In vivo synaptic activity-independent co-uptakes of amyloid \u03b21\u201342 and Zn2+ into dentate granule cells in the normal brain

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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.