Amyloid-β plaques affect astrocyte Kir4.1 protein expression but not function in the dentate gyrus of APP/PS1 mice

Abstract

Alzheimer pathology is accompanied by astrogliosis. Reactive astrocytes surrounding amyloid plaques may directly affect neuronal communication, and one of the mechanisms by which astrocytes impact neuronal function is by affecting K⁺ homeostasis. Here we studied, using hippocampal slices from 9-month-old Alzheimer mice (APP/PS1) and wild-type littermates, whether astrocyte function is changed by analyzing Kir4.1 expression and function and astrocyte coupling in astrocytes surrounding amyloid-β plaques. Immunohistochemical analysis of Kir4.1 protein in the dentate gyrus revealed localized increases in astrocytes surrounding amyloid-β plaque deposits. We subsequently focused on changes in astrocyte function by using patch-clamp slice electrophysiology on both plaque- and non-plaque associated astrocytes to characterize general membrane properties. We found that Ba²⁺ -sensitive Kir4.1 conductance in astrocytes surrounding plaques was not affected by changes in Kir4.1 protein expression. Additional analysis of astrocyte gap junction coupling efficiency in the dentate gyrus revealed no apparent changes. Quantification of basic features of glutamatergic transmission to granule cells did not indicate disturbed neuronal communication in the dentate gyrus of APP/PS1 mice. Together, these results suggest that astrocytes in the dentate gyrus of APP/PS1 mice maintain their ability to buffer extracellular K⁺ and attempt to rectify imbalances in K⁺ concentration to maintain normal neuronal and synaptic function, possibly by localized increases in Kir4.1 protein expression. Our earlier transcriptomic data indicated that chronically activated astrocytes lose their neuronal support function. Here we show that, despite localized increased Kir4.1 protein expression, astrocyte Kir4.1 channel dysfunction is likely not involved in the pathogenesis of Alzheimer's disease.

Keywords: Alzheimer's disease; RRID:AB_10013382; RRID:AB_2040120; RRID:AB_2651133; RRID:AB_477010; RRID:AB_570666; RRID:AB_662807; amyloid-β plaques; astrocytes; dentate gyrus; glia; inward rectification; potassium channels; reactive gliosis.