Biology and Biomedical Sciences: Neurosciences
Date of Award
Doctor of Philosophy (PhD)
Chair and Committee
The amyloid-β peptide: Aβ) 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 Aβ dynamics correlate with changes in neurological status. Because neurological status is generally diminished following injury, this correlation suggests that extracellular Aβ is reduced relative to baseline. However, human studies cannot assess pre-injury Aβ levels, very early post-injury Aβ levels, nor the relationship between extracellular Aβ and total tissue levels. Therefore, we developed a mouse model that combines experimental TBI with microdialysis to address these gaps. In this model, Aβ levels were stable at baseline and after sham-injury. Following controlled cortical impact TBI, we found that Aβlevels 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 Aβ. Similar decreases were observed in PBS-soluble hippocampal extracts, but no changes were found in carbonate or guanidine extracts. Reductions in Aβ were not due to changes in microdialysis probe function, APP levels nor Aβ 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 Aβ 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 Aβ is retained at the synapse following injury. To test this, we prepared synaptosomes in sham and injured PDAPP mice and measured levels of Aβ 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 Aβ. In summary, we have designed a mouse model to address questions that cannot be answered in patients. Using this model, we measured Aβ 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.
Schwetye, Katherine, "Dynamic Measurement Of Soluble Human Aβ In A Combined Microdialysis-Experimental Traumatic Brain Injury Mouse Model" (2011). All Theses and Dissertations (ETDs). 315.