Potassium homeostasis during disease progression of Alzheimer's disease.

Abstract

Alzheimer's disease (AD) is an age-dependent neurodegenerative disorder characterized by neuronal loss leading to dementia and ultimately death. Whilst the loss of neurons is central to this disease, it is becoming clear that glia, specifically astrocytes, contribute to the onset and progression of neurodegeneration. The role of astrocytes in maintaining ion homeostasis in the extracellular milieu is fundamental for multiple brain functions, including synaptic plasticity and neuronal excitability, which are compromised during AD and affect neuronal signalling. In this study, we measured the astrocytic K⁺ clearance rate in the hippocampus and somatosensory cortex of a mouse model for AD during disease progression. Our results establish that astrocytic [K⁺]_o (extracellular K⁺ concentration) clearance in the hippocampus is reduced in symptomatic 5xFAD mice, and this decrease is region-specific, as no significant alterations were detected in the superficial layers of the somatosensory cortex. The decrease in the [K⁺]_o clearance rate correlated with a significant reduction in the expression and conductivity of Kir4.1 channels and a decline in the number of primary connected astrocytes. Moreover, astrocytes in the hippocampus of symptomatic 5xFAD mice demonstrated increased reactivity which was accompanied by an increased excitability and altered spiking profile of nearby neurons. These findings indicate that the supportive function astrocytes typically provide to nearby neurons is diminished during disease progression, which affects the neuronal circuit signalling in this area and provides a potential explanation for the increased vulnerability of neurons in AD. KEY POINTS: Astrocytic potassium clearance from the extracellular milleu is fundamental for multiple brain functions. Alterations in the clearance rate can affect the excitability and overall viability of neurons. A symptomatic mouse model for Alzheimer's disease (5xFAD) exhibits a significant decline in astrocytic K⁺ clearance at the hippocampus, but not the somatosensory cortex. The decrease in the clearance rate correlated with a reduction in the expression and conductivity of astrocytic Kir4.1 channels and a decrease in the number of primary connected astrocytes, specifically at the stratum lacunosum moleculare layer of the CA1 region. Astrocytes in the hippocampus of symptomatic 5xFAD mice displayed increased reactivity. The excitability profile and firing patterns of neurons at the hippocampus were affected by alterations in K⁺ homeostasis, indicating that the supportive function astrocytes typically provide to nearby neurons is diminished during progression of Alzheimer's disease.