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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG023593-03
Application #
7027742
Study Section
Special Emphasis Panel (ZRG1-CDIN (01))
Program Officer
Snyder, Stephen D
Project Start
2004-04-15
Project End
2009-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
3
Fiscal Year
2006
Total Cost
$262,255
Indirect Cost
Name
University of Rochester
Department
Neurology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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Montgomery, Sara L; Bowers, William J (2012) Tumor necrosis factor-alpha and the roles it plays in homeostatic and degenerative processes within the central nervous system. J Neuroimmune Pharmacol 7:42-59
Montgomery, Sara L; Mastrangelo, Michael A; Habib, Diala et al. (2011) Ablation of TNF-RI/RII expression in Alzheimer's disease mice leads to an unexpected enhancement of pathology: implications for chronic pan-TNF-? suppressive therapeutic strategies in the brain. Am J Pathol 179:2053-70
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Park, Keigan M; Yule, David I; Bowers, William J (2010) Impaired TNF-alpha control of IP3R-mediated Ca2+ release in Alzheimer's disease mouse neurons. Cell Signal 22:519-26
de Silva, Suresh; Mastrangelo, Michael A; Lotta Jr, Louis T et al. (2010) Herpes simplex virus/Sleeping Beauty vector-based embryonic gene transfer using the HSB5 mutant: loss of apparent transposition hyperactivity in vivo. Hum Gene Ther 21:1603-13
de Silva, Suresh; Lotta Jr, Louis T; Burris, Clark A et al. (2010) Virion-associated cofactor high-mobility group DNA-binding protein-1 facilitates transposition from the herpes simplex virus/Sleeping Beauty amplicon vector platform. Hum Gene Ther 21:1615-22
Ryan, Deborah A; Narrow, Wade C; Federoff, Howard J et al. (2010) An improved method for generating consistent soluble amyloid-beta oligomer preparations for in vitro neurotoxicity studies. J Neurosci Methods 190:171-9
Ryan, Deborah A; Mastrangelo, Michael A; Narrow, Wade C et al. (2010) Abeta-directed single-chain antibody delivery via a serotype-1 AAV vector improves learning behavior and pathology in Alzheimer's disease mice. Mol Ther 18:1471-81
Lee, Byoung Dae; Shin, Joo-Ho; VanKampen, Jackalina et al. (2010) Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's disease. Nat Med 16:998-1000

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