Our previous work showed that OSN projections to the OB could restore their proper organization following broad axonal disruption (Cheng et al., 2011). This extraordinary capacity to rewire itself has enabled us to establish the olfactory system as a model for studying neural repair associated with disease related neurodegeneration or traumatic brain injury (TBI). We have established a mouse model of Alzheimers disease (AD) that expresses a humanized mutant form of the Amyloid Precursor Protein (hAPP) in olfactory sensory neurons (OSNs) and we observe clear active apoptosis in the hAPP expressing neurons, by 3 weeks of age. Since loss of the sense of smell occurs early in AD we have been exploring the possibility that cell loss at this very young age may also reflect an early cell autonomous phase of the disease. To better understand the underlying mechanism of the hAPP induced apoptosis in OSNs, we are exploring the role of the Amyloid Beta (Aβ) subunit of APP as the underlying cause of cell loss. Interestingly our findings show that that OSN apoptosis is independent of Aβthus highlighting the involvement of other mechanisms, possibly linked to this early cell autonomous phase that we revealed. Furthermore, we have recently shown that that hAPP expression induces ER-stress in OSNs and as a consequence activates the Unfolded Protein Response (UPR). Currently we are seeking to block these alternate pathways to test the potential for rescuing dying OSNs in this early phase. Our ongoing collaboration with Dr. Alan Koretsky (NINDS) on this project has also shown us that OSN loss and restoration can be detected in live animals using Manganese Enhanced MRI (MEMRI), thus providing a non-invasive mechanism for tracking the neurodegenerative process as well as the potential recovery. Our experiments with physical disruption of olfactory function as a model for TBI have also shown progress. We demonstrated that an Olfactory Bulb Impact (OBI) produces many of the same hallmarks, molecular and anatomical markers, of the more standardized Controlled cortical impact (CCI) model but with greater specificity for olfactory phenotypes that can easily be measured for loss and recovery. We published this model this past year and are currently testing the possibility that even deeper cortical injuries linked to the CCI model can be studied more effectively through olfactory system analysis. Finally, we are also collaborating with Col. Michael Xydakis (US-Air Force) at Uniformed Services University in a study that examines olfactory dysfunction as a consequence of blast injuries associated with active combat.

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5
Fiscal Year
2014
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Fan, Jianguo; Jia, Li; Li, Yan et al. (2017) Maturation arrest in early postnatal sensory receptors by deletion of the miR-183/96/182 cluster in mouse. Proc Natl Acad Sci U S A 114:E4271-E4280
Cheng, Ning; Jiao, Song; Gumaste, Ankita et al. (2016) APP Overexpression Causes A?-Independent Neuronal Death through Intrinsic Apoptosis Pathway. eNeuro 3:
Grier, Bryce D; Belluscio, Leonardo; Cheetham, Claire E J (2016) Olfactory Sensory Activity Modulates Microglial-Neuronal Interactions during Dopaminergic Cell Loss in the Olfactory Bulb. Front Cell Neurosci 10:178
Xydakis, Michael S; Mulligan, Lisa P; Smith, Alice B et al. (2015) Olfactory impairment and traumatic brain injury in blast-injured combat troops: a cohort study. Neurology 84:1559-67
Saar, Galit; Cheng, Ning; Belluscio, Leonardo et al. (2015) Laminar specific detection of APP induced neurodegeneration and recovery using MEMRI in an olfactory based Alzheimer's disease mouse model. Neuroimage 118:183-92
Steuer, Elizabeth; Schaefer, Michele L; Belluscio, Leonardo (2014) Using the olfactory system as an in vivo model to study traumatic brain injury and repair. J Neurotrauma 31:1277-91
Cheng, Ning; Bai, Li; Steuer, Elizabeth et al. (2013) Olfactory functions scale with circuit restoration in a rapidly reversible Alzheimer's disease model. J Neurosci 33:12208-17
Cheng, Kai; Bai, Li; Belluscio, Leonardo (2011) Fas-associated factor 1 as a regulator of olfactory axon guidance. J Neurosci 31:11905-13
Cheng, Ning; Cai, Huaibin; Belluscio, Leonardo (2011) In vivo olfactory model of APP-induced neurodegeneration reveals a reversible cell-autonomous function. J Neurosci 31:13699-704
Cummings, Diana M; Belluscio, Leonardo (2010) Continuous neural plasticity in the olfactory intrabulbar circuitry. J Neurosci 30:9172-80

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