Behavioral and electrophysiological evidence for a neuroprotective role of aquaporin-4 in the 5xFAD transgenic mice model
Open Access
- 12 May 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Acta Neuropathologica Communications
- Vol. 8 (1), 1-15
- https://doi.org/10.1186/s40478-020-00936-3
Abstract
Aquaporin-4 (AQP4) has been suggested to be involved in the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD), which may be due to the modulation of neuroinflammation or the impairment of interstitial fluid bulk flow system in the central nervous system. Here, we show an age-dependent impairment of several behavioral outcomes in 5xFAD AQP4 null mice. Twenty-four-hour video recordings and computational analyses of their movement revealed that the nighttime motion of AQP4-deficient 5xFAD mice was progressively reduced between 20 and 36 weeks of age, with a sharp deterioration occurring between 30 and 32 weeks. This reduction in nighttime motion was accompanied by motor dysfunction and epileptiform neuronal activities, demonstrated by increased abnormal spikes by electroencephalography. In addition, all AQP4-deficient 5xFAD mice exhibited convulsions at least once during the period of the analysis. Interestingly, despite such obvious phenotypes, parenchymal amyloid beta (A beta) deposition, reactive astrocytosis, and activated microgliosis surrounding amyloid plaques were unchanged in the AQP4-deficient 5xFAD mice relative to 5xFAD mice. Taken together, our data indicate that AQP4 deficiency greatly accelerates an age-dependent deterioration of neuronal function in 5xFAD mice associated with epileptiform neuronal activity without significantly altering A beta deposition or neuroinflammation in this mouse model. We therefore propose that there exists another pathophysiological phase in AD which follows amyloid plaque deposition and neuroinflammation and is sensitive to AQP4 deficiency.Funding Information
- Japan Society for the Promotion of Science (Grant-in-Aid for Challenging Exploratory Research (2567025), Grant-in-Aid for Challenging Research (Exploratory) (17K19637), Grant-in-Aid for Scientific Research (B) (18H02606))
- Ministry of Education, Science, Sports and Culture of Japan (Grant-in-Aid for Scientific Research on Innovative Areas “Platform of Advanced Animal Model Support” (16H06276))
- Suntory Global Innovation Center Ltd. (program “Water Channeling Life”)
- Keio University (Program for the Advancement of Research in Core Projects under Keio University’s Longevity Initiative)
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