Behavioral and Neural Plasticity in the Aged As a general hypothesis, we propose that age-related accumulation of aberrant forms of A?, including various soluble assembly states, as well as fibrillar deposits in the parenchyma and vessels activate innate immune responses, which induce a low level chronic cascade of proinflammatory cytokines and chemokine. The combination of elevated levels of pathological forms of A? and chronic inflammation disrupts trophic factor signaling and cerebrovascular function, and directly contributes to neurodegeneration. We will use novel transgenic model systems and specifically for the 3xTg-AD model which is marked by both AB and tau pathology, generate various crosses and draw comparisons to pathology and mechanisms in human control and AD brain tissues. To address this larger goal, we have assembled a team of investigators with expertise in A?, inflammation and brain pathology and who have a history of working together: Dr. C. Glabe who will investigate A?, A? oligomers and assembly states using conformation specific antibodies in transgenic models and human brain tissues. Dr. C. Cotman will examine the effects of A? assemblies on signal transduction mechanisms and AD pathology. Dr. F. LaFerla, who brings expertise on the development and characterization of novel transgenic model systems, will investigate the role A? and inflammation on the evolution of tau pathology. Dr. A. Tenner will investigate the role of complement on AD pathology and the balance between protective and detrimental effects on the brain and AD. Dr Cribbs will use transgenic models and brain tissues to investigate the mechanism for the development of vascular pathology and along with other program investigators determine how vascular pathology interacts with non-vascular pathology. The efforts of the team will be supported by an Administrative Core (Core A) and a Tissue and Peptide resources Core (Core B). Core B will generate A?, antibodies, assist in the maintenance of transgenic lines and provide well-characterized human brain tissues. PROGRAM PROJECT AS A WHOLE PRINCIPAL INVESTIGATOR: Dr. Cotman is a nationally and internationally recognized leader in aging and Alzheimer research. His excellent credentials for leading this Program are those collected over the years of his very successful directorship, his abilities in the area of leading and encouraging the development of young investigators, and his contribution to our understanding of the neuropathogenesis of Alzheimer's disease and potential therapeutic interventions. REVIEW OF INDIVIDUAL COMPONENTS CORE A - ADMINISTRATIVE CORE, Dr. Carl W. Cotman DESCRIPTION (provided by applicant): The Administrative Core will have the responsibility of overseeing the activities of the program and providing support for the interdisciplinary study of behavioral and neural plasticity in the aged. Research studies will include examining inflammation, gliosis, astrocytes, amyloid aggregation and intracellular accumulation. The Core will coordinate the shared use of facilities, services, equipment and supplies by all projects in the program and will coordinate the purchasing and maintenance of animals to meet the needs of all research operations. The Core will also monitor the Tissue and Peptide Resource Core, as well as oversee the availability and access of the ADRC database that incorporates clinical, neuropathological, neuroanatomical, and biochemical data on control and AD tissues. Additionally, the Core will be responsible for organizing meetings and colloquia, overseeing financial matters, and maintaining communication with other AD-related programs at UCI and the Alzheimer's Disease Research Centers of Orange, Los Angeles and San Diego Counties. The Core will also assist in material transfer agreements and oversee animal use/protocols and IRB issues.
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