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Abstract
Na+/Ca2+ exchange activity was measured by monitoring vesicular Ca2+ content after
incubation in buffers containing 45Ca2+. When Na+-loaded vesicles were placed into
Na+-free buffer, vesicular Ca2+ content increased rapidly and reached a plateau after
two to three minutes. Only preaggregated amyloid-beta1-40 (Abeta1-40) and Abeta25-35
reduced vesicular Ca2+ content. Both peptides produced a maximal reduction in Ca2+
content of approximately 50%. The peptides reduced Ca2+ content with similar potency
and half maximal effects were seen at less than 10 microM for Abeta25-35. Calcium-loaded
vesicles mediate a rapid Ca2+/Ca2+ exchange, which also was inhibited by aggregated
Abeta25-35. Aggregated Abeta25-35 did not affect the passive Ca2+ permeability of
the vesicles. Aggregated Abeta25-35 reduced Ca2+ content in plasma membrane vesicles
isolated from normal and Alzheimer's disease frontal cortex with less potency but
the same efficacy as seen in rat brain. Aggregated Abeta25-35 did not produce nonspecific
effects on vesicle morphology such as clumping or loss of intact vesicles. When placed
in the buffer used to measure Ca2+ content, Congo Red at molar ratios of less than
one blocked the inhibitory effect of preaggregated Abeta25-35. When added in equimolar
concentrations to freshly dissolved and unaggregated Abeta25-35, Congo Red also was
effective at blocking the inhibitory effect on Ca2+ content. In contrast, vitamin
E (antioxidant) and N-tert-butyl-alpha-phenylnitrone (spin trapping agent) failed
to block the inhibitory action of aggregated Abeta25-35. The exact mechanisms of Abeta-induced
neurotoxicity in cell culture has yet to be solved. Accumulation of free radicals
play a necessary role, but disruptions of Ca2+ homeostasis are also important. The
data presented here are consistent with a proposed mechanism where aggregated Abeta
peptides directly interact with hydrophobic surfaces of the exchanger protein and/or
lipid bilayer and interfere with plasma membrane Ca2+ transport.