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.

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Humanin (HN) is a secretory 24-residue peptide. HN was first identified as a cytoprotective factor that suppresses neuronal death in Alzheimer's disease and exerts the activity through cell surface receptors. Subsequent studies revealed that HN can reverse disease-associated change in cellular functions of various types of tissues including brain, muscle, and pancreas. It is also reported that HN increases mitochondrial ATP production in some cell types. The level of HN in circulation decreases age-dependently in rodents and human. However physiological roles of HN is largely unknown. In this study, we assessed the effect of HN against stress in mice. We gave immobilization stress to young male mice and measured their blood glucose levels over time. The immobilization stress caused increase in the glucose level after 30 min to 90 min of the treatment. Intraperitoneal injection of S14G-HN, a highly potent HN derivative, attenuated the stress-induced increase in the glucose level. S14G-HN alone showed no significant change in the glucose level which was similar to that of non-stressed mice. A neuroprotection-defective HN mutant did not affect the stress-induced increase in the blood glucose level, suggesting that this anti-stress effect of HN is mediated by a receptor.

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