Dynamic measurement of soluble human Abeta in a combined microdialysis-experimental traumatic brain injury mouse model.

摘要

The amyloid-beta peptide (Abeta) plays a central pathophysiological role in Alzheimer's disease, but little is known about its dynamics in the brain's extracellular space. A recent microdialysis-based study in human patients with severe brain injuries found that extracellular Abeta dynamics correlate with changes in neurological status. Because neurological status is generally diminished following injury, this correlation suggests that extracellular Abeta is reduced relative to baseline. However, human studies cannot assess pre-injury Abeta levels, very early post-injury Abeta levels, nor the relationship between extracellular Abeta and total tissue levels. Therefore, we developed a mouse model that combines experimental TBI with microdialysis to address these gaps. In this model, Abeta levels were stable at baseline and after sham-injury. Following controlled cortical impact TBI, we found that Abeta levels were immediately and persistently decreased in the ipsilateral hippocampus. These results were found in both wild-type mice and young pre-plaque PDAPP mice that produce human-sequence Abeta. Similar decreases were observed in PBS-soluble hippocampal extracts, but no changes were found in carbonate or guanidine extracts. Reductions in Abeta were not due to changes in microdialysis probe function, APP levels nor Abeta deposition. Hippocampal depth electrode recordings demonstrated that electroencephalographic activity was decreased over 24 hours following TBI. Thus, we propose that in mice and likely injured human patients, post-injury extracellular Abeta levels are acutely decreased relative to baseline. Reduced neuronal activity may contribute, though the underlying mechanisms have not been definitively determined.;One hypothesized mechanism for reduced extracellular levels is that Abeta is retained at the synapse following injury. To test this, we prepared synaptosomes in sham and injured PDAPP mice and measured levels of Abeta and APP by ELISA. No significant differences between sham and 2.0 mm-injured mice were detected. Future experiments will determine whether enhanced clearance accounts for decreased extracellular Abeta.;In summary, we have designed a mouse model to address questions that cannot be answered in patients. Using this model, we measured Abeta dynamics and their relationship to tissue levels and a possible relationship with neuronal activity. Studies of other peptides and treatment strategies might benefit from use of this model.