The parent award for this administrative supplement request investigates the patterns of odorant receptor responses evoked by odors and the cell and molecular biology of the olfactory sensory neurons that express these odorant receptors. Deficits in olfactory performance are an early symptom for many patients suffering from Alzheimer?s Disease (AD) and AD patients typically show neuropathology in brain regions that process olfactory information, including the loss of olfactory sensory neurons. This susceptibility of olfactory sensory neurons to AD-related neurodegeneration is a fundamental reason they are advantageous models for investigating the onset and progression of AD-related neurodegeneration. Another fundamental reason is our highly detailed understanding of the biology of these neurons, such as knowing the identity of all genes they express. Other reasons include their accessibility for experimental manipulation, their homogeneity and large population size (>5 million per mouse), and the numerous genetically modified mouse strains that have been made to study these neurons. Investigating the onset of AD is critical given that therapies targeting late stages of the disease have been unsuccessful. Olfactory sensory neurons are particularly well-suited for determining the onset and order of progression of events responsible for AD-related neurodegeneration. We propose to take advantage of our ongoing study of olfactory sensory neuron function to carefully and deeply investigate phenotypic changes in olfactory sensory neurons in two types of mouse models of AD. We expect to identify major events in the early stages of AD-related neurodegeneration and thereby demonstrate that olfactory sensory neurons are a powerful model for study of the onset of AD.

Public Health Relevance

Alzheimer?s Disease (AD) is the most common type of dementia, estimated to affect more than 5 million U.S. citizens and more than 25 million people worldwide. Therapies targeting late-stage AD neuropathology have proven unsuccessful and lack of understanding of disease onset has hampered development of better interventions and preventive measures. This proposal describes the development and initial study of the onset and progression of AD-related neurodegeneration in olfactory sensory neurons, already known to be susceptible to AD and having numerous advantages for deeply investigating the changes in phenotype responsible for AD-related neurodegeneration.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Sullivan, Susan L
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University of Kentucky
Schools of Medicine
United States
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Wang, Qiang; Titlow, William B; McClintock, Declan A et al. (2017) Activity-Dependent Gene Expression in the Mammalian Olfactory Epithelium. Chem Senses 42:611-624
Zhang, Guangfan; Titlow, William B; Biecker, Stephanie M et al. (2016) Lhx2 Determines Odorant Receptor Expression Frequency in Mature Olfactory Sensory Neurons. eNeuro 3: