Altered waste disposal system in aging and Alzheimer’s disease: focus on astrocytic aquaporin-4

Among the diverse cell types included in the general population named glia, astrocytes emerge as being the focus of a growing body of research aimed at characterizing their heterogeneous and complex functions. Alterations of both their morphology and activities have been linked to a variety of neurological diseases. One crucial physiological need satisfied by astrocytes is the cleansing of the cerebral tissue from waste molecules. Several data demonstrate that aquaporin-4 (AQP-4), a protein expressed by astrocytes, is crucially important for facilitating the removal of waste products from the brain. Aquaporins are water channels found in all district of the human organism and the most abundant isoform in the brain is AQP-4. This protein is involved in a myriad of astrocytic activities, including calcium signal transduction, potassium buffering, synaptic plasticity, astrocyte migration, glial scar formation and neuroinflammation. The highest density of AQP-4 is found at the astrocytic domains closest to blood vessels, the endfeet that envelop brain vessels, with low to zero expression in other astrocytic membrane regions. Increased AQP-4 expression and loss of polarization have recently been documented in altered physiological conditions. Here we review the latest findings related to aging and AD on this topic, as well as the available knowledge on pharmacological tools to target AQP-4.