Project Summary Depression, anxiety, and other neuropsychiatric co-morbidities have been found to predict or coincide with the earliest stages of Alzheimer's Disease (AD). These changes in the mental health of AD patients are believed to correlate with previously documented changes in the function of the Hypothalamic-Pituitary-Adrenal (HPA) axis which controls the release of cortisol into the bloodstream. We have demonstrated that these changes in behavior and endocrine output are due, in part, to mis-regulation of Corticotropin Releasing Factor (CRF) signaling, which controls HPA axis activity, in model mice. The proposed project is designed to answer how AD pathogenesis leads to mis-regulation of CRF signaling and HPA axis activity. Early evidence suggests that local production of toxic species may directly impact CRF neuron excitability. We have generated a novel mouse model in which we can mis-express disease-causing mutant forms of Amyloid Precursor Protein (APP) selectively in CRF neurons. These mice will allow us to test the hypothesis that cell autonomous APP dysfunction directly impacts CRF neuron activity to cause mood disturbances in Alzheimer's Disease. First, we will evaluate the anxiety-related changes in behavior and endocrine output that result from selective mis-expression of FAD mutant forms of APP in CRF neurons. Animals genetically designed to express humanized, FAD mutant APP, only in CRF neurons (CRF-APP mice) will be tested for changes in anxiety-related behavior and cognitive performance. The integrity of HPA axis regulation will be evaluated by measuring ACTH and corticosteroid levels at rest and at peak levels of stress as well as repeatedly during a prolonged stress exposure. Next, we will determine the impact of chronic selective mis-expression of FAD mutant APP on CRF neuron health. We will characterize CRF neurons to determine whether expression of APP mutants leads to changes in neuronal morphology, synaptic connectivity, neuronal excitability, and neurodegeneration. Finally, we will assess features of AD pathogenesis, specifically testing whether there is local deposition of A in regions containing high densities of CRF neurons. Our goal is to identify a direct mechanism connecting AD pathogenesis with CRF/HPA axis mis-regulation. The knowledge of such a mechanism would allow for new strategies for early diagnosis and treatment of AD, by examining stress responses and circulating cortisol levels in early stage patients. In addition, targeting of the CRF system with pharmacologic therapies (CRFR1 antagonists) to limit mis-regulation of the HPA axis might prevent the toxicity associated with higher levels of glucocorticoids in the circulation, and thereby limit progression of the disease. By selectively targeting this pathway, we might improve mood alterations such as depression, anxiety, and increased aggression to improve the quality of life for both patient and caregiver.