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 Zn 2+ 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 Zn 2+ into the dentate granule cell layer was not modified after co-injection of CNQX, an AMPA receptor antagonist, which blocks extracellular Zn 2+ influx, Both the rapid uptake of Aβ 1–42 and Zn 2+ 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 Zn 2+ 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 Zn 2+ -permeable ion channels.

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 β1-42 (Aβ1-42)-induced neurodegeneration in the dentate gyrus.A diet containing 3% NYT was administered to mice for 2 weeks and human Aβ1-42 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. Aβ staining (uptake) was not modified in the dentate granule cell layer by pre-administration of the diet for 2 weeks, while Aβ1-42induced increase in intracellular Zn 2+ was reduced, suggesting that pre-administration of NYT prior to Aβ injection is effective for reducing Aβ1-42-induced Zn 2+ toxicity in the dentate gyrus. As a matter of fact, Aβ1-42-induced neurodegeneration in the dentate gyrus was rescued by pre-administration of NYT. Interestingly, the level of metallothioneins, intracellular Zn 2+ -binding proteins, which can capture Zn 2+ from Zn-Aβ1-42 complexes, was elevated in the dentate granule cell layer by pre-administration of NYT. The present study suggests that pre-administration of NYT prevents Aβ1-42mediated neurodegeneration in the dentate gyurs by induced synthesis of metallothioneins, which reduces intracellular Zn 2+ toxicity induced by Aβ1-42.

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The pathological significance of amyloid-β 1-42 (Aβ 1-42) dynamics is poorly understood in the brain extracellular compartment. Here we test which of the concentration or the retention is critical for Aβ 1-42 toxicity after injection of equal dose into dentate granule cell layer of freely moving rats. The toxicity of Aβ 1-42 (25 µM) was compared between injections at the rate of 0.25 µL/min for 4 min (fast injection) and 0.025 µL/min for 40 min (slow injection). Dentate gyrus long-term potentiation (LTP) was affected 1 and 2 h after the fast injection, but not 4 h. In contrast, LTP was affected even 72 h after the slow injection. Aβ 1-42 staining 5 min after finish of the slow injection was more intense in the dentate granule cell layer than of the fast injection. The present study indicates that the retention of Aβ 1-42 in the extracellular fluid is correlated with neuronal Aβ 1-42 uptake and plays a key role in Aβ 1-42 neurotoxicity. In the extracellular fluid of the dentate gyrus, the retention period of Aβ 1-42 is much more critical for Aβ 1-42 toxicity than Aβ 1-42 concentration. It is likely that Aβ 1-42 toxicity is accelerated by the disturbance of Aβ 1-42 metabolism in the dentate gyrus.