Alzheimer's Disease (AD) presently afflicts more than million individuals in the U.S., and this number will increase as the population ages. Published and unpublished preliminary studies have shown that amyloid beta peptides (Abeta) directly activate the complement system in vitro leading to the formation of covalent complexes of Abeta with C3 activation products and to generation of the pro-inflammatory C5a and C5b- complement activation products. These in vitro findings provide potential inflammation based mechanisms to account for the presence of complement components in neuritic plaques (NP) in the AD brain together with damaged neurons and increased numbers of activated glial cells and neuronal damage. In the proposed studies, we will utilize a recently developed murine transgenic (tg) model of AD to evaluate complement and pro-inflammatory cytokine-mediated inflammatory processes in the pathogenesis and progression of AD. These studies are encompassed in the following three specific aims: 1. Molecular and functional analysis of the role of the complement system in the development of AD in AD tg mice. Abeta deposition, complement protein deposition, C5b-9 generation, NP formation with astrocyte and microglia activation and influx, and neuronal damage in the brain will be tracked as a function of time in AD tg mice, and in AD tg mice crossed with C5 deficient, and C3, CR1/CR2 and C5a receptor knockout novel functions of C5 in neuronal homeostasis will also be sought. 2. Molecular and functional analysis of the role of pro-inflammatory cytokines in the development of AD in AD tg mice. The same parameters will be tracked in AD tg mice, and in AD tg mice crossed with pro- inflammatory cytokine (IL-1, IL-6, TNF-alpha) knockout mice as a function of time. 3. Evaluation of the effects of persistent neuronal expression of a neurotropic viral gene product (LCMV NP) or an aberrant host protein (PrP/SC) on the development of AD in AD tg mice. The kinetics of AD development in AD tg mice crossed with NSE-LCMV NP and AD tg mice crossed with NSE-hamster PrP mice inoculated with hamster scrapie will be assessed in collaboration with M. Oldstone. These studies will definitively show whether complement and pro- inflammatory cytokines play major roles in the pathogenesis and progression of AD. A demonstration of critical roles for complement and cytokines in AD will offer numerous potential targets for the development of therapeutic agents to prevent or treat AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG004342-17
Application #
6200952
Study Section
Project Start
1999-12-01
Project End
2000-11-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
17
Fiscal Year
2000
Total Cost
$149,274
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Oldstone, Michael B A (2014) Molecular mimicry: its evolution from concept to mechanism as a cause of autoimmune diseases. Monoclon Antib Immunodiagn Immunother 33:158-65
Priola, Suzette A; Ward, Anne E; McCall, Sherman A et al. (2013) Lack of prion infectivity in fixed heart tissue from patients with Creutzfeldt-Jakob disease or amyloid heart disease. J Virol 87:9501-10
Siggs, Owen M; Cruite, Justin T; Du, Xin et al. (2012) Disruption of copper homeostasis due to a mutation of Atp7a delays the onset of prion disease. Proc Natl Acad Sci U S A 109:13733-8
Sun, Binggui; Halabisky, Brian; Zhou, Yungui et al. (2009) Imbalance between GABAergic and Glutamatergic Transmission Impairs Adult Neurogenesis in an Animal Model of Alzheimer's Disease. Cell Stem Cell 5:624-33
Trifilo, Matthew J; Sanchez-Alavez, Manuel; Solforosi, Laura et al. (2008) Scrapie-induced defects in learning and memory of transgenic mice expressing anchorless prion protein are associated with alterations in the gamma aminobutyric acid-ergic pathway. J Virol 82:9890-9
Biasini, Emiliano; Seegulam, M Esa; Patti, Brianna N et al. (2008) Non-infectious aggregates of the prion protein react with several PrPSc-directed antibodies. J Neurochem 105:2190-204
Balch, William E; Morimoto, Richard I; Dillin, Andrew et al. (2008) Adapting proteostasis for disease intervention. Science 319:916-9
Trifilo, Matthew J; Ying, Ge; Teng, Chao et al. (2007) Chronic wasting disease of deer and elk in transgenic mice: oral transmission and pathobiology. Virology 365:136-43
Leclerc, E; Serban, H; Prusiner, S B et al. (2006) Copper induces conformational changes in the N-terminal part of cell-surface PrPC. Arch Virol 151:2103-9
Kunz, Stefan; Rojek, Jillian M; Roberts, Amanda J et al. (2006) Altered central nervous system gene expression caused by congenitally acquired persistent infection with lymphocytic choriomeningitis virus. J Virol 80:9082-92

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