The regenerative ability of the olfactory system is quite extraordinary and provides an ideal platform to study neural circuit disruption and repair. In addition the presence of precisely defined anatomical maps both at the surface of the olfactory bulb (OB) and deep within the central circuitry of the OB enable a clear framework from which to determine circuit organization. We previously showed that the OB maps maintain a capacity for restoration following disruption, which we have utilized to establish animal models for studying neural repair associated with neurodegeneration or injury. In previous work we developed an olfactory-based mouse model of Alzheimers Disease (AD) to study the basis of early loss of olfactory function that is commonly reported in AD patients. This transgenic mouse enables us to reversibly express a humanized mutant form of the Amyloid Precursor Protein (hAPP) in olfactory sensory neurons (OSNs) and detect clear neural apoptosis in hAPP expressing neurons. We determined that by turning off hAPP expression after extensive degeneration had occurred the olfactory system is still capable of recovering both in its neural structure and function. Thus we are using this mouse model for various ongoing AD related studies: 1) to uncover the underlying mechanism by which hAPP expression induces cell-autonomous neural apoptosis; 2) increase our capacity for detection and monitoring the progression of hAPP induced degeneration; 3) to assess the downstream network consequences of selective neuronal loss; and 4) to test the potential for drugs or treatments to restore olfactory organization and function. Current work shows that this mouse model has proven useful in all areas. We have used it in combination with Manganese-Enhanced MRI (MEMRI) to follow both the progression and recovery of olfactory circuitry in intact live animals. We have applied Electron Microscopy 3D analysis to OB neuronal circuits following hAPP induced neurodegeneration and uncovered clear changes to local network structure. We have also determined that hAPP expression activates ER-stress pathways which has lead us to test specific blockers in this same model as potential drug treatments to rescue the neurodegenerative affects of hAPP. Together with our collaborative efforts at Uniformed Services University Health Sciences to examine the link between olfactory loss and Traumatic Brain Injury, we continue to use the olfactory system as a model to study neural disruption and repair.
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