Dysregulation of Ion Channels and Transporters and Blood-Brain Barrier Dysfunction in Alzheimer's Disease and Vascular Dementia.

The blood-brain barrier (BBB) plays a critical role in maintaining ion and fluid homeostasis, essential for brain metabolism and neuronal function. Regulation of nutrient, water, and ion transport across the BBB is tightly controlled by specialized ion transporters and channels located within its unique cellular components. These dynamic transport processes not only influence the BBB's structure but also impact vital signaling mechanisms, essential for its optimal function. Disruption in ion, pH, and fluid balance at the BBB is associated with brain pathology and has been implicated in various neurological conditions, including stroke, epilepsy, trauma, and neurodegenerative diseases such as Alzheimer's disease (AD). However, knowledge gaps exist regarding the impact of ion transport dysregulation on BBB function in neurodegenerative dementias. Several factors contribute to this gap: the complex nature of these conditions, historical research focus on neuronal mechanisms and technical challenges in studying the ion transport mechanisms in in vivo models and the lack of efficient in vitro BBB dementia models. This review provides an overview of current research on the roles of ion transporters and channels at the BBB and poses specific research questions: 1) How are the expression and activity of key ion transporters altered in AD and vascular dementia (VaD); 2) Do these changes contribute to BBB dysfunction and disease progression; and 3) Can restoring ion transport function mitigate BBB dysfunction and improve clinical outcomes. Addressing these gaps will provide a greater insight into the vascular pathology of neurodegenerative disorders.

NOX activation in reactive astrocytes regulates astrocytic LCN2 expression and neurodegeneration.

Reactive astrocytes (RA) secrete lipocalin-2 (LCN2) glycoprotein that regulates diverse cellular processes including cell death/survival, inflammation, iron delivery and cell differentiation. Elevated levels of LCN2 are considered as a biomarker of brain injury, however, the underlying regulatory mechanisms of its expression and release are not well understood. In this study, we investigated the role of astrocytic Na+/H+ exchanger 1 (NHE1) in regulating reactive astrocyte LCN2 secretion and neurodegeneration after stroke. Astrocyte specific deletion of Nhe1 in Gfap-CreER+/-;Nhe1f/f mice reduced astrogliosis and astrocytic LCN2 and GFAP expression, which was associated with reduced loss of NeuN+ and GRP78+ neurons in stroke brains. In vitro ischemia in astrocyte cultures triggered a significant increase of secreted LCN2 in astrocytic exosomes, which caused neuronal cell death and neurodegeneration. Inhibition of NHE1 activity during in vitro ischemia with its potent inhibitor HOE642 significantly reduced astrocytic LCN2+ exosome secretion. In elucidating the cellular mechanisms, we found that stroke triggered activation of NADPH oxidase (NOX)-NF-κB signaling and ROS-mediated LCN2 expression. Inhibition of astrocytic NHE1 activity attenuated NOX signaling and LCN2-mediated neuronal apoptosis and neurite degeneration. Our findings demonstrate for the first time that RA use NOX signaling to stimulate LCN2 expression and secretion. Blocking astrocytic NHE1 activity is beneficial to reduce LCN2-mediated neurotoxicity after stroke.