Late-onset Alzheimer's disease (AD) afflicts millions of individuals and is thought to be the most important single cause of senile dementia. This disease has no clearly defined etiology at the present time, and the detailed events that initiate and maintain the pathogenic process ending in the disease remain to be elucidated. However, one risk factor for development of late-onset AD has been identified: possession of the APOE E4 allele. The investigators demonstrated that the obligate intracellular bacterial parasite Chlamydia pneumoniae is associated with late-onset AD. That is, they showed that autopsy tissues from affected brain regions of AD patients are PCR-positive for the organism in 90% of samples examined, whereas virtually no congruent tissues from control brains, or tissues from unaffected brain areas of AD patients, were similarly positive. Extensive electron microscopic, immunoelectron microscopic and immunohistochemical study of AD and control brains allowed visualization of the organism in these samples, definition of host cells as microglia and astroglia, and provided clear evidence that chlamydia-infected cells are located almost exclusively in brain regions showing AD related neuropathology. Importantly, in more recent studies they demonstrated that the APOE E4 allele or its gene product is actually associated with increased pathobiology of C pneumoniae. In the present application, they describe studies to extend these provocative initial observations. They will extend their initial studies of the presence and location of C. pneumoniae in the AD brain in another, larger, and more clinically well defined set of AD and control tissues. They will determine whether similar chlamydial infection obtains in other neurodegenerative diseases, and they will define the relationship between C. pneumoniae infected cells/cell types to neuropathology. Further, they will define the contribution of C. pneumoniae to the production of inflammatory mediators known to be associated with AD pathology, and they will determine whether C. pneumoniae-infected astroglia and microglia contribute to production and deposition of aberrant amyloid and PHF-tau in the AD brain. The research proposed in this application will confirm that C pneumoniae infection of the brain is specific to patients with late-onset AD and define molecular mechanisms by which the organism promotes/exacerbates the disease. Such new information may well provide important new insights for development of novel therapeutic modalities to prevent or ameliorate late-onset AD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI044055-03
Application #
6374003
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Taylor, Christopher E,
Project Start
1999-06-01
Project End
2003-05-31
Budget Start
2001-06-01
Budget End
2002-05-31
Support Year
3
Fiscal Year
2001
Total Cost
$282,524
Indirect Cost
Name
Wayne State University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202
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Balin, Brian J; Little, C Scott; Hammond, Christine J et al. (2008) Chlamydophila pneumoniae and the etiology of late-onset Alzheimer's disease. J Alzheimers Dis 13:371-80
Gerard, Herve C; Fomicheva, Ekaterina; Whittum-Hudson, Judith A et al. (2008) Apolipoprotein E4 enhances attachment of Chlamydophila (Chlamydia) pneumoniae elementary bodies to host cells. Microb Pathog 44:279-85
Dreses-Werringloer, Ute; Gerard, Herve C; Whittum-Hudson, Judith A et al. (2006) Chlamydophila (Chlamydia) pneumoniae infection of human astrocytes and microglia in culture displays an active, rather than a persistent, phenotype. Am J Med Sci 332:168-74
Gerard, Herve C; Dreses-Werringloer, Ute; Wildt, Kristin S et al. (2006) Chlamydophila (Chlamydia) pneumoniae in the Alzheimer's brain. FEMS Immunol Med Microbiol 48:355-66
Gerard, Herve C; Wildt, Kristin L; Whittum-Hudson, Judith A et al. (2005) The load of Chlamydia pneumoniae in the Alzheimer's brain varies with APOE genotype. Microb Pathog 39:19-26
Wagner, A D; Wittkop, U; Prahst, A et al. (2003) Dendritic cells co-localize with activated CD4+ T cells in giant cell arteritis. Clin Exp Rheumatol 21:185-92
MacIntyre, A; Abramov, R; Hammond, C J et al. (2003) Chlamydia pneumoniae infection promotes the transmigration of monocytes through human brain endothelial cells. J Neurosci Res 71:740-50
Swanborg, Robert H; Whittum-Hudson, Judith A; Hudson, Alan P (2003) Infectious agents and multiple sclerosis--are Chlamydia pneumoniae and human herpes virus 6 involved? J Neuroimmunol 136:1-8
MacIntyre, Angela; Hammond, Christine J; Little, C Scott et al. (2002) Chlamydia pneumoniae infection alters the junctional complex proteins of human brain microvascular endothelial cells. FEMS Microbiol Lett 217:167-72

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