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.
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