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Astrocyte dysfunction emerges early in Alzheimer's disease (AD) and may contribute to its pathology and progression. Recently, the voltage gated potassium channel KV3.4 subunit, which underlies the fast-inactivating K(+) currents, has been recognized to be relevant for AD pathogenesis and is emerging as a new target candidate for AD. In the present study, we investigated both in in vitro and in vivo models of AD the expression and functional activity of KV3.4 potassium channel subunits in astrocytes. In primary astrocytes our biochemical, immunohistochemical, and electrophysiological studies demonstrated a time-dependent upregulation of KV3.4 expression and functional activity after exposure to amyloid-β (Aβ) oligomers. Consistently, astrocytic KV3.4 expression was upregulated in the cerebral cortex, hippocampus, and cerebellum of 6-month-old Tg2576 mice. Further, confocal triple labeling studies revealed that in 6-month-old Tg2576 mice, KV3.4 was intensely coexpressed with Aβ in nonplaque associated astrocytes. Interestingly, in the cortical and hippocampal regions of 12-month-old Tg2576 mice, plaque-associated astrocytes much more intensely expressed KV3.4 subunits, but not Aβ. More important, we evidenced that the selective knockdown of KV3.4 expression significantly downregulated both glial fibrillary acidic protein levels and Aβ trimers in the brain of 6-month-old Tg2576 mice. Collectively, our results demonstrate that the expression and function of KV3.4 channel subunits are precociously upregulated in cultured astrocytes exposed to Aβ oligomers and in reactive astrocytes of AD Tg2576 mice.

An ever increasing number of reports shows the involvement of free radicals in the functional and structural changes occurring in the brain as a part of the "normal" aging process. Given that plasma membrane and intracellular ion channels play a critical role in maintaining intracellular ion homeostasis, which is crucial for neuronal cell survival, in the present review we have attempted to elaborate on the idea that functional changes in ion channel activity induced by reactive oxygen species (ROS) and reactive nitrogen species (RNS) might occur during the aging process. To this aim, we have reviewed the available literature and the data obtained in our laboratory on the ability of ROS and RNS to modify the activity of several plasma membrane and intracellular ion channels and transporters, in an attempt to correlate such changes with those occurring with the aging process. Particular emphasis is given to voltage-gated Na(+), Ca(2+), and K(+) channels, although second messenger-activated channels like Ca(2+)- and ATP-dependent K(+) channels, and intracellular channels controlling intracellular Ca(2+) storage and release will also be discussed. On the basis of the available data it is not yet possible to establish a strict correlation between the changes in neuronal electrophysiological properties induced by oxidative modification at the level of ion channels and the neurodegenerative process accompanying brain aging. However, an increasing amount of information suggests that the modulatory effects exerted by ROS and RNS on ion channel proteins might have a relevant role for neuronal cell survival or death. Obviously, more work is needed to establish the possible involvement of ion channels and of their modulation by ROS and RNS as important mechanisms for the aging process. Only when a more complete molecular picture of the aging process will be available, it will be possible to test the fascinating hypothesis that aging might be pharmacologically delayed by modulating ROS and RNS action on ion channels or the biochemical pathways involved in their modulation.