Adrenergic β receptor activation reduces amyloid β1-42-mediated intracellular Zn2+ toxicity in dentate granule cells followed by rescuing impairment of dentate gyrus LTP

Abstract

Adrenergic β receptor activation prevents human soluble amyloid β (Aβ)-induced impairment of long-term potentiation (LTP) in slices. On the basis of the evidence that human Aβ1–42-induced impairment of LTP is due to Aβ1–42-mediated Zn2+ toxicity, we postulated that adrenergic β receptor activation reduces Aβ1–42-mediated intracellular Zn2+ toxicity followed by rescuing Aβ1–42 toxicity. To test the effect of adrenergic β receptor activation, LTP was recorded at perforant pathway-dentate granule cell synapses of anesthetized rats 60 min after Aβ1–42 injection into the dentate granule cell layer. Human Aβ1–42-induced impairment of LTP was rescued by co-injection of isoproterenol, an adrenergic β receptor agonist, but not by co-injection of phenylephrine, an adrenergic α1 receptor agonist. Isoproterenol did not reduce Aβ1–42 uptake into dentate granule cells, but reduced increase in intracellular Zn2+ in dentate granule cells induced by Aβ1–42. In contrast, phenylephrine did not reduce both Aβ1–42 uptake and increase in intracellular Zn2+ by Aβ1–42. In the case of human Aβ1−40 and rat Aβ1–42, which do not increase intracellular Zn2+, human Aβ1−40- and rat Aβ1–42-induced impairments of LTP were not rescued by co-injection of isoproterenol. The present study indicates that adrenergic β receptor activation reduces Aβ1–42-mediated increase in intracellular Zn2+ in dentate granule cells, resulting in rescuing Aβ1–42-induced impairment of LTP. It is likely that noradrenergic neuron activation by stimulating the locus coeruleus is effective for rescuing Aβ1–42-induced cognitive decline that is caused by intracellular Zn2+ dysregulation in the hippocampus.