In vivo synaptic activity-independent co-uptakes of amyloid ß 1–42 and Zn 2+ into dentate granule cells in the normal brain

Abstract

Neuronal amyloid ß 1–42 (Aß 1–42 ) accumulation is considered an upstream event in Alzheimer’s disease pathogenesis. Here we report the mechanism on synaptic activity-independent Aß 1–42 uptake in vivo. When Aß 1–42 uptake was compared in hippocampal slices after incubating with Aß 1–42 , In vitro Aß 1–42 uptake was preferentially high in the dentate granule cell layer in the hippocampus. Because the rapid uptake of Aß 1–42 with extracellular Zn 2+ is essential for Aß 1–42 -induced cognitive decline in vivo, the uptake mechanism was tested in dentate granule cells in association with synaptic activity. In vivo rapid uptake of Aß 1–42 was not modified in the dentate granule cell layer after co-injection of Aß 1–42 and tetrodotoxin, a Na + channel blocker, into the dentate gyrus. Both the rapid uptake of Aß 1–42 and Zn 2+ into the dentate granule cell layer was not modified after co-injection of CNQX, an AMPA receptor antagonist, which blocks extracellular Zn 2+ influx, Both the rapid uptake of Aß 1–42 and Zn 2+ 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 Aß 1–42 and Zn 2+ 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-Aß 1–42 oligomers formed in the extracellular compartment are directly incorporated into neuronal plasma membranes and form Zn 2+ -permeable ion channels.