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

Abstract

Neuronal amyloid β_1-42 (Aβ_1-42) accumulation is considered an upstream event in Alzheimer's disease pathogenesis. Here we report the mechanism on synaptic activity-independent Aβ_1-42 uptake in vivo. When Aβ_1-42 uptake was compared in hippocampal slices after incubating with Aβ_1-42, In vitro Aβ_1-42 uptake was preferentially high in the dentate granule cell layer in the hippocampus. Because the rapid uptake of Aβ_1-42 with extracellular Zn²⁺ is essential for Aβ_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 Aβ_1-42 was not modified in the dentate granule cell layer after co-injection of Aβ_1-42 and tetrodotoxin, a Na⁺ channel blocker, into the dentate gyrus. Both the rapid uptake of Aβ_1-42 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 Aβ_1-42 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 Aβ_1-42 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-Aβ_1-42 oligomers formed in the extracellular compartment are directly incorporated into neuronal plasma membranes and form Zn²⁺-permeable ion channels.