Adrenergic ß receptor activation reduces amyloid ß1-42-mediated intracellular Zn2+ toxicity in dentate granule cells followed by rescuing impairment of dentate gyrus LTP.

Adrenergic ß receptor activation prevents human soluble amyloid ß (Aß)-induced impairment of long-term potentiation (LTP) in slices. On the basis of the evidence that human Aß1-42-induced impairment of LTP is due to Aß1-42-mediated Zn2+ toxicity, we postulated that adrenergic ß receptor activation reduces Aß1-42-mediated intracellular Zn2+ toxicity followed by rescuing Aß1-42 toxicity. To test the effect of adrenergic ß receptor activation, LTP was recorded at perforant pathway-dentate granule cell synapses of anesthetized rats 60 min after Aß1-42 injection into the dentate granule cell layer. Human Aß1-42-induced impairment of LTP was rescued by co-injection of isoproterenol, an adrenergic ß receptor agonist, but not by co-injection of phenylephrine, an adrenergic α1 receptor agonist. Isoproterenol did not reduce Aß1-42 uptake into dentate granule cells, but reduced increase in intracellular Zn2+ in dentate granule cells induced by Aß1-42. In contrast, phenylephrine did not reduce both Aß1-42 uptake and increase in intracellular Zn2+ by Aß1-42. In the case of human Aß1-40 and rat Aß1-42, which do not increase intracellular Zn2+, human Aß1-40- and rat Aß1-42-induced impairments of LTP were not rescued by co-injection of isoproterenol. The present study indicates that adrenergic ß receptor activation reduces Aß1-42-mediated increase in intracellular Zn2+ in dentate granule cells, resulting in rescuing Aß1-42-induced impairment of LTP. It is likely that noradrenergic neuron activation by stimulating the locus coeruleus is effective for rescuing Aß1-42-induced cognitive decline that is caused by intracellular Zn2+ dysregulation in the hippocampus.

In vivo synaptic activity-independent co-uptakes of amyloid ß1-42 and Zn2+ into dentate granule cells in the normal brain.

Neuronal amyloid ß1-42 (Aß1-42) accumulation is considered an upstream event in Alzheimer's disease pathogenesis. Here we report the mechanism on synaptic activity-independent Aß1-42 uptake in vivo. When Aß1-42 uptake was compared in hippocampal slices after incubating with Aß1-42, In vitro Aß1-42 uptake was preferentially high in the dentate granule cell layer in the hippocampus. Because the rapid uptake of Aß1-42 with extracellular Zn2+ is essential for Aß1-42-induced cognitive decline in vivo, the uptake mechanism was tested in dentate granule cells in association with synaptic activity. In vivo rapid uptake of Aß1-42 was not modified in the dentate granule cell layer after co-injection of Aß1-42 and tetrodotoxin, a Na+ channel blocker, into the dentate gyrus. Both the rapid uptake of Aß1-42 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 Aß1-42 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 Aß1-42 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-Aß1-42 oligomers formed in the extracellular compartment are directly incorporated into neuronal plasma membranes and form Zn2+-permeable ion channels.