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Abstract
Grant Number: 1R01AG023593-01 Project Title: Novel Mouse Modeling to Dissect AD Pathophysiology
PI Information: Name Title BOWERS, WILLIAM J. william_bowers@urmc.rochester.edu ASSISTANT PROFESSOR Abstract: DESCRIPTION (provided by applicant): Alzheimer's Disease (AD) is a neurodegenerative disorder associated with progressive functional decline, dementia and neuronal loss initiated in specific brain regions and progressing by a disease-specific mode. Elucidating the origin(s) of the pathogenic cascade could likely result in the development of novel diagnostic methodologies and potentially stage-specific therapeutics. Inflammatory processes have been proposed as being integral for initiating and/or propagating AD-associated pathology within the brain, as the elaboration of inflammatory cytokine expression and other markers of inflammation is more pronounced in individuals with known AD pathology. Our proposal addresses both the role of inflammation temporally and spatially in pathogenesis as well as examines the interplay between vaccination and inflammation to either slow or exacerbate neurodegeneration. We hypothesize that focal activation of an inflammatory process within the entorhinal cortex of a mouse model of Alzheimer's disease will lead to the exacerbated stepwise propagation of AD-like pathology within the hippocampus and measurable changes in inflammatory mediator transcript levels in the central nervous system. Moreover, peripheral administration of an ABeta-based vaccine delivered via an HSV amplicon vector will attenuate these histological and biochemical and electrophysiological outcomes in a manner dependent upon the form of the delivered immunogen. We propose to create a novel anatomically and temporally controlled inflammation mouse model, that when combined with an established mouse model of Alzheimer's disease, will be utilized to elucidate the role of brain inflammation in propagation of AD-related pathogenesis and how peripheral vaccination modulates this process. Quantitative bionomic technologies will be used in parallel with standard histochemical, biochemical and electrophysiological assays to correlate the molecular mechanisms by which inflammation influences the initiation and propagation of AD-like pathology and degradation of hippocampal-associated synapses.
Public Health Relevance:
This Public Health Relevance is not available.Thesaurus Terms:
Alzheimer's disease, disease /disorder model, inflammation, pathologic process
active immunization, amyloid protein, biomarker, cerebral degeneration, entorhinal cortex, gene expression profiling, hippocampus, interferon gamma, model design /development, neuroimmunomodulation, neurotrophic factor, presenilin, tau protein
genetically modified animal, histopathology, immunocytochemistry, laboratory mouse
Institution: UNIVERSITY OF ROCHESTER 517 Hylan Bldg., Box 270140 ROCHESTER, NY 14627 Fiscal Year: 2004 Department: NEUROLOGY Project Start: 15-APR-2004 Project End: 31-MAR-2009 ICD: NATIONAL INSTITUTE ON AGING IRG: ZRG1