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.