Alzheimer's disease (AD) is a complex disease of unknown etiologic origin with both environmental and genetic risk factors, contributing to its onset. Systemic and brains local inflammation precedes neurodegenerative processes and predicts clinical onset of AD. Studies suggested that high burden of host inflammation may be responsible for amyloidogenic processes in AD, at least in preclinical models. Fibrillary amyloid ? (A?) is central to the disease neuropathology, is neurotoxic, and has the capacity to inappropriately activate the innate immune responses including release of cytokines. However, susceptibility to peripheral microbial infections appears to increase during advancing age with the innate immune system becoming inadvertently activated as a disease promoting factor. Periodontal diseases (PD) are among the most common chronic infections of humans, characterized by loss of tooth supporting tissues and caused my complex bacteria underneath the gingiva. Numerous studies link PD associated chronic inflammation with increased risk of dementia, including AD. Plasma levels of antibodies to periodontal bacteria are significantly higher in AD patients compared to non- demented controls. A second study directly demonstrated the presence of multiple different oral bacterial species, causative of periodontal disease, in autopsy brains from AD subjects. We have shown Porphyromonas gingivalis lipopolysaccharide present in 4 out of 10 AD brain tissues and subsequently the innate immune activation as a critical risk factor for developing AD. Following chronic infection of mouse periodontal cavity with P. gingivalis, we could also detect the bacterial genomic DNA and viable bacteria in brains of infected mice. In spite of these findings, the mechanism by which periodontitis may be considered a risk factor for specific pathological hallmark proteins found in AD remains obscure. Despite interesting links between AD and PD and growing evidence that oral bacteria can regulate pathological hallmarks of AD, there is no in vivo study targeting a role for oral bacterium in the initiation of AD. The mechanistic link between chronic inflammation induced by oral bacteria and AD pathology is a high priority for exploration. We hypothesize that chronic systemic inflammation caused by the oral bacterium infection will seed higher A? plaque load, and NFT pathology in the TgCRND8 mice and enhance neuroinflammation and neuronal injury.
The specific aims are to explore the role of oral bacteria P. gingivalis in regulating A? pathology in TgCRND8 AD mouse model. The major objective is to determine the possible causal link between oral bacteria with AD hallmark pathology in vivo. Our long-term goal is to determine how an oral microbe P. gingivalis that can induce systemic effects can influence the development of amyloid and tau pathologies. This is a multidisciplinary project between laboratories that has expertise in periodontal disease research (Dr. Lakshmyya Kesavalu) and neuroinflammatory mechanisms of neurodegenerative diseases (Drs. Todd Golde and Yona Levites).

Public Health Relevance

Several reports suggest a complex etiology of Alzheimer's disease (AD) and unresolved etiology. Periodontal disease is a peripheral, chronic infection due to complex bacteria in the mouth that induce systemic inflammatory response. Oral bacteria are clearly linked with AD but the role of these bacteria in induction of AD are not known. This proposal provide evidence for a complex interplay between the oral bacteria, overt infection, and the brain immune system that could play a role in AD pathology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS102926-01
Application #
9372139
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Corriveau, Roderick A
Project Start
2017-08-01
Project End
2019-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Florida
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611