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With Alzheimer’s Disease and other forms of dementia becoming increasingly prevalent, it is more important than ever to understand the connections between physical health and cognitive decline. Recent research has suggested that poor oral health may be linked to an increased risk of cognitive decline which can progress towards Alzheimer’s Disease or other forms of dementia. Periodontitis, a chronic periodontal disease caused by bacteria that attacks the gums is linked to the development and exacerbation of Alzheimer’s Disease. Today, researchers are exploring regenerative therapeutics that can restore damaged gums and bone loss to improve oral care outcomes.

Reducing the adverse effects of periodontitis before it exacerbates cognitive decline may reveal positive outcomes for aging patients in need of regenerative medicines (Guo et al. 2021). In this blog post, we will explore how researchers are exploring the connection between the mouth and brain to develop therapeutics that target shared molecular pathways and offer innovative approaches for improving oral and cognitive health in the aging population.

Systemic effects of periodontal disease include neuroinflmmation within the  brain linked to Alzheimer's Disease among many other systemic diseases caused by infection.
Figure from review article written by George Hajishengallis & Triantafyllos Chavakis for Nature Reviews Immunology (2021).

What is Alzheimer’s Disease and how is it related to periodontal disease?

Alzheimer’s Disease (AD) is a neurodegenerative disease and form of dementia that affects an individual’s cognitive functioning. Over time, the disease destroys parts of the brain involved in learning and memory, making it difficult for individuals to remember and perform daily activities. AD differs from senility which causes a memory decline. AD differs at a pathophysiological level, where neurodegeneration is characterized as clumps of abnormal proteins (amyloid plaques) and bundles of neurofibrillary tangles (tau proteins) found in neurons throughout regions involved in learning and memory until death. Regions that also regulated mood, movement, swallowing, and speaking are irreparably damaged. Eventually, daily activities like maintaining good oral hygiene become impossible. Over the last two decades, researchers have suggested that oral diseases like periodontal disease or periodontitis may be considered an early marker for developing AD.

Periodontitis is a chronic gum disease that can lead to the loss of teeth if left untreated. It’s caused by harmful bacteria that attack the tissues and structures that support your teeth. These bacteria multiply and progress in stages of damage that irritate the gums and create pockets between the gum line and the teeth. Chronic inflammation of the periodontal tissue can spread from the mouth through the body, increasing an individual’s risk of developing systemic diseases. Bacteria found in the mouth can be detected in the heart, brain, and lungs. Microbiologists identified that there are at least four periodontal bacteria that are associated with AD. These bacteria are Aggregatibacter actinomycetemcomitans, Fusobacterium, P. gingivalis, and T. denticola (Eslami S et al., 2023).

Porphyromonas gingivalis (P. gingivalis) is one of the most common and well-documented bacteria that can secrete gingipains, which are proteases that can travel to the brain and accumulate in neurons slowly destroying them. In over 90% of the brains of patients diagnosed with periodontitis prior to AD, P. gingivalis was detected in the cerebrospinal fluid while immunoreactivity of gingipains was detected in neurons and astrocytes within the hippocampus and cerebral cortex (Dominy et al., 2019). These data suggested that P. gingivalis is associated with AD pathophysiology and may function as a biomarker of AD.

The Role of Genetics in the Brain-Tooth Connection

The intricate connection between our brain and teeth has long been studied by experts in dentistry and neuroscience. Recent advancements in genetic sequencing have shed new light on the underlying mechanisms. There are several genes involved in molecular pathways that overlap in periodontal pathogenesis and neuroinflammation. These genes C4A, C4B, CXCL12, FCGR3A, IL1B, and MMP3, may function as druggable targets that can be modulated to understand the brain-tooth connection (Jin et al, 2021). By studying the variations in these genes, scientists are uncovering how they influence the health of our teeth and gums, as well as our ability to respond to periodontal pathogens that target the brain.

Which Animal Models do Researchers use to Study the Brain-Tooth Connection?

Humanized rodent models can be selected to study the regenerative properties of biomaterials for periodontal disease and are ideal for preliminary and IND-enabling studies for regenerative therapeutics (Rojas et al, 2021). These models allow researchers to understand how their therapeutic is involved in repair mechanisms after periodontal damage. A popular translational animal model used in periodontology is the ligature-induced periodontitis model induced in transgenic mice predisposed for Alzheimer’s Disease neuropathology. The model mimics chronic periodontitis observed in Alzheimer’s patients. Suggested models are APP-Tg mice, PDAPP mice, and AβPP mice.

Researchers investigating neurodegeneration identified that chronic periodontitis exacerbated symptoms of impaired cognitive function in P. gingivalis inoculated PDAPP and AβPP mice, as well as immunocompromised rats. Our team has explored using similar models to study biomaterials that can support functional recovery from periodontal damage, potentially leading to neurorestorative properties. Ask our preclinical Dental Medicine Scientists for more information about these models.  

Key Histopathology Biomarkers for Periodontal Disease & Alzheimer’s Disease

Looking for morphological markers of Alzheimer’s disease and periodontal disease includes an examination of brain tissue stained to identify amyloid plaques and tau pathology characterized by neurofibrillary tangles. Additionally, probing for immunoreactivity of periodontal bacteria proteases colocalized with neurodegeneration/neuroinflammatory biomarkers can provide an understanding of which regions are targeted for degeneration and one can further elucidate the molecular pathways that can be modulated.

Our histopathology analysis to investigate periodontal therapeutics can include spatial transcriptomic analysis and next-generation sequencing of periodontal tissue in your selected animal model. Spatial transcriptomics is ideal data providing supporting evidence of the mechanism of action at the molecular and tissue level.

However, when executing these periodontal studies in animal models, there are some limitations to address. The main challenges are species-specific differences in mouth microbiota, differences in immune responses in immunoglobulins, cytokines, chemokines, Toll-like receptors, and T-cell signaling pathways that need to be evaluated for translation to human responses. Ultimately, the goal of these in vivo studies is to identify morphological markers and functional recovery processes that may lead to new treatments for periodontal diseases in humans.

Can Regenerative Therapeutics Restore Damaged Gums & Bone Loss?

Periodontal disease can severely damage tissue and supporting structures within the mouth, resulting in gum and bone degeneration that can lead to tooth loss. However, regenerative therapeutics offer a promising intervention. Periodontal disease can cause bone loss and bone grafting is a procedure that attempts to restore bone loss in your jaw to avoid tooth loosening and tooth loss. Stem cell therapy in dental medicine combines gene and cell therapies to treat degenerated gums and bone.

Stem cell therapy has emerged as a leading modality for treating degeneration in the dental field. When combined with enzyme therapy and biomaterials such as hydrogel scaffolds and inorganic biomaterial scaffolds, there are endless drug delivery systems that can enhance the regenerative potential treatment for periodontal diseases. While more extensive testing is needed in living systems to assess these interventions, each modality provides an exciting new avenue for regenerative dental therapy.

Case Study

Dental implants with Regenerative Biomaterials Used in Preclinical Animal Models of Periodontitis

Dental implants have come a long way from being used as cosmetic solutions to replace missing teeth. With the innovative use of regenerative biomaterials, dental implants can function as bioactive scaffolds that improve blood supply to damaged tissue, allowing immune cells and repair mechanisms to reduce tissue loss and improve outcomes of periodontal restoration. Preclinical testing of regenerative biomaterials can utilize our animal models of chronic periodontitis in small and large animals for acute and long-term efficacy evaluation and safety assessments.

A Final Look at the Brain-Tooth Connection

In conclusion, research continues to explore the intricate connection between the brain and our oral health, and new therapeutic treatments are emerging that offer exciting possibilities for patients. The ability to intervene and address oral health before the onset of symptoms associated with cognitive decline is the challenge. The novel therapies discussed in this blog post are promising functional and restorative approaches to reducing the risk of periodontitis, a condition linked to a range of progressive, systemic health concerns beyond oral hygiene. As we take a final look at the latest developments in the brain-tooth connection, we agree that these cutting-edge therapies are game-changing to regenerative medicine therapies because they address two common diseases found in the aging population: periodontitis and Alzheimer’s Disease.

Although more research needs to be done on these intriguing topics, it’s clear that taking steps toward good oral health can go a long way in treating progressive neurodegenerative disorders. Contact us to learn more about our preclinical solutions designed specifically for your novel therapeutics.

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