Isoproterenol, an adrenergic ß receptor agonist, induces metallothionein synthesis followed by canceling amyloid ß1-42-induced neurodegeneration.

Adrenergic ß receptor activation may ameliorate amyloid ß toxicity. We examined whether isoproterenol, an adrenergic ß receptor agonist reduces neurodegeneration caused by Aß1-42, for which intracellular Zn2+ dysregulation is a trigger. Neurodegeneration was assessed in the dentate granule cell layer 14 days after intracerebroventricular injection of human Aß1-42 into the mouse brain. Neurodegeneration was canceled after co-injection of isoproterenol. Isoproterenol did not affect Aß staining (uptake) in the dentate granule cell layer 1 h after Aß injection. In contrast, isoproterenol reduced intracellular Zn2+ level increased by Aß. The synthesis of intracellular metallothioneins (MTs), Zn2+-binding proteins was not enhanced in the dentate granule cell layer 24 h after Aß1-42 injection, but significantly enhanced after co-injection of isoproterenol. These data indicate that isoproterenol enhances MT synthesis and cancels neurodegeneration via intracellular Zn2+ toxicity after Aß1-42 injection. It is likely that MT synthesis enhanced by adrenergic ß receptor-mediated signaling contributes to ameliorating Aß1-42 toxicity in the brain.

Preventive effect of Ninjin-yoei-to, a Kampo medicine, on amyloid ß1-42-induced neurodegeneration via intracellular Zn2+ toxicity in the dentate gyrus.

Ninjin-yoei-to (NYT), a Kampo medicine, has ameliorative effects on cognitive dysfunction via enhancing cholinergic neuron activity. To explore an efficacy of NYT administration for prevention and cure of Alzheimer's disease, here we examined the effect of NYT on amyloid ß1-42 (Aß1-42)-induced neurodegeneration in the dentate gyrus. A diet containing 3% NYT was administered to mice for 2 weeks and human Aß1-42 was intracerebroventricularly injected. Neurodegeneration in the dentate granule cell layer of the hippocampus, which was determined 2 weeks after the injection, was rescued by administration of the diet for 4 weeks. Aß staining (uptake) was not modified in the dentate granule cell layer by pre-administration of the diet for 2 weeks, while Aß1-42-induced increase in intracellular Zn2+ was reduced, suggesting that pre-administration of NYT prior to Aß injection is effective for reducing Aß1-42-induced Zn2+ toxicity in the dentate gyrus. As a matter of fact, Aß1-42-induced neurodegeneration in the dentate gyrus was rescued by pre-administration of NYT. Interestingly, the level of metallothioneins, intracellular Zn2+-binding proteins, which can capture Zn2+ from Zn-Aß1-42 complexes, was elevated in the dentate granule cell layer by pre-administration of NYT. The present study suggests that pre-administration of NYT prevents Aß1-42-mediated neurodegeneration in the dentate gyurs by induced synthesis of metallothioneins, which reduces intracellular Zn2+ toxicity induced by Aß1-42.

Dehydroeffusol Pprevents Amyloid ß1-42-mediated Hippocampal Neurodegeneration via Reducing Intracellular Zn2+ Toxicity.

Dehydroeffusol, a phenanthrene isolated from Juncus effusus, is a Chinese medicine. To explore an efficacy of dehydroeffusol administration for prevention and cure of Alzheimer's disease, here we examined the effect of dehydroeffusol on amyloid ß1-42 (Aß1-42)-mediated hippocampal neurodegeneration. Dehydroeffusol (15 mg/kg body weight) was orally administered to mice once a day for 6 days and then human Aß1-42 was injected intracerebroventricularly followed by oral administration for 12 days. Neurodegeneration in the dentate granule cell layer, which was determined 2 weeks after Aß1-42 injection, was rescued by dehydroeffusol administration. Aß staining (uptake) was not reduced in the dentate granule cell layer by pre-administration of dehydroeffusol for 6 days, while increase in intracellular Zn2+ induced with Aß1-42 was reduced, suggesting that pre-administration of dehydroeffusol prior to Aß1-42 injection is effective for Aß1-42-mediated neurodegeneration that was linked with intracellular Zn2+ toxicity. As a matter of fact, pre-administration of dehydroeffusol rescued Aß1-42-mediated neurodegeneration. Interestingly, pre-administration of dehydroeffusol increased synthesis of metallothioneins, intracellular Zn2+-binding proteins, in the dentate granule cell layer, which can capture Zn2+ from Zn-Aß1-42 complexes. The present study indicates that pre-administration of dehydroeffusol protects Aß1-42-mediated neurodegeneration in the hippocampus by reducing intracellular Zn2+ toxicity, which is linked with induced synthesis of metallothioneins. Dehydroeffusol, a novel inducer of metallothioneins, may protect Aß1-42-induced pathogenesis in Alzheimer's disease.

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.