, finding reduced levels of mature olfactory sensory neurons (OSNs) in mice lacking AQP4ex (AQP4ex-KO) or OAPs (OAP-null). Moreover, the reduced number of OSNs, SUSs, and globose basal cells (GBCs) suggests that AQP4 isoforms are involved in maintaining an optimal microenvironment in the OE, preserving the overall cell density. Then, we explored the role of AQP4 in modulating odorant-evoked responses through electro-olfactogram recordings, finding reduced odorant responses in mice lacking AQP4 isoforms. Olfactory ability assessments revealed deficits in odor-guided food-seeking test in AQP4ex-KO and OAP-null mice. Furthermore, AQP4ex-KO mice showed a reduced ability to discriminate between different odorants, while OAP-null mice were unable to recognize them as distinct. Overall, our data highlight the role of AQP4 isoforms in modulating neuronal homeostasis, affecting odorant-evoked responses and cell density in the OE. These results shed light on SUSs involvement in mediating these processes and establish a foundation for further understanding their role in controlling OE physiology.

neuroscience↗