Did you know that not following your dentist’s recommendations on brushing and flossing can put you at increased risk for developing Alzheimer’s Disease? Not to be an alarmist, but recent studies suggest just that.
It has long been known that there is a strong link between oral health and overall health, with the impact of gum disease on cardiovascular conditions the most widely known. Researchers on the cutting edge of identifying these connections, such as ICMH investigator Dr. Alexandru Movila, PhD, continue to unravel the mystery of how oral hygiene has such a large impact on an array of other diseases and conditions.
The human mouth is chock-full of over 500 different species of bacteria. While the vast majority of these are harmless or even promote health, some are major contributors to periodontitis. Periodontitis, better know as gum disease, is an infection that causes inflammation of the soft tissue in the mouth and becomes worse if left untreated. At its worst, periodontitis can destroy the bone supporting teeth.
This inflammation and bone loss become the basis from which systemic conditions are triggered or exacerbated. This means preventing these effects from occurring is massively important to overall health. And while there is a large body of research indicating that periodontitis plays a role in many systemic diseases, the exact mechanisms behind this are not well known. Understanding these mechanisms is the key to mitigating the impact of periodontitis on overall health.
The Lab of Dr. Movila is especially interested in understanding the mechanisms behind the connection between periodontitis and Alzheimer’s Disease (AD). As Dr. Movila states, “Preventing Alzheimer’s is proving to be very challenging but understanding how these pathogens provoke or exacerbate the disease is a promising approach to developing treatments that reduce symptoms, such as chronic pain.”
Orofacial pain and Alzheimer’s Disease are often co-morbid. In fact, the prevalence of this pain may be underestimated due to patients suffering from AD being unable to effectively communicate what they are feeling. To Dr. Movila, this represents an opportunity to greatly improve the quality of life for these patients.
In pursuit of this goal, Dr. Movila has published findings that the Liposaccharide-Toll-like receptors axis (a well-known pathway) is not a major factor in bone loss and inflammation in aged animal models. This led the lab to begin exploring alternative pathways playing a role in these effects, focusing specifically on sphingolipids produced by the key periodontal pathogen Porphyromonas Gingivalis. Sphingolipids are commonly found in cellular membranes in the human body. Long believed to just have a structural function, Dr. Movila’s recent work has shown they are engaged as activators of signaling pathways independent of toll-like receptors.
Interestingly, sphingolipids can also be produced by a limited number of bacterial species. One sphingolipid in particular (phosphoglycerol dihydroceramide) is produced by a key periodontal pathogen. Further published work done by the Movila Lab shows this species of sphingolipid promotes bone loss and neuroinflammatory effects.
These findings imply that fully understanding how the pathology of these sphingolipids, in the context of periodontitis, is contributing to AD and chronic pain could open new possibilities for treatment. The question then becomes, how can we gain this full understanding? The Movila Lab’s answer to this is dynamic imaging.
Intravital Imaging of Mineralized Tissue
After earning his PhD from the Moldova Academy of Science, Dr. Movila was offered a postdoctoral position studying numerous pathogens via confocal microscopy. Confocal microscopy is a technique that allows high-resolution imaging deep into tissues. At the time, the technology underpinning this technique was rudimentary and difficult to use. In the intervening years, the technology advanced remarkedly and is now commonly used to perform dynamic imaging of live tissue.
As Dr. Movila cultivated expertise in this type of imaging, he also began to shift his attention to the study of oral pathogens, eventually focusing on oral and brain pathways. This shift left Dr. Movila uniquely positioned in how to utilize this advanced imaging. As he says, “the technique of live imaging is routine in soft tissue, but problems arise when applying it to hard tissue, like bone. The number of people who are able to do this is minimal. That is the beauty of our research, it is quite novel.”
The benefits of this dynamic imaging are immense as it allows researchers to see how cells are communicating with each other in a live organism. Being able to see this live communication is vital in understanding underlying pathologies and their mechanisms. In the case of Dr. Movila’s research, the lab is able to purify sphingolipids from cultivated bacteria and locally inject them into live mouse models. From there, they perform confocal microscopy on the models, thus observing the interaction of the injected sphingolipids and the cells in the tissue of the mouse subject.
The hope is that the observations from these studies will ultimately identify the mechanisms triggered by these sphingolipids that induce inflammation. As Dr. Movila says, “This is really a mystery. We are just at the beginning, but confocal microscopy has the ability to really shift the paradigm on how these periodontal pathogens are understood. We know the cells are communicating on an individual level, but dynamic imaging allows us to see that communication on a systemic level. This opens an entirely new understanding.”
To advance the use of this groundbreaking technique, the ICMH is in the process of forming an Intravital Imaging on Mineralized Tissues Core, of which Dr. Movila will be the Director. The goal of this core will be to use confocal technology, along with Dr. Movila’s expertise, to progress not only his research but that of all ICMH Members, into clinical stages.
ICMH Executive Director Dr. Lynda Bonewald, PhD, states, “This core will allow us to track the movements of bone and muscle cells and how they interact in real-time. This technology is widely applied to soft tissues such as the brain, liver, and kidney but not to hard tissues such as bones and teeth. Being able to visualize these actions and interactions in real-time will advance our knowledge and lead to new therapeutics for musculoskeletal disorders and diseases."
The core, under Dr. Movila’s leadership, is currently in the process of procuring the necessary equipment with hopes of officially launching by the end of 2022.
To learn more about Dr. Movila’s research, please find his publications below.
1. Akkaoui J, Yamada C, Duarte C, Ho A, Vardar-Sengul S, Kawai T, Movila A. Contribution of Porphyromonas gingivalis lipopolysaccharide to experimental periodontitis in relation to aging. Geroscience. 2021;43(1):367-76. doi: 10.1007/s11357-020-00258-1. PubMed PMID: 32851571; PMCID: PMC8050187.
2. Duarte C, Yamada C, Garcia C, Akkaoui J, Ho A, Nichols F, Movila A. Crosstalk between dihydroceramides produced by Porphyromonas gingivalis and host lysosomal cathepsin B in the promotion of osteoclastogenesis. J Cell Mol Med. 2022. Epub 20220416. doi: 10.1111/jcmm.17299. PubMed PMID: 35429112.
3. Kanzaki H, Movila A, Kayal R, Napimoga MH, Egashira K, Dewhirst F, Sasaki H, Howait M, Al-Dharrab A, Mira A, Han X, Taubman MA, Nichols FC, Kawai T. Phosphoglycerol dihydroceramide, a distinctive ceramide produced by Porphyromonas gingivalis, promotes RANKL-induced osteoclastogenesis by acting on non-muscle myosin II-A (Myh9), an osteoclast cell fusion regulatory factor. Biochimica et biophysica acta. 2017;1862(5):452-62. doi: 10.1016/j.bbalip.2017.01.008. PubMed PMID: 28153611.
4. Yamada C, Akkaoui J, Ho A, Duarte C, Deth R, Kawai T, Nichols F, Lakshmana MK, Movila A. Potential Role of Phosphoglycerol Dihydroceramide Produced by Periodontal Pathogen Porphyromonas gingivalis in the Pathogenesis of Alzheimer's Disease. Front Immunol. 2020;11:591571. Epub 2020/12/18. doi: 10.3389/fimmu.2020.591571. PubMed PMID: 33329577; PMCID: PMC7719741.
Written by Kyle Bone, ICMH Operations Manager