Perspectives on the Intracellular Bacterium Chlamydia pneumoniae in Late-Onset Dementia

Purpose of Review Chronic diseases remain a daunting challenge for clinicians and researchers alike. While difficult to completely understand, most chronic diseases, including late-onset dementias, are thought to arise as an interplay between host genetic factors and environmental insults. One of the most diverse and ubiquitous environmental insults centers on infectious agents. Associations of infectious agents with late-onset dementia have taken on heightened importance, including our investigations of infection by the intracellular respiratory bacterium, Chlamydia pneumoniae (Cpn), in late-onset dementia of the Alzheimer’s type. Recent Findings Over the last two decades, the relationship of this infection to pathogenesis in late-onset dementia has become much clearer. This clarity has resulted from applying contemporary molecular genetic, biochemical, immunochemical, and cell culture techniques to analysis of human brains, animal models, and relevant in vitro cell culture systems. Data from these studies, taken in aggregate form, now can be applied to evaluation of proof of concept for causation of this infection with late-onset disease. In this evaluation, modifications to the original Koch postulates can be useful for elucidating causation. Summary All such relevant studies are outlined and summarized in this review, and they demonstrate the utility of applying modified Koch postulates to the etiology of late-onset dementia of the Alzheimer’s type. Regardless, it is clear that even with strong observational evidence, in combination with application of modifications of Koch’s postulates, we will not be able to conclusively state that Cpn infection is causative for disease pathogenesis in late-onset dementia. Moreover, this conclusion obtains as well for the putative causation of this condition by other pathogens, including herpes simplex virus type 1, Borrelia burgdorferi, and Porphyromonas gingivalis

Emerging Microbial and Viral Infections of the Central Nervous System

This review focuses on emerging viral and bacterial infections in the human central nervous system (CNS) that are responsible for significant global morbidity and mortality. These infections include those responsible for acute neurological disease such as meningitis and encephalitis as well those associated with chronic neurodegenerative conditions. Recent changes in climate conditions and pollution have been precipitating factors leading to the emergence of many of these pathogenic organisms. In addition, increased urbanization, global travel, life span, and exposure to new vectors have promoted the organisms’ spread across the globe. Categorization of many of these organisms includes identification of new species, recognition of new tropism to the CNS, spread into naïve demographic areas, increased human contact with zoonotic repositories including insect vectors, and reemergence of well-known organisms. These mechanisms are highlighted for the different organisms included in this review. Other mechanisms for CNS emergence such as genetic mutation of the organisms and immunosuppression and/or immunosenescence of the host are addressed. Viral and bacterial infections in chronic neurodegenerative diseases traditionally not thought to be infectious are considered. Although this review cannot be all-inclusive, the organisms included represent a sampling of extremely important microbes and their role in CNS pathogenesis in the twenty-first century

Editorial: Infection, inflammation, and neurodegeneration: A critical path to Alzheimer\u27s disease, Volume II.

No abstract availabl

Chlamydia pneumoniae Infection of Monocytes in vitro Stimulates Innate and Adaptive Immune Responses Relevant to those in Alzheimer\u27s Disease.

Background: Alzheimer\u27s disease (AD) is a progressive neurodegenerative disorder in which infection with Chlamydia pneumoniae (Cpn) has been associated. Cpn is an obligate intracellular respiratory pathogen that may enter the central nervous system (CNS) following infection and trafficking of monocytes through the blood-brain barrier. Following this entry, these cells may secrete pro-inflammatory cytokines and chemokines that have been identified in the AD brain, which have been thought to contribute to AD neurodegeneration. The objectives of this work were: (i) to determine if Cpn infection influences monocyte gene transcript expression at 48 hours post-infection and (ii) to analyze whether pro-inflammatory cytokines are produced and secreted from these cells over 24 to 120 hours post-infection. Methods: Gene transcription was analyzed by RT-PCR using an innate and adaptive immunity microarray with 84 genes organized into 5 functional categories: inflammatory response, host defense against bacteria, antibacterial humoral response, septic shock, and cytokines, chemokines and their receptors. Statistical analysis of the results was performed using the Student\u27s t-test. P-values ≤ 0.05 were considered to be significant. ELISA was performed on supernatants from uninfected and Cpn-infected THP1 monocytes followed by statistical analysis with ANOVA. Results: When Cpn-infected THP1 human monocytes were compared to control uninfected monocytes at 48 hours post-infection, 17 genes were found to have a significant 4-fold or greater expression, and no gene expression was found to be down-regulated. Furthermore, cytokine secretion (IL-1ß, IL-6, IL-8) appears to be maintained for an extended period of infection. Conclusions: Utilizing RT-PCR and ELISA techniques, our data demonstrate that Cpn infection of THP1 human monocytes promotes an innate immune response and suggests a potential role in the initiation of inflammation in sporadic/late-onset Alzheimer\u27s disease

Evaluation of Smell and miRNA Biomarkers in Alzheimer’s Disease (AD)

Abstract and poster under embargo until May 31, 2019

Role of Microbes in the Development of Alzheimer\u27s Disease: State of the Art - An International Symposium Presented at the 2017 IAGG Congress in San Francisco.

This article reviews research results and ideas presented at a special symposium at the International Association of Gerontology and Geriatrics (IAGG) Congress held in July 2017 in San Francisco. Five researchers presented their results related to infection and Alzheimer\u27s disease (AD). Prof. Itzhaki presented her work on the role of viruses, specifically HSV-1, in the pathogenesis of AD. She maintains that although it is true that most people harbor HSV-1 infection, either latent or active, nonetheless aspects of herpes infection can play a role in the pathogenesis of AD, based on extensive experimental evidence from AD brains and infected cell cultures. Dr. Miklossy presented research on the high prevalence of bacterial infections that correlate with AD, specifically spirochete infections, which have been known for a century to be a significant cause of dementia (e.g., in syphilis). She demonstrated how spirochetes drive senile plaque formation, which are in fact biofilms. Prof. Balin then described the involvement of brain tissue infection by th

Assessment of the impact of race and proxies of socioeconomic status on the prevalence and health outcome of peripartum cardiomyopathy (PPCM) using the “All of Us” Databank

Background: Peripartum Cardiomyopathy (PPCM) is a form of cardiomyopathy occurring during the last month of pregnancy or within months after giving birth in women with previously normal hearts. PPCM is an idiopathic systolic dysfunction that causes a reduced left ventricle ejection fraction. The estimated incidence of PPCM worldwide is 1 diagnosis out of 2,000 live births, and the causes of PPCM remain unknown. A retrospective cohort study conducted at the University of Pennsylvania Health System by Getz et al. showed that black race and socioeconomic proxies (like neighborhood disadvantage index (NDI)) were independently associated with sustained cardiac dysfunction (Getz et al., Am Heart J 2021). This study also showed that from all the components of NDI (education, high rental occupied housing, annual income below poverty line, female headed household, adults unemployed, adults on public assistance), low education and high rental occupied housing were significantly associated with sustained cardiac dysfunction. The central aim of the present project is to assess the effect of socioeconomic proxies (including NDI, lack of access to health care and food insecurity) on the prevalence of sustained cardiac dysfunction from PPCM across the US using the “All of Us” databank. A secondary aim is to test the compliance of the All of Us database capacity to interrogate this potential association. Lastly, we aim to compare the results obtained from the All of Us database with the UK Biobank. Methods: The All of Us databank (Ramirez et al., Patterns 2022; The All of US Research Program, NEJM 2019) will be used to conduct a retrospective cohort study to assess how proxies of socioeconomic status may affect the incidence and prevalence of sustained cardiac dysfunction from PPCM across different ethnicities in the US. The All of Us database focuses on enrolling people in the US from diverse groups that have historically been underrepresented in medical research. Therefore, it includes a more diverse population than the population targeted in the retrospective study conducted at the University of Pennsylvania in which only black women from Philadelphia, PA, were included. To further interrogate the impact that geographic location and population ethnicity may have on the prevalence of sustained cardiac dysfunction from PPCM, the results obtained from the “All of Us” database will be compared against data obtained from the UK Biobank. Expected Results: We expect that the socioeconomic proxies interrogated in this study will have a significant impact on the prevalence of sustained cardiac dysfunction from PPCM. Current knowledge is limited on how socioeconomic status affects sustained cardiac dysfunction resulting from PPCM. Previous studies have been done on populations restricted to small geographic areas and did not analyze factors such as food security, access to care, or disability status. Understanding how these factors affect the incidence and prevalence of sustained cardiac dysfunction from PPCM may be used to improve prevention, early diagnosis, and management of PPCM

Chlamydophila (Chlamydia) pneumoniae promotes Ab 1-42 amyloid processing in Neuronal Cells: A Pathogenic Trigger for Alzheimer\u27s Disease

Background: Previously, our laboratory identified Chlamydophila (Chlamydia) pneumoniae (Cpn) in autopsied sporadic AD brains. Furthermore, we have developed a BALB/c mouse model that demonstrated infection-induced amyloid plaques similar to those found in AD, and demonstrated that Cpn infection of neuronal cells inhibited apoptotic pathways of cell death. Hypothesis: Our current studies address whether infection with Cpn in neuronal cells triggers abnormal cleavage of the beta amyloid precursor protein (bAPP) into Ab1-42, thereby contributing to amyloid plaque formation characteristic of the pathology identified in AD. Materials and Methods: Human neuroblastoma cells were infected with the respiratory strain AR39 Cpn in vitro, then amyloid processing was analyzed and quantitated using immunocytochemistry, Western blotting and ELISA assays. Results: Cpn was shown to infect neuronal cells and induce intracellular amyloid processing. Cpn infection yielded cytoplasmic labeling of Ab 1-42 that was increased relative to uninfected cells. The ELISA assay revealed that in neuronal cell lysates, Ab 1-42 in the infected cells was increased 3 to 16-fold over the uninfected cells, from 24 to 72hr post infection. Western blot analysis confirmed an increase in Ab 1-42 in the infected neuronal cell lysates. Conclusions: These data suggest that infection of neuronal cells with Chlamydophila (Chlamydia) pneumoniae alters the processing of bAPP, thereby producing Ab1-42. Therefore, these studies and previous research reported by our laboratory support the implication of Cpn as a pathogenic agent in perpetuating the hallmark amyloid plaque formations observed in AD. This concept holds major therapeutic considerations for future studies.https://digitalcommons.pcom.edu/posters/1004/thumbnail.jp

Immunohistological detection of Chlamydia pneumoniae in the Alzheimer's disease brain

<p>Abstract</p> <p>Background</p> <p>Sporadic late-onset Alzheimer's disease (AD) appears to evolve from an interplay between genetic and environmental factors. One environmental factor that continues to be of great interest is that of <it>Chlamydia pneumoniae </it>infection and its association with late-onset disease. Detection of this organism in clinical and autopsy samples has proved challenging using a variety of molecular and histological techniques. Our current investigation utilized immunohistochemistry with a battery of commercially available anti-<it>C. pneumoniae </it>antibodies to determine whether <it>C. pneumoniae </it>was present in areas typically associated with AD neuropathology from 5 AD and 5 non-AD control brains.</p> <p>Results</p> <p>Immunoreactivity for <it>C. pneumoniae </it>antigens was observed both intracellularly in neurons, neuroglia, endothelial cells, and peri-endothelial cells, and extracellularly in the frontal and temporal cortices of the AD brain with multiple <it>C. pneumoniae</it>-specific antibodies. This immunoreactivity was seen in regions of amyloid deposition as revealed by immunolabeling with two different anti-beta amyloid antibodies. Thioflavin S staining, overlaid with <it>C. pneumoniae </it>immunolabeling, demonstrated no direct co-localization of the organism and amyloid plaques. Further, the specificity of <it>C. pneumoniae </it>labeling of AD brain sections was demonstrated using <it>C. pneumoniae </it>antibodies pre-absorbed against amyloid β 1-40 and 1-42 peptides.</p> <p>Conclusions</p> <p>Anti-<it>C. pneumoniae </it>antibodies, obtained commercially, identified both typical intracellular and atypical extracellular <it>C. pneumoniae </it>antigens in frontal and temporal cortices of the AD brain. <it>C. pneumoniae</it>, amyloid deposits, and neurofibrillary tangles were present in the same regions of the brain in apposition to one another. Although additional studies are required to conclusively characterize the nature of Chlamydial immunoreactivity in the AD brain, these results further implicate <it>C. pneumoniae </it>infection with the pathogenesis of Alzheimer's disease.</p

Autophagy and apoptotic genes implicated in Alzheimer’s disease are modulated following infection of neuronal cells with Chlamydia pneumoniae

Background: The focus of the current studies was to determine the relationship between the molecular mechanisms interconnecting autophagy and apoptosis following Chlamydia pneumoniae infection in neuronal cells. Dysfunctions in apoptosis and autophagy have been implicated in the neurodegeneration associated with Alzheimer’s disease (AD). Autophagy in AD pathogenesis has been shown to play a role in amyloid processing through the endosomal-lysosomal system. Apoptosis may contribute to the neuronal cell loss observed in AD; however, there is limited evidence of the apoptotic process proceeding to terminal completion. Although Aβ1-42 has been shown to induce apoptosis in neurons and may be an early factor in AD, our previous investigations demonstrated that neurons infected with Chlamydia pneumoniae are resistant to apoptosis, and that Aβ1-42 is induced following this infection. Thus, these studies address infection as an initiator/trigger or inhibitor for the processes of autophagy and apoptosis observed in Alzheimer’s disease. Methods: SKNMC neuronal cells obtained from ATCC were infected with the AR39 strain of Chlamydia pneumoniae at an MOI=1 for 24, 48, and 72hrs and were analyzed using Real-time PCR arrays from SABiosciences specific for autophagy and apoptosis genetic markers. Results: Some major genes associated with apoptosis such as BID, DAPK1, TP53, TP73 were down regulated by 72hrs post-infection. Genes associated with the regulation of autophagic vacuole formation such as ATG3, ATG4B, ATG4C, ATG9A, ATG9B, ATG12, IRGM, and BECN1 were up-regulated within 72hrs post-infection. With regards to genes involved with co-regulation of autophagy and apoptosis, BNIP3 was significantly up-regulated within 48-72hrs post-infection. Of the genes linking autophagosomes to lysosomes, FAM176A was up-regulated throughout 24-72hrs post-infection. Conclusions: Modulation of autophagy and apoptosis genes occurs in neuronal cells at 24, 48, and 72hrs post- infection with Chlamydia pneumoniae. These genetic changes lead to dysfunction in these basic cellular processes; dysfunction in these processes has been shown to contribute to the neuropathology of late-onset Alzheimer’s disease. This work will allow future studies to further focus on the apoptotic and autophagic pathways to better understand how a pathogen such as Chlamydia pneumoniae plays a role in the development of late-onset Alzheimer’s disease.https://digitalcommons.pcom.edu/posters/1009/thumbnail.jp