Studies of the mechanism underlying increased Na+/Ca2+ exchange activity in Alzheimer's disease brain

The Na+/Ca2+ exchanger was characterized in plasma membrane vesicles derived from frozen human postmortem tissues. The frontal cortex, temporal cortex and cerebellum of control and Alzheimer's disease (AD) tissues were compared. Na+/Ca2+ exchange activity was defined as the change in vesicular Ca2+ content seen after Na+ loaded vesicles were diluted into choline buffer. The time course of changes in Ca2+ content after dilution was similar in all three regions of control brain. In AD brain, both frontal and temporal cortex vesicles showed elevated Ca2+ content, most evident as an increased peak Ca2+ content at 2 min. The AD cerebellar cortex time course was similar to control and did not show an elevated peak at 2 min. No differences were seen in the passive permeability to Ca2+ when comparing plasma membrane vesicles prepared from control and AD brain. Vesicles from the frontal and temporal cortex of AD brain showed increases in the Vmax of the initial velocity of Ca2+ uptake when compared to control brain, whereas, the cerebellum did not. There were no significant effects of AD on the Km for Ca2+ activation of the initial velocity. Ca2+ influx measured during the rise in vesicular Ca2+ content was elevated in vesicles from AD temporal cortex when compared to control. Two known inhibitors (exchange inhibitory peptide and dichlorobenzamil) of the cardiac Na+/Ca2+ exchanger inhibited the human brain exchanger equally well in control and AD vesicles. Increased Na+/Ca2+ exchange activity was not due to astrocytic gliosis.