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 β (Aβ) 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 Aβ 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.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and is the most common cause of dementia
AQP4 deficiency accelerated a loss of activity and induced motor dysfunction in female 5xFAD mice We observed that female 5xFAD/AQP4 KO mice exhibited motor dysfunction, for example demonstrating difficulty in holding food while eating
To clarify the onset and quantify the degree of this immobility, we observed the behavior of female 5xFAD, AQP4 KO, and 5xFAD/AQP4 KO mice using Digital VivariumTM (Vium, San Mateo, CA), a 24-h video recording and computational analysis system which assesses the movements of individual mice, between 20 and 36 weeks of age
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and is the most common cause of dementia. It has been reported that the expression of AQP4 is upregulated around amyloid plaques in AD patients and mouse models of AD [14, 15, 57,58,59], but the functional significance of these findings are unclear. In models of chronic Parkinson’s disease [50], cryoinjury [46], and focal cerebral ischemia [47] AQP4 deficiency enhanced neuroinflammation, leading to severe neuronal damage. These findings suggest that AQP4 function might be implicated in the pathogenesis of AD
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