Retention Period of Amyloid β1–42 in the Brain Extracellular Fluid as the Toxicological Determinant in Freely Moving Rats

The pathological significance of amyloid-β1-42 (Aβ1-42) dynamics is poorly understood in the brain extracellular compartment. Here we test which of the concentration or the retention is critical for Aβ1-42 toxicity after injection of equal dose into dentate granule cell layer of freely moving rats. The toxicity of Aβ1-42 (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. Aβ1-42 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 Aβ1-42 in the extracellular fluid is correlated with neuronal Aβ1-42 uptake and plays a key role in Aβ1-42 neurotoxicity. In the extracellular fluid of the dentate gyrus, the retention period of Aβ1-42 is much more critical for Aβ1-42 toxicity than Aβ1-42 concentration. It is likely that Aβ1-42 toxicity is accelerated by the disturbance of Aβ1-42 metabolism in the dentate gyrus.