The Periodontal Pathogen Fusobacterium nucleatum Exacerbates Alzheimer’s Pathogenesis via Specific Pathways

 

ORIGINAL RESEARCH article


Front. Aging Neurosci., 23 June 2022
Sec.Alzheimer's Disease and Related Dementias 
https://doi.org/10.3389/fnagi.2022.912709


Hongle Wu1,2,3†Wei Qiu4†Xiaofang Zhu3,5Xiangfen Li2Zhongcong Xie6Isabel Carreras7,8Alpaslan Dedeoglu9,10Thomas Van Dyke11,12Yiping W. Han13,14Nadeem Karimbux5Qisheng Tu3,5Lei Cheng2*and Jake Chen3,5,15,16*
  • 1Department of Endodontics, Stomatological Hospital, Southern Medical University, Guangzhou, China
  • 2State Key Laboratory of Oral Disease, West China Hospital of Stomatology, National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu, China
  • 3Division of Oral Biology, Tufts University School of Dental Medicine, Boston, MA, United States
  • 4Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
  • 5Department of Periodontology, Tufts University School of Dental Medicine, Boston, MA, United States
  • 6Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, United States
  • 7Department of Veterans Affairs, VA Boston Healthcare System, Boston, MA, United States
  • 8Department of Neurology and Department of Biochemistry School of Medicine, Boston University, Boston, MA, United States
  • 9Department of Veterans Affairs, VA Boston Healthcare System, Boston, MA, United States
  • 10Department of Neurology School of Medicine, Boston University, Boston, MA, United States
  • 11The Forsyth Institute, Clinical and Translational Research, Cambridge, MA, United States
  • 12Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, MA, United States
  • 13Section of Oral, Diagnostic and Rehabilitation Sciences, College of Dental Medicine, University Irvign Medical Center, New York, NY, United States
  • 14Department of Microbiology & Immunology, Vagelos College of Physicians & Surgeons, Columbia University Irvign Medical Center, New York, NY, United States
  • 15Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, United States
  • 16Graduate School of Biomedical Sciences, Tufts University, Boston, MA, United States

Alzheimer’s Disease (AD) is the most common form of dementia in older adults and has a devastating impact on the patient’s quality of life, which creates a significant socio-economic burden for the affected individuals and their families. In recent years, studies have identified a relationship between periodontitis and AD. Periodontitis is an infectious/inflammatory disease that destroys the supporting periodontal structure leading to tooth loss. Dysbiosis of the oral microbiome plays a significant role in the onset and development of periodontitis exhibiting a shift to overgrowth of pathobionts in the normal microflora with increasing local inflammation. Fusobacterium nucleatum is a common pathogen that significantly overgrows in periodontitis and has also been linked to various systemic diseases. Earlier studies have reported that antibodies to F. nucleatum can be detected in the serum of patients with AD or cognitive impairment, but a causal relationship and a plausible mechanism linking the two diseases have not been identified. In this study, we conducted both in vivo and in vitro experiments and found that F. nucleatum activates microglial cells causing morphological changes, accelerated proliferation and enhanced expression of TNF-α and IL-1β in microglial cells. In our in vivo experiments, we found that F. nucleatum-induced periodontitis resulted in the exacerbation of Alzheimer’s symptoms in 5XFAD mice including increased cognitive impairment, beta-amyloid accumulation and Tau protein phosphorylation in the mouse cerebrum. This study may suggest a possible link between a periodontal pathogen and AD and F. nucleatum could be a risk factor in the pathogenesis of AD. We are currently further identifying the pathways through which F. nucleatum modulates molecular elements in enhancing AD symptoms and signs. Data are available via ProteomeXchange with identifier PXD033147.

https://www.frontiersin.org/articles/10.3389/fnagi.2022.912709/full