Na+ and K+ ion imbalances in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is associated with impaired glutamate clearance and depressed Na+/K+ ATPase levels in AD brain that might lead to a cellular ion imbalance. To test this hypothesis, [Na+] and [K+] were analyzed in postmortem brain samples of 12 normal and 16 AD individuals, and in cerebrospinal fluid (CSF) from AD patients and matched controls. Statistically significant increases in [Na+] in frontal (25%) and parietal cortex (20%) and in cerebellar [K+] (15%) were observed in AD samples compared to controls. CSF from AD patients and matched controls exhibited no differences, suggesting that tissue ion imbalances reflected changes in the intracellular compartment. Differences in cation concentrations between normal and AD brain samples were modeled by a 2-fold increase in intracellular [Na+] and an 8–15% increase in intracellular [K+]. Since amyloid beta peptide (Aβ) is an important contributor to AD brain pathology, we assessed how Aβ affects ion homeostasis in primary murine astrocytes, the most abundant cells in brain tissue. We demonstrate that treatment of astrocytes with the Aβ 25–35 peptide increases intracellular levels of Na+ (~2–3-fold) and K+ (~1.5-fold), which were associated with reduced levels of Na+/K+ ATPase and the Na+-dependent glutamate transporters, GLAST and GLT-1. Similar increases in astrocytic Na+ and K+ levels were also caused by Aβ 1–40, but not by Aβ 1–42 treatment. Our study suggests a previously unrecognized impairment in AD brain cell ion homeostasis that might be triggered by Aβ and could significantly affect electrophysiological activity of brain cells, contributing to the pathophysiology of AD.