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.

Extracellular Zn2+-independently attenuated LTP by human amyloid ß1-40 and rat amyloid ß1-42.

Human amyloid-ß1-40 (Aß1-40) and rat Aß1-42 have lower affinity for extracellular Zn2+ than human Aß1-42. Here we report extracellular Zn2+-independent attenuation of dentate gyrus long-term potentiation (LTP) by human Aß1-40 and rat Aß1-42. On the basis of the data that dentate gyrus LTP is extracellular Zn2+-dependently attenuated after local injection of human Aß1-42 (25 pmol, 1 µl) into the dentate gyrus, which increases intracellular Zn2+ in the dentate gyrus, the toxicity of human Aß1-40 and rat Aß1-42 was compared in the in vivo system with human Aß1-42. Dentate gyrus LTP was attenuated after injection of human Aß1-40 and rat Aß1-42 (25 pmol, 1 µl) into the dentate gyrus, which did not increase intracellular Zn2+ in the dentate gyrus. The attenuated LTP was not rescued by co-injection of CaEDTA, an extracellular Zn2+ chelator. The present study suggests that human Aß1-40 and rat Aß1-42 affect cognitive activity via extracellular Zn2+-independent mechanism at low micromolar concentration.

Adrenergic ß receptor activation in the basolateral amygdala, which is intracellular Zn2+-dependent, rescues amyloid ß1-42-induced attenuation of dentate gyrus LTP.

On the basis of the evidence that the basolateral amygdala (BLA) modulates hippocampal memory processes via synaptic plasticity, here we report that adrenergic ß receptor activation in the BLA rescues amyloid ß1-42 (Aß1-42)-induced attenuation of long-term potentiation (LTP) at perforant pathway-dentate granule cell (DGC) synapses. When 500 µM isoproterenol (2 µl), an adrenergic ß receptor agonist, was injected into the BLA 20 min before LTP induction, LTP was enhanced. Isoproterenol-mediated enhancement of LTP was blocked by co-injection with 100 µM ZnAF-2DA, an intracellular Zn2+ chelator, suggesting that intracellular Zn2+ is required for the intracellular signaling cascade after adrenergic ß receptor activation in the BLA. Aß1-42-induced attenuation of LTP, which was induced by Aß1-42 injection into the dentate gyrus 60 min before LTP induction, was rescued by isoproterenol injection into the BLA 20 min before LTP induction, but not by 500 µM phenylephrine (2 µl), an adrenergic α1 receptor agonist, injection into the BLA, which did not enhance LTP unlike the case of isoproterenol injection. Interestingly, Aß1-42-induced attenuation of LTP was also rescued by 100 µM isoproterenol injection into the BLA 20 min before LTP induction, which did not enhance LTP. The present study demonstrates that adrenergic ß receptor activation in the BLA, which is linked with intracellular Zn2+ signaling, rescues Aß1-42-induced attenuation of dentate gyrus LTP. It is likely that adrenergic ß receptor activation in the BLA is a strategy for rescuing Aß1-42-induced cognitive decline that is associated with hippocampal synaptic plasticity.