In vivo synaptic activity-independent co-uptakes of amyloid β1-42 and Zn2+ into dentate granule cells in the normal brain.

Neuronal amyloid β1-42 (Aβ1-42) accumulation is considered an upstream event in Alzheimer's disease pathogenesis. Here we report the mechanism on synaptic activity-independent Aβ1-42 uptake in vivo. When Aβ1-42 uptake was compared in hippocampal slices after incubating with Aβ1-42, In vitro Aβ1-42 uptake was preferentially high in the dentate granule cell layer in the hippocampus. Because the rapid uptake of Aβ1-42 with extracellular Zn2+ is essential for Aβ1-42-induced cognitive decline in vivo, the uptake mechanism was tested in dentate granule cells in association with synaptic activity. In vivo rapid uptake of Aβ1-42 was not modified in the dentate granule cell layer after co-injection of Aβ1-42 and tetrodotoxin, a Na+ channel blocker, into the dentate gyrus. Both the rapid uptake of Aβ1-42 and Zn2+ into the dentate granule cell layer was not modified after co-injection of CNQX, an AMPA receptor antagonist, which blocks extracellular Zn2+ influx, Both the rapid uptake of Aβ1-42 and Zn2+ into the dentate granule cell layer was not also modified after either co-injection of chlorpromazine or genistein, an endocytic repressor. The present study suggests that Aβ1-42 and Zn2+ are synaptic activity-independently co-taken up into dentate granule cells in the normal brain and the co-uptake is preferential in dentate granule cells in the hippocampus. We propose a hypothesis that Zn-Aβ1-42 oligomers formed in the extracellular compartment are directly incorporated into neuronal plasma membranes and form Zn2+-permeable ion channels.