The causes of non-familial, sporadic Alzheimer's disease (AD) remain unknown. Sporadic AD is likely caused by complex interactions between genetic influences and environmental factors. Psychosocial stress is one of these environmental factors. Individuals prone to experience psychological distress are twice as likely to develop AD. Also, increased plasma cortisol levels are correlated with cognitive decline in AD patients. CRF is an excitatory neuromodulator within the central nervous system. Our prior studies provide strong support for the hypothesis that stress can accelerate the neurodegeneration that is characteristic of AD, probably through CRF1 receptor activation. However, it is not known whether the effects of stress and CRF on neuronal structure are mediated only by changes in Aβ, or whether they may be mediated through other, more direct, changes in neuronal function. We have developed a transgenic mouse line that conditionally over-expresses CRF and constitutively over-expresses human APP (triple transgenic or 'TT' transgenic mice). This transgenic model will allow us to directly evaluate the effects of CRF1 receptor antagonists on CRF-mediated synapse loss and memory-related behavioral impairments, and Aβ tissue levels. We also will expose wild-type, aged mice and aged rats to chronic isolation stress, which decreases synapse density and increases memory-related behavioral impairments, and determine whether these changes are linked to changes in tissue levels of Aβ. CRF1 antagonists will be administered to aged stressed and unstressed mice and rats to see if the stress effects can be blocked. The proposed studies represent an effort to develop a new treatment strategy aimed toward slowing or preventing age-related neurodegeneration. Since we cannot alter the genetic predisposition to AD, the possibility of delaying the onset or progression of neuropathology and concomitant cognitive decline by mitigating the CNS effects of common environmental factors (i.e., psychosocial stress) would be groundbreaking.