Due to copyright issues, an electronic copy of the thesis must be ordered from the faculty. For the faculty to have time to process the order, the order must be received by the faculty at the latest 2 days before the public defence. Orders received later than 2 days before the defence will not be processed. After the public defence, please address any inquiries regarding the thesis to the candidate.
Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Professor Alexei Verkhratsky, University of Manchester, UK
- Second opponent: Overlege Eli Gunnarson, The Karolinska Institute, Sweden
- Third member and chair of the evaluation committee: Associate Professor Johanne Egge Rinholm, University of Oslo
Chair of the Defence
Associate Professor Jan Magnus Aronsen, University of Oslo
Principal Supervisor
Professor Mahmood Amiry-Moghaddam, University of Oslo
Summary
Astrocytes are among the most abundant cell types in the CNS, playing crucial homeostatic roles. They possess specialized membrane domains abutting microvessels and processes communicating with neighboring astrocytes through gap junctions. The perivascular membrane domains are endowed with the water channel protein Aquaporin-4 (AQP4), which is anchored to these domains by interacting with α-syntrophin, a component of the dystrophin-associated protein complex (DAPC).
Aberrant expression and mislocalization of AQP4 are common features of various neurological and neurodegenerative disorders, including Alzheimer’s disease, stroke, and epilepsy. The mechanisms underlying the altered expression and mislocalization of AQP4 remain elusive.
In this thesis, we demonstrate that the deletion of astrocytic gap junction proteins results in a decrease in the expression level and perivascular density of AQP4, while deletion of syntrophins leads to the mislocalization of AQP4, an increased number of astrocytic gap junctions, and reduced levels of the AQP4-ex isoform. Mislocalization of AQP4 and reduced levels of its AQP4-ex isoform are also observed during the early stages of scar formation following experimental stroke. Furthermore, we identify the canonical BMP signaling pathway as the key regulator of the expression and mislocalization of AQP4.
We propose that the altered expression and mislocalization of AQP4 can be influenced by various intra-, inter-, and extracellular factors, with BMP signaling potentially playing a significant role in regulating these processes under pathological conditions. Our findings offer new insights on possible approaches to control AQP4 expression and localization, which could aid in the development of therapeutic interventions for neurological conditions such as stroke.
Additional information
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