Abstract
Alzheimer’s disease (AD) is one of the most frequently diagnosed neurodegenerative disorders worldwide and poses a major challenge for both affected individuals and their caregivers. AD is a progressive neurological disorder associated with high rates of brain atrophy. Despite its durable influence on human health, understanding AD has been complicated by its enigmatic and multifactorial nature. Neurofibrillary tangles and the deposition of amyloid-beta (Aβ) protein are typical pathological features and fundamental causes of cognitive impairment in AD patients. Dysbiosis of oral and gut microbiota has been reported to induce and accelerate the formation of Aβ plaques and neurofibrillary tangles. For instance, some oral microbes can spread to the brain through cranial nerves or cellular infections, which has been suggested to increase the risk of developing AD. Importantly, the interaction between intestinal microbiota and brain cells has been recognized as influencing the development of AD as well as other neurodegenerative diseases. In particular, the metabolites produced by certain intestinal microorganisms can affect the activity of microglia and further mediate neuroinflammation, which is a leading cause of neuronal necrosis and AD pathogenesis. Which pathogens and associated pathways are involved in the development and progression of AD remains to be elucidated; however, it is well-known that gut microbiota and their metabolites can affect the brain by both direct and indirect means. Understanding the specific mechanisms involved in the interaction between these pathogens and the nervous system is vital for the early intervention in AD. In this review, we aim to comprehensively discuss the possible mechanistic pathways underlying the oral-brain, the gut-brain and the oral-gut-brain associations.
Highlights
First described by the German neuropathologist Alois Alzheimer in 1906, Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by continued cognitive and behavioral impairment such as the inability to make new memories and loss of primordial memories (Alzheimer, 1906; Goedert and Spillantini, 2006)
We have previously reported that mice infected with P. gingivalis exhibit reduced blood-brain barrier (BBB) integrity, as evidenced by the lower numbers of tight junction-related proteins and the increased influx of Aβ from the periphery into the brain when compared with uninfected controls (Zeng et al, 2020)
The gut microbiota and their products can affect the brain either directly through the enteric nervous system (ENS) or indirectly through mediating systemic inflammation. Both direct and indirect effects from oral and intestinal microbiota can contribute to microglia-mediated neuroinflammation, resulting in AD-related pathologies (Figure 1)
Summary
First described by the German neuropathologist Alois Alzheimer in 1906, Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by continued cognitive and behavioral impairment such as the inability to make new memories and loss of primordial memories (Alzheimer, 1906; Goedert and Spillantini, 2006). A recent comparative study of postmortem cerebral tissue reported that, compared with aged people without AD, the brain of AD patients had a higher proportion of gingipains, the toxic protein produced by P. gingivalis, the keystone pathogen in chronic periodontitis. These gingipains were present in the individuals not diagnosed with AD, albeit in smaller quantities, which was suggested to represent an asymptomatic preclinical stage of this disease (Dominy et al, 2019)
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