Microbial Pathogenesis in Alzheimer’s Disease Grant

Angela Brown, PhD, Lehigh University, for her project, “Establishing the Role of Oral Bacterial Outer Membrane Vesicles in Alzheimer’s Disease”. Dr. Brown’s goal of this project is to understand how vesicles (OMVs) produced by periodontal pathogens transport bacterial components, including certain enzymes, to the brain. Derived from the bacterial membrane, OMVs resemble the surface of the parent bacterium. Recent evidence has demonstrated the presence of certain molecules from periodontal pathogens in the brains of patients with Alzheimer’s Disease, but the process by which these molecules cross the blood brain barrier is unknown. They hypothesize that OMVs, which are able to cross the blood-brain barrier, enable this transport. In this project, they will study the mechanism by which OMVs cross this barrier as well as the interactions between pathogenic proteins, including Aβ and tau, and the vesicle surface. Ultimately, they anticipate that by studying the role(s) of OMVs in Alzheimer’s Disease, this work will lead to the identification of novel therapeutic and diagnostic targets. “I am thrilled to be awarded a “Microbial Pathogenesis in Alzheimer’s Disease Grant”! We are so grateful to the IDSA for the support of our research project which will provide the opportunity to apply our experience in bacterial pathogenesis to contribute to a better understanding of the important relationships between chronic bacterial infections and Alzheimer’s Disease.”

Catherine Butler, PhD, Melbourne Dental School, The University of Melbourne, for her project, “Bacterial membrane vesicles in Alzheimer’s disease”. Dr. Butler’s research examine the extensive preclinical, epidemiological, clinical, and other data to support the oral pathogen Porphyromonas gingivalis as playing a role in Alzheimer’s disease (AD) progression in a susceptible subpopulation of AD sufferers with active periodontal disease. In their current work, outer membrane vesicles (OMVs) from P. gingivalis were detected in the brains of mice that had been repeatedly orally inoculated with live P. gingivalis for longer than 12 weeks, and the brains of these mice displayed AD-like pathology. The requested funding will enable us to remove whole, live bacteria from the animal model and test the hypothesis that P. gingivalis OMVs alone can cause AD-like pathology, and that this is specific to P. gingivalis OMVs due to their unique combination of virulence factors. P. gingivalis OMVs, and OMVs from the oral commensal bacteria Neisseria oralis, will be fluorescently labelled, then injected peripherally into mice and imaged in vivo to determine where the OMVs are located and how long they subsist in the body. Brain tissue from these mice will be examined for AD-like pathology using immunohistochemistry and transmission electron microscopy, whilst real time PCR will be used to determine changes in host gene expression. This will test the hypothesis that AD-like pathology is not necessarily caused by a bacterial infection of the brain but can result from P. gingivalis OMVs invading brain tissue from a focal infection elsewhere in the body. Employing OMVs from a commensal oral bacterium will determine whether this pathogenesis is specific to proteolytic, invasive, and iron accumulating bacteria such as P. gingivalis or whether there is a more general mechanism at play. “The funding support from the Infectious Diseases Society of America Foundation allowed me to jumpstart research projects that are changing how we approach Alzheimer’s disease. As a result of this program, we have already identified microbes and their products that affect this debilitating disease and have very exciting results coming out soon.”

Daniel Czyz, PhD, University of Florida, for his project, “Deciphering the Effect of Human Microbiota on Alzheimer’s Disease using C. elegans”. Dr. Czyz’s research finished characterizing the effect of all culturable isolates from the Human Microbiome Project on host proteostasis. Out of over 240 unique bacterial strains, they found ones that suppress protein aggregation tissues and ones that enhance it. Interestingly, many of the proteotoxic bacteria they identified in their model are overrepresented in patients suffering from neurodegenerative diseases, including AD. They are currently trying to determine how the detrimental bacteria affect protein folding upon intestinal colonization. We are exploring several mechanisms, including their recent finding that bacteria produce protein aggregates that disrupt host proteostasis. They are hoping that the ongoing project will help them identify bacterial signals and products that contribute to the disruption of the protein folding environment in the host. “The funding support from the Infectious Diseases Society of America Foundation allowed me to jumpstart research projects that are changing how we approach Alzheimer’s disease. As a result of this program, we have already identified microbes and their products that affect this debilitating disease and have very exciting results coming out soon.”

Eric Hamlett, PhD, Medical University of South Carolina, for his project, “Can brain-derived extracellular vesicles reveal microbial shedding with Alzheimer’s disease?”. Dr. Hamlett says IDSA has given their lab a precious opportunity to embark on discovery. As they continue to research and refine their understanding of microbial pathogens and AD, they will remain open to new ideas and perspectives. Dr. Hamlett welcomes all funders and affiliates of IDSA to reach out anytime so that they may successfully learn together. There is no substitute for an effective team in leveraging diverse strengths toward complex problems. “I want to thank IDSA for creating an opportunity for my lab to test a novel hypothesis in microbial pathogenesis. My lab was eager to apply our novel EV discovery platform to learn more about microbial mechanisms with AD. IDSA prioritizes advancing scientific research to improve the health of individuals, communities, and society. We are so excited to be a part of that bold mission.”

Fred Turek, PhD, Northwestern University, for his project, “Can brain-derived extracellular vesicles reveal microbial shedding with Alzheimer’s disease.”. Dr. Turek’s research will be using phase restricted feeding to only the “right” time of day (i.e., during the dark phase of an LD cycle, when mice normally eat) or the “wrong” time of day (i.e., during the light phase when mice eat very little) to determine if they can delay or mitigate the onset and severity of AD-like symptoms. They have used such an experimental design in previous studies and have found it can have beneficial (dark-fed) or adverse (light-fed) effects on peripheral disorders such as obesity and diabetes. They are now in position to determine if such an approach can be beneficial for delaying or reducing the progression of AD-like symptoms in an animal model: results which could lead to novel ways of delaying and/or treating AD in humans. “I was part of the research team that discovered the first circadian clock gene in mammals (named Clock). We discovered that the “Clock mutant” mouse has large alterations in the circadian period of the circadian clock which often leads to the loss of 24-hour rhythmicity. The discovery of the clock mutant animal has led me to determine what effects does the genetic disruption of normal rhythms have on body weight, diabetes, GI disorders, composition of the gut microbiota. Now I am interested in investigating how genetic and environmental alterations in circadian rhythms and sleep may lead to changes in neurological function, including AD and Parkinson’s Disease —the two leading neurodegenerative diseases afflicting older humans around the world.”

Gagan Deep, PhD, Wake Forrest School of Medicine, for his project, “Role of gut-dysbiotic bacterial metabolite L-histidinol in Alzheimer’s disease”. Dr. Deep’s research identified a bacterial metabolite that is altered under gut dysbiosis conditions and could play a critical role in Alzheimer’s disease pathogenesis. Through this research grant, their goal is to evaluate the levels of this metabolite in healthy versus cognitively impaired individuals. Their next goal is to assess the role of bacterial extracellular vesicles in delivering this metabolite from the gut to the brain. “My lab is interested in understanding the role of extracellular vesicles in long-distant communication in the body. The gut-brain axis is well established in various diseases, but the underlying mechanisms are still unclear. We propose to assess the role of bacterial extracellular vesicles in mediating the effect of gut/microbiome on distant organs, including the brain, in the body. The major causes of nonfamilial Alzheimer’s disease still remain largely unknown. This research project could inform us about the potential role of a gut microbial metabolite in Alzheimer’s disease pathogenesis.”

Jingchun Chen, PhD, University of Nevada, Las Vegas, for her project, “The impact of COVID-19 on Alzheimer’s disease, focusing on sharing genes and pathways in immune cells”. Dr. Chen’s research focuses on how the etiology of viral infection has been postulated for Alzheimer’s disease (AD) for decades. Since the Coronavirus Disease 2019 (COVID-19) outbreak, studies show that the aging population, including AD patients, is highly susceptible to being severely affected by and dying of COVID-19. It remains unknown whether and how COVID-19 is associated with increased risk for AD, especially at genetic and cell-type specific levels. They recently found that genetic susceptibility for COVID-19 infection and severity is positively correlated with AD diagnosis, even after adjusting for age, indicating shared genetic risks between the two conditions. This project will test the hypothesis that COVID-19 increases the risk for AD from their shared genetic risk factors that are enriched in immune cells and pro-inflammatory pathways. The long-term objective is to identify genes/pathways that cause the high comorbidity and mortality between COVID-19 and AD for better control of the diseases. “My research interest has been the genetic studies of many complex diseases, including psychiatric disorders and Alzheimer’s disease. With COVID-19 pandemic, evidence shows that COVID-19 not only affects the respiratory system, but also other systems such as the central nervous system. Studies also show that there are higher comorbidity and mortality between COVID-19 and Alzheimer’s disease. I want to identify shared genetic risks for both diseases, and optimally find the therapeutic targets for the two diseases.”

Martin Blaser, M.D., Rutgers, The State University of New Jersey, for his project, “Role of the perturbed early-life microbiome in Alzheimer’s Disease pathogenesis”. Dr. Blaser says they have been studying the human microbiome for the past 20 years, with a focus on how it develops during early life. They have shown that antibiotics perturb the microbiome, and that those changes lead to clinical consequences, sometimes years later. In other studies, they provided evidence through epidemiologic analyses suggesting that early life microbial characteristics can affect late-in-life diseases. For those reasons, they decided to study the effects of early life antibiotic treatment that perturbs the microbiome on the development of AD in a suitable mouse model. They have all of the tools they need; they just need to get started. “This is a special grant—it is based on an original idea that we would like to test that could change the time dimension relevant to the development of AD. We are most excited about this study, because the results could be paradigm-shifting, and affect how we approach the prevention, and possibly the treatment of AD.”

Kamada Lwere, MM, Islamic university in Uganda, for his project, “The gut microbiome and immunopathogenesis of ADRD in a Ugandan population.”. Dr. Lwere’s research is a case-control study, aimed to investigate the distribution of the gut microbiome and proinflammatory cytokines (like IL-1β, IL-6, IL-17, and TNF-α.) involved in the pathogenesis of Alzheimer’s disease and related Dementia (ADRD) in an African population, using Uganda as a case study of individuals of African ancestry. Extracted DNA from rectal swabs of older persons shall undergo 16S rRNA gene sequencing. Differences will be tested at the operational taxonomic unit (OTU), genus, and family levels. In addition, they shall measure plasma concentrations of cytokines using Luminex assays. Dr. Lwere has applied and successfully defended the proposal at the Research and Ethics and committee. He hopes to start participant recruitment by 18th April, 2023. With the research grant, he plans to recruit participants, do laboratory analysis, analyse data, write manuscript and publish. “At my University, I happen to be the only scientist doing work on the microbial pathogenesis of Alzheimer’s disease, therefore I was really excited to be part of the team of grantees under the same research theme. I anticipate sharing of ideas, experiences and challenges, so I believe will grow further in the field.”

Martin Darvas, PhD, University of Washington, for his project, “The role of PILRA in the microbial etiology of Alzheimer’s disease”. Dr. Darvas’s research is at the stage where they have established all models and most procedures and are currently analyzing their first batches of RNA-seq data sets that they generated in their NIH-funded R01 grant. Their analysis shows a striking gene-expression profile in brain tissue (during latency) of HSV-1 infected mice that underwent multiple reactivations. They have been using DNA/RNA and protein extractions to generate RNA samples for RNAseq, DNA samples for quantification of HSV-1 titers by TaqMan assays, protein samples to test whether HSV-1 reactivation impacts on amyloid levels in a model for late-onset Alzheimer’s disease (AD), and they complement this with behavior testing. Their group includes expert systems biologists so that they can integrate multiple omics datasets and employ state-of the art analysis of transcriptional regulatory networks and to perform AD-BioDomain analysis based on AD-specific GO-terms. They will examine the role of PILRA in modulating Alzheimer’s disease (AD) pathogenesis through its involvement in the microglia response to Herpes Simplex Virus 1 (HSV-1) infection. They will use a novel model of late-onset AD risk that also harbors a protective variant of PILRA that is associated with reduced risk for AD. We hypothesize that the protective PILRA variant reduces the HSV-1 titers in the brain and limit the spread of HSV-1 across brain regions. They will use digital-spatial transcriptomics approaches to characterize microglial cell states in response to HSV-1 and the protective PILRA variant. “My motivation stems from the unmet medical need for interventions that slow down, perhaps even delay or prevent, dementia symptoms resulting from Alzheimer’s disease (AD) and other neurodegenerative diseases. My particular interest in a viral etiology of AD was initially inspired by Ruth Itzhaki’s ground-breaking work and by the modifiable nature of HSV-1 infections.”

Bhanu Priya Ganesh, PhD, The University of Texas Health Science Center at Houston, for her project, “Enhance Microbiome-Derived Tryptophan Metabolites In The Gut To Improve The Central Immune Function And Reduce Aß Burden”. Dr. Ganesh’s research is focused on the “BRAIN-GUT Axis”. They are investigating how the interaction of the microbiome and their secretory products on modulating physiology of brain in diseases of age. Dr. Ganesh has been involved in the development of novel germ-free rodent models that help them understand the interaction between single or multiple known bacterial species and their secretory products on shaping intestinal epithelium and beyond. She has used germ-free mouse models extensively to investigate the effects of both pathogenic or beneficial (probiotic) bacteria in understanding the role of different bacteria in gut homeostasis. In addition, she is looking at the interactions between the microbiome and its secretory products on modulating goblet cell physiology of mucus synthesis. Dr. Ganesh hopes to identify the changes in mucosal modifications, including the immune response with respect to dysbiotic gut microbiome as possible biomarkers in predicting aging related diseases at an earlier stage. “We are very excited to receive IDSA funding that will help us explore the gut-brain axis studies further. We will be looking into key microbial metabolites and their complex communication with the central immune system. This will help us explore new therapeutic strategies to treat dementia patients before the symptoms show up in the brain when the treatment becomes futile. In this study we primarily focus on amyloid pathology. We strongly believe that fixing the gut early might retard or remit AD progression.”

Melissa Lodoen, PhD, University of California, Irvine, for her project, “Reduction in amyloid plaque burden by Toxoplasma gondii infection of AD mice”. Dr. Lodoen’s research investigates mechanisms of innate immunity and host-pathogen interactions during infection with Toxoplasma gondii, a foodborne parasite that establishes chronic infection in the brain. Interestingly, T. gondii infection of Alzheimer’s disease mice reduces amyloid plaque burden in the brain and improves cognition. Her lab is examining the role of infiltrating immune cells and brain-resident microglia in reducing amyloid plaques in the brain during infection. Since they are still in the early stages of determining the mechanisms of infection-induced neuroprotection, the IDSA Microbial Pathogenesis in Alzheimer’s Disease Award will make a significant impact on their ability to generate preliminary data and build key collaborations with researchers in the Alzheimer’s disease field. Dr. Lodoen hopes that this research will reveal novel processes in the brain that are neuroprotective and that could be enhanced to combat neurogenerative diseases. “The IDSA Microbial Pathogenesis in Alzheimer’s Disease Award will have a major impact on my research program because it will provide necessary support at a critical stage in our research on Alzheimer’s disease. My lab recently established a model of infection and Alzheimer’s disease, and our early data show that Toxoplasma gondii infection of Alzheimer’s disease mice results in a profound reduction in amyloid plaques in the brain. We also detect a significant infiltration of immune cells to the brain and activation of brain-resident microglia. These findings have led to our hypothesis that T. gondii infection activates microglia in the brain to clear amyloid, thereby reducing plaques. We are now poised to investigate this process mechanistically, and the support of the IDSA Microbial Pathogenesis in Alzheimer’s Disease Award will enable us to generate critical preliminary data that we hope will open the door to future funding opportunities from federal funding agencies.”

Panos Zanos, PhD, University of Cyprus, Department of Psychology, for his project, “Identification of viral-mediated pathogenic mechanisms in comorbid Alzheimer’s Disease and Major Depression using Systems Bioinformatics”. Dr. Zanos says Alzheimer’s Disease (AD) is a chronic neurodegenerative disease of the central nervous system and the most common cause of dementia in older people. Although AD is mainly known for its impact on memory and thinking, it can also cause other symptoms like depression and sleep problems. There are currently no effective drugs to treat AD, and having depression alongside AD further worsens prognosis. In this project, they will use advanced bioinformatics techniques to better understand the role and mechanisms by which viral infections can lead to comorbid AD and depression. They will study how different viruses increase susceptibility risk towards the development of these conditions and identify viruses whose co-infection can result in enhanced pathogenic effects that will further increase vulnerability of AD/depression development. By doing this, they hope to identify existing drugs that can quickly and effectively alleviate depressive symptoms in AD patients, and discover new targets for the development of more effective treatments for comorbid AD and depression. “I am deeply grateful and thrilled to receive this grant by IDSA Foundation, which will enable me and my team to pursue cutting-edge research on the identification of viral-mediated pathogenic mechanisms in comorbid Alzheimer’s and major depression using systems bioinformatics approaches. This funding will provide a unique opportunity to uncover novel insights into the microbial pathogenesis of Alzheimer’s disease and its comorbid diseases. I am excited to dive into the data with the aim to advance our understanding how viral infections contribute to the emergence of this complex and devastating diseases.”

Roger Lippé, PhD, University of Montreal & Research Center of the Sainte-Justine University Hospital, for his project, “Infectious etiology of Alzheimer’s disease: Molecular links between HSV-1 and APP”. Dr. Lippé says Alzheimer’s disease (AD) is a neurodegenerative disease that affects an estimated 6.5 million Americans alone, over 55 million individuals worldwide and is expected to affect 139 million people by 2050. It is characterized by neuronal death, cognitive decline, neuroinflammation, hyperactive glia and synaptic disruption. It is also associated with neurofibrillary tangles, alternative amyloid protein precursor processing (APP), Abeta amyloid oligomerization and ultimately senile plaques. Yet, the root cause of AD remains enigmatic. Recent evidence points to an infectious etiology, with herpes simplex virus 1 commonly cited since typically present in the brains of AD patients. This correlation is nonetheless insufficient to draw a causal link since the bulk of both the healthy and AD positive population harbours this latent virus. Recent work demonstrating the virus reconstitutes the hallmarks of the disease in 3D tissue culture models and mice, however, strongly support this model and warrants further studies. Defining the molecular links between the virus and the disease are therefore critical. This proposal will examine this essential aspect based on their recent findings that the herpes simplex virus 1 (HSV-1) glycoprotein M (gM) physically and functionally interacts with ITM2B. Most interestingly, this protein, also called BRI2, is a known modulator of APP processing and thus AD. Interestingly, BRI2 functionality is itself modulated by proteolytic cleavage on its way to the cell surface. They will therefore characterize how HSV-1 alters the expression levels of BRI2 and APP, their intracellular localization and processing as well as Abeta oligomerization. This work will provide the first direct molecular evidence between HSV-1 and AD and will ultimately enable us to design innovative therapies specifically targeting this host-pathogen interaction. “Given our current population aging, neurological diseases are becoming an evermore-pressing issue to address. In addition, as a fundamental research lab, it is very appealing to translate our research so that patients can ultimately benefit from our work. As virology experts, we are in a unique position to examine how HSV-1, which afflicts most people and which has been found in the brains of Alzheimer’s disease patients, interacts molecularly with APP, a hallmark of this illness.”

Shuqi Li, PhD, Harvard Medical School and Brigham and Women’s Hospital, for her project, “Does the Mediterranean diet suppress pathogenic function in the gut microbiota in Alzheimer’s disease?”. Dr. Li’s research objective is investigating the role of pathogenic bacterial species in the gut microbiota of cognitive impaired patients and the mechanisms by which the gut microbiota can modulate the gut-brain axis via metabolic changes. She is currently at the early stage of career as a postdoc being trained and mentored by Dr. Laura Cox. Dr. Li’s hypothesis in this research grant is that Mediterranean diet ameliorates Alzheimer’s disease by suppressing pathogenic gut microbiota and microbial metabolites. Therefore, she has two aims that she hopes to accomplish through this research grant: Aim 1 is to identify microbes and microbial functions altered by the Mediterranean diet and linked to amyloid beta protein aggregation, Aim 2 is to identify metabolites parallel altered in intestinal, serum, and brain by Mediterranean diet that are linked to A-beta pathology. “Accumulating evidence suggest Alzheimer’s disease may have a link to infectious diseases or a microbial mechanism, but this potential significant link was largely unexplored. As an organic chemist, a microbiologist, and a bioinformatician focusing on the gut microbiome in the Neurology Department, I believe the gut microbiome has big impacts on the neurologic health via gut-brain axis. The knowledge gap and my research interest thus has motivated me to get involved in this area of research.”

Zhen Zhao, PhD, University of Southern California, for his project, “cGAS-STING innate immune response modulates neuroinflammation in Alzheimer’s disease”. Dr. Zhao says Infection, aging and AD proteinopathies from Aβ and Tau species can collectively cause the activation of innate immune responses. Their current studies have revealed that the innate immune cGAS-STING pathway is an essential regulator of brain microglia status and neuroinflammation, and represents a missing link between infection and the Alzheimer’s diseases. This grant funding from IDSAF will support their next level of endeavors to further define the exact cellular mechanism of how cGAS-STING pathway contributes to amyloid pathology and neurodegeneration in AD, in conjunction to herpes virus infection. More importantly, they will be able to provide new insights on the beneficial effects of STING, cGAS and TBK1 inhibitors in an animal model of AD, and determine their potential beneficial effects on neuroinflammation, amyloid pathology and neurodegeneration. “Infection and Alzheimer’s disease are affecting almost every family in the world, including mine. During my graduate school and postdoctoral training, I was lucky enough to receive training from renowned experts in both fields, and they also inspired me to continue my journey to this conjuncture of research areas.”