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Background: Alzheimer's 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's 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-1β, 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's disease.

Helicobacter pylori (H. pylori) is involved in the development of several gastroduodenal diseases. Since the latest decade, several studies have reported on the link between chronic H. pylori infection and a variety of extragastric manifestations, including dementia. To identify the publications on the association between H. pylori and dementia, a MEDLINE search was conducted. Although case-control studies reported controversial data, a recent longitudinal population-based cohort study found that after 20 years of follow-up, 28.9% of H. pylori-positive versus 21.1% of H. pylori-negative subjects developed dementia. After correction for confounding factors, the infection was significantly associated with higher risk of developing dementia (P=0.04). Moreover, in another study evaluating the effect of H. pylori eradication on the progression of dementia in Alzheimer's disease patients with peptic ulcer, the cure of the bacterium was associated with a decreased risk of dementia progression compared to persistent infection. To date, defining H. pylori as a target for prevention or treatment of dementia remains a topic with much controversy but of essence, as any relationship would reduce, due to the cost-effectiveness of the therapy, a burden on the National Health Care budget. The need for extensive studies with appropriate epidemiological and clinical approaches is crucial to investigate a potential causal relationship.

Imbalances in gut microbiota are associated with metabolic disorder, which are a group of obesity-related metabolic abnormalities that increase an individual's risk of developing type 2 diabetes (T2D) and Alzheimer's disease (AD). Although a number of risk factors have been postulated that may trigger the development of AD, the root cause of this disease is still a matter of debate. This review further investigates the etiology of AD by accumulating the current role played by gut microbiota in human, and trying to establish an inter-link between T2D and AD pathogenesis. There is a growing body of evidence which suggests that obesity is associated with alteration in the normal gut flora, reduced bacterial diversity, metabolic pathways and altered representation of bacterial genes. Obesity and T2D are considered to be induced as a result of changes within the composition of gut microbiota. The evidence gathered so far clearly advocates the involvement of gut microbes in causing obesity, a state of chronic and low-grade inflammation. Hence, understanding the microbiota of the gut is significant in relation to inflammation, as it is a key contributor for diabetes which has a direct relation to the AD pathogenesis. Comparative analysis of gut microbiota may enable further novel insight into the complex biology of AD, which is very important in order to take preventive measure such as early diagnosis, identification of new therapeutic targets and development of novel drugs.

In recent years, there is a growing interest in research to investigate the importance of gut microbiome in health and diseases. This opens a new area of research for the role of microbial flora of the human gut in inflammation, energy homeostasis, pathogenesis of obesity and other associated disorders. Recent studies propose association of the gut microbiome with development of obesity and metabolic syndromes, such as type 2 diabetes mellitus (T2DM). The T2DM is a metabolic disease that is mainly caused by obesity-linked insulin resistance. The vascular effects of obesity appears to play a role in the development of Alzheimer's disease (AD) that is one of the rapidly growing diseases of a late stage of life all over the world. Studies from both humans and mice models have been demonstrated the engagement of gut microbial flora in the pathogenesis of obesity and host metabolism. The aim of this review is to discuss the current findings that may explain the cascade of gut microbial flora participation in the development of obesity, T2DM and further initiation of AD. In addition, the available data regarding the mechanisms that have been proposed to elucidate the role of gut microbiota in weight gain and possible cause of T2DM and AD have been examined.

Background: Dental infections are frequent and have recently been implicated as a possible risk factor for Alzheimer's disease (AD). Despite a lack of studies investigating orofacial pain in this patient group, dental conditions are known to be a potential cause of pain and to affect quality of life and disease progression., Objectives: To evaluate oral status, mandibular function and orofacial pain in patients with mild AD versus healthy subjects matched for age and gender., Methods: Twenty-nine patients and 30 control subjects were evaluated. The protocol comprised a clinical questionnaire and dental exam, research diagnostic criteria for temporomandibular disorders, the McGill Pain Questionnaire, the decayed, missing, and filled teeth index, and included a full periodontal evaluation. AD signs and symptoms as well as associated factors were evaluated by a trained neurologist., Results: A higher prevalence of orofacial pain (20.7%, p < 0.001), articular abnormalities in temporomandibular joints (p < 0.05), and periodontal infections (p = 0.002) was observed in the study group compared to the control group., Conclusion: Orofacial pain and periodontal infections were more frequent in patients with mild AD than in healthy subjects. Orofacial pain screening and dental and oral exams should be routinely performed in AD patients in order to identify pathological conditions that need treatment thus improving quality of life compromised due to dementia.

It has been proposed that changes in the composition of gut microbiota contribute to the development of diabetes Types 1, 2 and 3 (the latter known as Alzheimer's disease). The onset of these diseases is affected by complex interactions of genetic and several environmental factors. Alterations in gut microbiota in combination with specific diets can result in increased intestinal permeability leading via a continuous state of low-grade inflammation to the development of insulin resistance. Since a change in composition of gut microbiota is also suggested to be the underlying factor for the development of obesity, it is obvious to link gut microbiota with the pathogenesis of diabetes. In addition, insulin resistance in the brain has been recently associated with Alzheimer's disease. These new paradigms in combination with data from studies with prebiotics and probiotics may lead to a novel way to control and even prevent diabetes in general.

The aim of this study was to establish a link between periodontal disease and Alzheimer's disease (AD) with a view to identifying the major periodontal disease bacteria (Treponema denticola, Tannerella forsythia, and Porphyromonas gingivalis) and/or bacterial components in brain tissue from 12 h postmortem delay. Our request matched 10 AD cases for tissue from Brains for Dementia Research alongside 10 non-AD age-related controls with similar or greater postmortem interval. We exposed SVGp12, an astrocyte cell line, to culture supernatant containing lipopolysaccharide (LPS) from the putative periodontal bacteria P. gingivalis. The challenged SVGp12 cells and cryosections from AD and control brains were immunolabeled and immunoblotted using a battery of antibodies including the anti-P. gingivalis-specific monoclonal antibody. Immunofluorescence labeling demonstrated the SVGp12 cell line was able to adsorb LPS from culture supernatant on its surface membrane; similar labeling was observed in four out of 10 AD cases. Immunoblotting demonstrated bands corresponding to LPS from P. gingivalis in the SVGp12 cell lysate and in the same four AD brain specimens which were positive when screened by immunofluorescence. All controls remained negative throughout while the same four cases were consistently positive for P. gingivalis LPS (p = 0.029). This study confirms that LPS from periodontal bacteria can access the AD brain during life as labeling in the corresponding controls, with equivalent/longer postmortem interval, was absent. Demonstration of a known chronic oral-pathogen-related virulence factor reaching the human brains suggests an inflammatory role in the existing AD pathology.

Exotoxin Y (ExoY) is a type III secretion system effector found in ~ 90% of the Pseudomonas aeruginosa isolates. Although it is known that ExoY causes inter-endothelial gaps and vascular leak, the mechanisms by which this occurs are poorly understood. Using both a bacteria-delivered and a codon-optimized conditionally expressed ExoY, we report that this toxin is a dual soluble adenylyl and guanylyl cyclase that results in intracellular cAMP and cGMP accumulation. The enzymatic activity of ExoY caused phosphorylation of endothelial Tau serine 214, accumulation of insoluble Tau, inter-endothelial cell gap formation, and increased macromolecular permeability. To discern whether the cAMP or cGMP signal was responsible for Tau phosphorylation and barrier disruption, pulmonary microvascular endothelial cells were engineered for the conditional expression of either wild-type guanylyl cyclase, which synthesizes cGMP, or a mutated guanylyl cyclase, which synthesizes cAMP. Sodium nitroprusside stimulation of the cGMP-generating cyclase resulted in transient Tau serine 214 phosphorylation and gap formation, whereas stimulation of the cAMP-generating cyclase induced a robust increase in Tau serine 214 phosphorylation, gap formation, and macromolecular permeability. These results indicate that the cAMP signal is the dominant stimulus for Tau phosphorylation. Hence, ExoY is a promiscuous cyclase and edema factor that uses cAMP and, to some extent, cGMP to induce the hyperphosphorylation and insolubility of endothelial Tau. Because hyperphosphorylated and insoluble Tau are hallmarks in neurodegenerative tauopathies such as Alzheimer disease, acute Pseudomonas infections cause a pathophysiological sequela in endothelium previously recognized only in chronic neurodegenerative diseases.

Background: Chronic inflammation in periodontal disease has been suggested as a potential risk factor in Alzheimer's disease (AD). The purpose of this study was to examine serum antibody levels to bacteria of periodontal disease in participants who eventually converted to AD compared with the antibody levels in control subjects., Methods: Serum samples from 158 participants in the Biologically Resilient Adults in Neurological Studies research program at the University of Kentucky were analyzed for immunoglobulin G antibody levels to seven oral bacteria associated with periodontitis, including Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Campylobacter rectus, Treponema denticola, Fusobacterium nucleatum, Tannerella forsythia, and Prevotella intermedia. All 158 participants were cognitively intact at baseline venous blood draw. In all, 81 of the participants developed either mild cognitive impairment (MCI) or AD or both, and 77 controls remained cognitively intact in the years of follow-up. Antibody levels were compared between controls and subjects with AD at baseline draw and after conversion and controls and subjects with MCI at baseline draw and after conversion using the Wilcoxon rank-sum test. AD and MCI participants were not directly compared. Linear regression models were used to adjust for potential confounding., Results: Antibody levels to F nucleatum and P intermedia were significantly increased (α = 0.05) at baseline serum draw in the patients with AD compared with controls. These results remained significant when controlling for baseline age, Mini-Mental State Examination score, and apolipoprotein epsilon 4 status., Conclusions: This study provides initial data that demonstrate elevated antibodies to periodontal disease bacteria in subjects years before cognitive impairment and suggests that periodontal disease could potentially contribute to the risk of AD onset/progression. Additional cohort studies profiling oral clinical presentation with systemic response and AD and prospective studies to evaluate any cause-and-effect association are warranted., (Published by Elsevier Inc.)

Recent case-control studies reported an association between H. pylori infection and Alzheimer's disease (AD). Our aim was to compare cognitive impairment, neuroinflammation, and cerebrovascular lesion load in a group of AD patients according to their H. pylori status. For the 53 AD patients included, we assessed: clinical data (vascular comorbidities and cognitive assessment), biological data (especially fibrinogen, homocysteine levels, apolipoprotein E4 genotype; cerebrospinal fluid [CSF] total tau protein [Tau], phospho-tau(181) protein [pTau(181)]), and amyloid beta peptide levels, serum/CSF-cytokines (interleukin [IL]-1β, IL-6, IL-8, tumor necrosis factor [TNF]-α) and pepsinogen I/pepsinogen II (PgI/PgII) ratio, and cerebrovascular lesion load (magnetic resonance imaging [MRI] fluid-attenuated inversion recovery [FLAIR] with the Fazekas and Schmidt scale). H. pylori infection was diagnosed by enzyme-linked immunosorbent assay (ELISA) and immunoblot test. H. pylori infection was associated with a decreased Mini Mental State Examination (MMS) (p = 0.024), and higher CSF pTau(181) (p = 0.014) and tau (p = 0.021) levels. A decreased PgI/II ratio (i.e., an increased gastric atrophy) was associated with the infection (p = 0.005). Homocysteine levels were positively correlated to Fazekas score (r = 0.34; p = 0.032) and to H. pylori immunoglobulin (Ig)G levels (r = 0.44; p = 0.001). Higher CSF cytokine levels (IL-8, p = 0.003; TNF-α, p = 0.019) were associated with the infection, but systemic inflammation results were controversial. Finally, in multivariate analysis, a lower MMSE score (odds ratio [OR], 0.83 [0.72-0.97]; p = 0.017), plasma IL-1β level (OR, 0.31 [0.11-0.87]; p = 0.025), an increased gastric atrophy, i.e., a lower PgI/PgII ratio (OR, 0.63 [0.43-0.93]; p = 0.020) were still associated with the infection. AD patients infected by H. pylori tended to be more cognitively impaired. Studies are needed to attest to the impact of H. pylori infection on AD course, especially on cerebrovascular lesions and neuroinflammation., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Chronic spirochetal infection can cause slowly progressive dementia, cortical atrophy and amyloid deposition in the atrophic form of general paresis. There is a significant association between Alzheimer disease (AD) and various types of spirochete (including the periodontal pathogen Treponemas and Borrelia burgdorferi), and other pathogens such as Chlamydophyla pneumoniae and herpes simplex virus type-1 (HSV-1). Exposure of mammalian neuronal and glial cells and organotypic cultures to spirochetes reproduces the biological and pathological hallmarks of AD. Senile-plaque-like beta amyloid (Aβ) deposits are also observed in mice following inhalation of C. pneumoniae in vivo, and Aβ accumulation and phosphorylation of tau is induced in neurons by HSV-1 in vitro and in vivo. Specific bacterial ligands, and bacterial and viral DNA and RNA all increase the expression of proinflammatory molecules, which activates the innate and adaptive immune systems. Evasion of pathogens from destruction by the host immune reactions leads to persistent infection, chronic inflammation, neuronal destruction and Aβ deposition. Aβ has been shown to be a pore-forming antimicrobial peptide, indicating that Aβ accumulation might be a response to infection. Global attention and action is needed to support this emerging field of research because dementia might be prevented by combined antibiotic, antiviral and anti-inflammatory therapy.

Although two studies have indicated a possible link between Alzheimer's disease (AD) and Helicobacter pylori (H. pylori) infection, these were reported from Europe, where the prevalence of H. pylori infection is not very high. In this study, the prevalence of H. pylori infection was examined in AD patients in Japan, where there is a high prevalence of H. pylori. Consecutive patients referred to the Memory and Dementia Outpatient Clinic from August 2002 to March 2009 were studied. H. pylori infection status was determined by measuring urinary levels of anti-H. pylori antibody (RAPIRUN(®)). Multiple stepwise logistic regression analyses were used to examine the associations of AD with the main predictor variables. Of the 917 patients who visited the clinic, 385 were diagnosed as having AD. Ninety-seven patients did not have dementia and were considered controls. On univariate analysis, average age and the proportion of males were significantly higher in AD patients than in controls. There was no difference in the prevalence of H. pylori infection between patients with AD and controls (62.0% vs. 59.7%, p = 0.67, crude odds ratio (OR), 1.10). Multiple logistic regression analysis showed that older age and male sex, but not H. pylori status, were significantly associated with AD (p < 0.001, p = 0.01, p = 0.83, respectively). The prevalence of H. pylori infection did not differ between AD patients and controls among Japanese subjects. The high prevalence of H. pylori in controls may contribute to the discrepancy with previous reports.

Alzheimer's disease (AD) is the most common cause of dementia in the elderly, whereby it is customary to distinguish between early familial FAD and late-onset AD (LOAD). The development of LOAD, the most prevalent form of AD, is believed to be a multifactorial process that may also involve infections with bacterial or viral pathogens. After the first report on the presence of Chlamydia pneumoniae (Cpn) in brains of patients with AD appeared in 1998, this bacterium has most often been implicated in AD pathogenesis. However, while some studies demonstrate a clear association between Cpn infection and AD, others have failed to confirm these findings. This might be due to heterogeneity of the specimens analyzed and lack of standardized detection methods. Additionally, non-availability of suitable chlamydial infection models severely hampers research in the field. In this review, we will critically discuss the possible role of Cpn in the pathogenesis of LOAD in light of the available data. We will also present three mutually non-exclusive hypotheses how Cpn might contribute to the pathogenesis of AD.

Background: 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 Chlamydia pneumoniae 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-C. pneumoniae antibodies to determine whether C. pneumoniae was present in areas typically associated with AD neuropathology from 5 AD and 5 non-AD control brains., Results: Immunoreactivity for C. pneumoniae 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 C. pneumoniae-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 C. pneumoniae immunolabeling, demonstrated no direct co-localization of the organism and amyloid plaques. Further, the specificity of C. pneumoniae labeling of AD brain sections was demonstrated using C. pneumoniae antibodies pre-absorbed against amyloid β 1-40 and 1-42 peptides., Conclusions: Anti-C. pneumoniae antibodies, obtained commercially, identified both typical intracellular and atypical extracellular C. pneumoniae antigens in frontal and temporal cortices of the AD brain. C. pneumoniae, 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 C. pneumoniae infection with the pathogenesis of Alzheimer's disease.

Background: Alzheimer disease (AD) is a progressive, fatal neurodegenerative condition., Objective: We tested the hypothesis that eradication of Helicobacter pylori infection (Hp-I) could improve survival in a Greek cohort of AD patients, in a 5-year follow-up., Method: Forty-six patients diagnosed with probable AD were enrolled in the analysis. Study population was classified into 3 groups: patients for whom Hp eradication treatment was successful; those for whom eradication of Hp had failed, they refused, and/or were noncompliant with eradication therapy; and those who were Hp negative at baseline. Cox proportional hazards model was built with all-cause mortality as the dichotomous outcome., Results: During the 5-year follow-up [47.19±15.11 mo (range 12 to 60)], overall 21 patients died and 25 patients remained alive. Patients who died were older and exhibited lower mean MMSE score compared with the patients still alive. Successful eradication of Hp-I was associated with a significantly lower mortality risk [HR (95% CI)=0.287 (0.114-0.725), P=0.008]. The results were similar in adjusted and unadjusted models, for age and MMSE at baseline., Conclusion: Hp eradication regimen in AD patients is associated with a higher 5-year survival rate.

Protein aggregation and amyloid fibril deposits in the central nervous system are characteristic features of more than 2 dozens of pathologic conditions. The various peptides thought to underlie these disorders have striking structural and functional similarities. The main difference between them at the molecular level is whether they are endogenously produced particles, exogenously transmitted infectious agents, or both. These similarities and novel approaches to their transmissibility are discussed in this review-based hypothesis., (2010 S. Karger AG, Basel.)

While our understanding of the neuropathology of Alzheimer's disease continues to grow, its pathogenesis remains a subject of intense debate. Genetic mutations contribute to a minority of early-onset autosomal dominant cases, but most cases are of either late-onset familial or sporadic form. CNS infections, most notably herpes simplex virus type 1, Chlamydophila pneumoniae and several types of spirochetes, have been previously suggested as possible aetiological agents in the development of sporadic Alzheimer's disease but with little consistent evidence. However, peripheral infections may have a role to play in accelerating neurodegeneration in Alzheimer's disease by activating already primed microglial cells within the CNS. Potential pharmacological interventions could aim at modification of this peripheral inflammatory response through targeting various agents involved in this inflammatory pathway. However, benefit could also be gained clinically through the meticulous detection, treatment and prevention of infections in individuals either alone or in combination with anti-inflammatory therapy.

The associations of inflammation/immune responses with clinical presentations of Alzheimer's disease (AD) remain unclear. We hypothesized that TNF-alpha and elevated antibodies to periodontal bacteria would be greater in AD compared to normal controls (NL) and their combination would aid clinical diagnosis of AD. Plasma TNF-alpha and antibodies against periodontal bacteria were elevated in AD patients compared with NL and independently associated with AD. The number of positive IgG to periodontal bacteria incremented the TNF-alpha classification of clinical AD and NL. This study shows that TNF-alpha and elevated numbers of antibodies against periodontal bacteria associate with AD and contribute to the AD diagnosis.

Infection with several important pathogens could constitute risk factors for cognitive impairment, dementia, and Alzheimer's disease (AD) in particular. This review summarizes the data related to infectious agents that appear to have a relationship with AD. Infections with herpes simplex virus type 1, picornavirus, Borna disease virus, Chlamydia pneumoniae, Helicobacter pylori, and spirochete were reported to contribute to the pathophysiology of AD or to cognitive changes. Based on these reports, it may be hypothesized that central nervous system or systemic infections may contribute to the pathogenesis or pathophysiology of AD, and chronic infection with several pathogens should be considered a risk factor for sporadic AD. If this hypothesis holds true, early intervention against infection may delay or even prevent the future development of AD.

Previous studies from this laboratory provided evidence that the intracellular bacterial pathogen Chlamydophila (Chlamydia) pneumoniae is present in the late-onset Alzheimer's disease (AD) brain. Here we report culture of the organism from two AD brain samples, each of which originated from a different geographic region of North America. Culturable organisms were detectable after one and two passages in HEp-2 cells for the two samples. Both isolates, designated Tor-1 and Phi-1, were demonstrated to be authentic C. pneumoniae using PCR assays targeting the C. pneumoniae-specific genes Cpn0695, Cpn1046, and tyrP. Assessment of inclusion morphology and quantitation of infectious yields in epithelial (HEp-2), astrocytic (U-87 MG), and microglial (CHME-5) cell lines demonstrated an active, rather than a persistent, growth phenotype for both isolates in all host cell types. Sequencing of the omp1 gene from each isolate, and directly from DNA prepared from several additional AD brain tissue samples PCR-positive for C. pneumoniae, revealed genetically diverse chlamydial populations. Both brain isolates carry several copies of the tyrP gene, a triple copy in Tor-1, and predominantly a triple copy in Phi-1 with a minor population component having a double copy. This observation indicated that the brain isolates are more closely related to respiratory than to vascular/atheroma strains of C. pneumoniae.

Unlabelled: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with progressive dementia. Multiple processes have been implicated in AD, notably including abnormal beta-amyloid production, tau hyperphosphorylation and neurofibrillary tangles (NFTs), synaptic pathology, oxidative stress, inflammation, protein processing or misfolding, calcium dyshomeostasis, aberrant reentry of neurons into the cell cycle, cholesterol synthesis, and effects of hormones or growth factors. The complexity of the disease, which affects numerous molecules, cells, and systems and impedes attempts to determine which alterations are specifically associated with early pathology. Chlamydia pneumoniae is an obligate intracellular bacterium. Infection with this organism has been suggested to be a risk factor for AD. C. pneumoniae has two phages phiCPAR39 and phage related to phiCPG1., Hypothesis: we propose that these two phages by entering into mitochondria of chlamydia's host cell can work as slow viruses and can initiate AD.

Microorganisms, bacteria and viruses may infect and cause a range of acute and chronic diseases in humans dependent on the genetic background, age, sex, immune and health status of the host, as well as on the nature, virulence and dose of infectious agent. Late onset Alzheimer's disease (AD) is a progressive neurodegenerative illness of broad aetiology with a strong genetic component and a significant contribution of age, sex and life style factors. Both infectious diseases and AD are characterised by an increased production of an array of immune mediators, cytokines, chemokines and complement proteins by the host cells as well as by changes in the host lipid metabolism. In this review, we re-examine a dangerous liaison between several viral and bacterial infections and the most significant genetic factor for AD, APOE epsilon4, and the possible impact of this alliance on AD development. This connection was discussed in the broader context of lipid metabolism and in the light of different capacity of various infectious agents, their toxic lipophilic products and host lipoprotein particles for binding to cell receptor(s).

Alzheimer's disease (AD) is associated with dementia, brain atrophy and the aggregation and accumulation of a cortical amyloid-beta peptide (Abeta). Chronic bacterial infections are frequently associated with amyloid deposition. It had been known from a century that the spirochete Treponema pallidum can cause dementia in the atrophic form of general paresis. It is noteworthy that the pathological hallmarks of this atrophic form are similar to those of AD. Recent observations showed that bacteria, including spirochetes contain amyloidogenic proteins and also that Abeta deposition and tau phosphorylation can be induced in or in vivo following exposure to bacteria or LPS. Bacteria or their poorly degradable debris are powerful inflammatory cytokine inducers, activate complement, affect vascular permeability, generate nitric oxide and free radicals, induce apoptosis and are amyloidogenic. All these processes are involved in the pathogenesis of AD. Old and new observations, reviewed here, indicate that to consider the possibility that bacteria, including several types of spirochetes highly prevalent in the population at large or their persisting debris may initiate cascade of events leading to chronic inflammation and amyloid deposition in AD is important, as appropriate antibacterial and antiinflammatory therapy would be available to prevent dementia.

Sporadic, late-onset Alzheimer's disease (LOAD) is a non-familial, progressive neurodegenerative disease that is now the most common and severe form of dementia in the elderly. That dementia is a direct result of neuronal damage and loss associated with accumulations of abnormal protein deposits in the brain. Great strides have been made in the past 20 years with regard to understanding the pathological entities that arise in the AD brain, both for familial AD ( approximately 5% of all cases) and LOAD ( approximately 95% of all cases). The neuropathology observed includes: neuritic senile plaques (NSPs), neurofibrillary tangles (NFTs), neuropil threads (NPs), and often deposits of cerebrovascular amyloid. Genetic, biochemical, and immunological analyses have provided a relatively detailed knowledge of these entities, but our understanding of the "trigger" events leading to the many cascades resulting in this pathology and neurodegeneration is still quite limited. For this reason, the etiology of AD, in particular LOAD, has remained elusive. However, a number of recent and ongoing studies have implicated infection in the etiology and pathogenesis of LOAD. This review focuses specifically on infection with Chlamydophila (Chlamydia) pneumoniae in LOAD and how this infection may function as a "trigger or initiator" in the pathogenesis of this disease.

Background: Chlamydophila (Chlamydia) pneumoniae is an intracellular bacterium that has been identified within cells in areas of neuropathology found in Alzheimer disease (AD), including endothelia, glia, and neurons. Depending on the cell type of the host, infection by C. pneumoniae has been shown to influence apoptotic pathways in both pro- and anti-apoptotic fashions. We have hypothesized that persistent chlamydial infection of neurons may be an important mediator of the characteristic neuropathology observed in AD brains. Chronic and/or persistent infection of neuronal cells with C. pneumoniae in the AD brain may affect apoptosis in cells containing chlamydial inclusions., Results: SK-N-MC neuroblastoma cells were infected with the respiratory strain of C. pneumoniae, AR39 at an MOI of 1. Following infection, the cells were either untreated or treated with staurosporine and then examined for apoptosis by labeling for nuclear fragmentation, caspase activity, and membrane inversion as indicated by annexin V staining. C. pneumoniae infection was maintained through 10 days post-infection. At 3 and 10 days post-infection, the infected cell cultures appeared to inhibit or were resistant to the apoptotic process when induced by staurosporine. This inhibition was demonstrated quantitatively by nuclear profile counts and caspase 3/7 activity measurements., Conclusion: These data suggest that C. pneumoniae can sustain a chronic infection in neuronal cells by interfering with apoptosis, which may contribute to chronic inflammation in the AD brain.

Brain structure in health is a dynamic energized equation incorporating chemistry, neuronal structure, and circuitry components. The chemistry "piece" is represented by multiple neurotransmitters such as Acetylcholine, Serotonin, and Dopamine. The neuronal structure "piece" incorporates synapses and their connections. And finally circuits of neurons establish "architectural blueprints" of anatomic wiring diagrams of the higher order of brain neuron organizations. In Alzheimer's disease, there are progressive losses in all of these components. Brain structure crumbles. The deterioration in Alzheimer's is ordered, reproducible, and stepwise. Drs. Braak and Braak have described stages in the Alzheimer disease continuum. "Progressions" through Braak Stages benchmark "Regressions" in Cognitive function. Under the microscope, the Stages of Braak commence in brain regions near to the hippocampus, and over time, like a tsunami wave of destruction, overturn healthy brain regions, with neurofibrillary tangle damaged neurons "marching" through the temporal lobe, neocortex and occipital cortex. In effect the destruction ascends from the limbic regions to progressively destroy the higher brain centers. Rabies infection also "begins low and finishes high" in its wave of destruction of brain tissue. Herpes Zoster infections offer the paradigm of clinical latency of infection inside of nerves before the "marching commences". Varicella Zoster virus enters neurons in the pediatric years. Dormant virus remains inside the neurons for 50-80 years, tissue damage late in life (shingles) demonstrates the "march of the infection" down neural pathways (dermatomes) as linear areas of painful blisters loaded with virus from a childhood infection. Amalgamation of Zoster with Rabies models produces a hybrid model to explain all of the Braak Stages of Alzheimer's disease under a new paradigm, namely "Alzheimer's neuroborreliosis" in which latent Borrelia infections ascend neural circuits through the hippocampus to the higher brain centers, creating a trail of neurofibrillary tangle injured neurons in neural circuits of cholinergic neurons by transsynaptic transmission of infection from nerve to nerve.

Although degenerative diseases of the central nervous system, including Alzheimer's disease (AD), have an increasingly high impact on aged population their association with Helicobacter pylori (H. pylori) infection has not as yet been thoroughly researched. Current H. pylori infection appears to induce irregular humoral and cellular immune responses that, owing to the sharing of homologous epitopes (molecular mimicry), cross-react with components of nerves, thereby contributing and possibly perpetuating the apoptotic neural tissue damage observed in neurodegenerative diseases including AD. An association between AD and H. pylori infection has been recently addressed by two studies. A higher seropositivity for anti-H. pylori immunoglobulin G antibodies in 30 patients with AD than in 30 age-matched controls was reported in one study; this serological test, however, has limitations because it does not discriminate between current and old infections. In the other study, by introducing the histological method (the actual gold standard) for diagnosis of H. pylori infection, we reported a higher prevalence of H. pylori infection in 50 AD patients than in 30 anemic controls. This pathogen may influence the pathophysiology of AD by promoting platelet and platelet-leukocyte aggregation; releasing various pro-inflammatory and vasoactive substances; developing cross-mimicry with host antigens; producing reactive oxygen metabolites and circulating lipid peroxides; influencing the apoptotic process; and increasing, through induction of atrophic gastritis, homocysteine, which contributes to vascular disorders implicated in endothelial damage and neurodegeneration.

We assessed the presence and characteristics of the intracellular pathogen Chlamydophila (Chlamydia) pneumoniae in brain-tissue samples from 25 patients with late-onset Alzheimer's disease (AD) and 27 non-AD control individuals. 20/27 AD patients, but only 3/27 controls, were PCR-positive in multiple assays targetting the Cpn1046 and Cpn0695 genes. Culture of the organism from brain-tissue homogenate from one AD patient, and assessment of various chlamydial transcripts in RNA preparations from several patients, demonstrated that the organisms were viable and metabolically active in those samples. Immunohistochemical analyses showed that astrocytes, microglia, and neurons all served as host cells for C. pneumoniae in the AD brain, and that infected cells were found in close proximity to both neuritic senile plaques and neurofibrillary tangles in the AD brain. These observations confirm and significantly extend our earlier study suggesting that this unusual pathogen may play a role in the neuropathogenesis characteristic of AD.

The pathological hallmarks of Alzheimer's disease (AD) consist of beta-amyloid plaques and neurofibrillary tangles in affected brain areas. The processes, which drive this host reaction are unknown. To determine whether an analogous host reaction to that occurring in AD could be induced by infectious agents, we exposed mammalian glial and neuronal cells in vitro to Borrelia burgdorferi spirochetes and to the inflammatory bacterial lipopolysaccharide (LPS). Morphological changes analogous to the amyloid deposits of AD brain were observed following 2-8 weeks of exposure to the spirochetes. Increased levels of beta-amyloid precursor protein (AbetaPP) and hyperphosphorylated tau were also detected by Western blots of extracts of cultured cells that had been treated with spirochetes or LPS. These observations indicate that, by exposure to bacteria or to their toxic products, host responses similar in nature to those observed in AD may be induced.

Chlamydia pneumoniae has recently been implicated in the pathogenesis of several neurological diseases. As an intracellular parasite with its unusual life cycle it is able to circumvent the immune system and to persist in the organism. It has the ability to modify the function of the infected cell and supposedly induce autoimmune reactions. These properties can make it pathogenic in several chronic neurological diseases including multiple sclerosis, atherosclerosis, stroke, Alzheimer dementia and giant cell arteritis. The evaluation of the available, often contradictory, data that are based on various different methods is not easy. The importance of the issue is enhanced by the potential need for antibiotic treatment.

Chlamydophila pneumoniae biotype TWAR is classified in the Chlamydiacea family and used to be considered a cause of pneumonia. Lately it has been also proved that it can cause heart disease and diseases of the blood vessels and also take part in the pathogenesis Alzheimer and multiple sclerosis, which shows that biotype TWAR has expanded its spectrum.

Alzheimer's disease is a complex neurodegenerative disorder. Several risk factors have been reported and compiled from genetic and epidemiological studies. Many theories on the cause of Alzheimer's disease have been proposed over the past. Amyloid hypothesis is still the most important one and guides a lot of scientific research on AD. But there is general consent that amyloid deposits are the products of degenerating neurons, not a cause of degeneration. Recently, epidemiological data for the correlation between HSV-1 infection and AD have been collected. It was revealed that HSV-1 is present in a latent form in the brains of a high proportion of elderly people and is a risk factor for AD in carriers of APOEepsilon4. On the other hand, there is negative evidence for HSV-1 as a risk factor of APOEepsilon4 positive AD cases. Finally, some investigations raise a possibility that viruses other than HSV-1 may influence Alzheimer's disease. In the present paper the possible role of HSV-1 infection in pathology of AD is discussed.

Studies from this laboratory have indicated that the intracellular eubacterial respiratory pathogen Chlamydophila (Chlamydia) pneumoniae is commonly found in brain regions displaying characteristic neuropathology in patients with late-onset Alzheimer's disease (AD) but not in congruent samples from non-AD control individuals. In later work, we provided evidence suggesting that some relationship exists between the APOE epsilon4 gene product and the pathobiology of this organism. In the present report, in situ hybridization analyses indicated that the number of C. pneumoniae-infected cells in affected brain regions of epsilon4-bearing AD patients was higher overall than that in congruent brain regions from AD patients lacking that allele. Quantitative real-time PCR analyses of AD brain tissue samples demonstrated that actual bacterial burden in those samples varied over several orders of magnitude, but that samples from epsilon4-bearing patients did have significantly higher bacterial loads than did congruent samples from patients without the allele (ANOVA, p<0.05). These results may explain in part the observations that epsilon4-bearing individuals have a higher risk of developing AD, and that such patients progress more rapidly to cognitive dysfunction than do individuals lacking this allele.

Objectives: To determine the relationships between Chlamydia pneumoniae infection, carotid atherosclerosis, and dyslipidemia in patients with vascular dementia (VaD) and Alzheimer's disease (AD)., Design: Case control study., Setting: Showa University Karasuyama Hospital, Tokyo, Japan., Participants: One hundred twenty-four elderly subjects: 31 with VaD, 61 with AD, and 32 age-matched controls without dementia., Measurements: Presence of antibodies to C. pneumoniae (immunoglobulin G (IgG) and IgA), the serum concentrations of high-sensitive C-reactive protein (hs-CRP) and atherogenic lipoproteins, and the carotid artery intima-media thickness (IMT) and plaques were determined., Results: Age; body mass index; systolic and diastolic blood pressures; and fasting plasma glucose, hemoglobin A(1c), high-density lipoprotein cholesterol, and apolipoprotein A-I, B, and E concentrations did not differ significantly between the three groups, but the mean IMT and frequency of atherosclerotic plaques in the carotid arteries, as well as the serum concentrations of low-density lipoprotein cholesterol (LDL-C), lipoprotein(a), and lipid peroxides were significantly greater in VaD patients than in AD patients or nondemented controls. Hs-CRP concentrations and prevalence of C. pneumoniae IgG and IgA antibodies also were significantly higher in VaD patients than in AD patients and nondemented controls. Multiple logistic regression analysis revealed that carotid IMT and plaques, LDL-C, lipid peroxides, hs-CRP, and IgG and IgA C. pneumoniae seropositivity were independent risk factors for VaD., Conclusion: These results suggest that carotid atherosclerosis, atherogenic lipoproteins, and C. pneumoniae infection (as documented by the IgG and IgA seropositivity together with increased hs-CRP) may be VaD risk factors.

The cause, or causes, of the vast majority of Alzheimer's disease cases are unknown. A number of contributing factors have been postulated, including infection. It has long been known that the spirochete Treponema pallidum, which is the infective agent for syphilis, can in its late stages cause dementia, chronic inflammation, cortical atrophy and amyloid deposition. Spirochetes of unidentified types and strains have previously been observed in the blood, CSF and brain of 14 AD patients tested and absent in 13 controls. In three of these AD cases spirochetes were grown in a medium selective for Borrelia burgdorferi. In the present study, the phylogenetic analysis of these spirochetes was made. Positive identification of the agent as Borrelia burgdorferi sensu stricto was based on genetic and molecular analyses. Borrelia antigens and genes were co-localized with beta-amyloid deposits in these AD cases. The data indicate that Borrelia burgdorferi may persist in the brain and be associated with amyloid plaques in AD. They suggest that these spirochetes, perhaps in an analogous fashion to Treponema pallidum, may contribute to dementia, cortical atrophy and amyloid deposition. Further in vitro and in vivo studies may bring more insight into the potential role of spirochetes in AD.

Despite very numerous studies on Alzheimer's disease (AD), especially on amyloid plaques and neurofibrillary tangles, little information has been obtained thus on the causes of the disease. Evidence is described here that implicates firstly herpes simplex virus type 1 (HSV1) as a strong risk factor when it is present in brain of carriers of the type 4 allele of the gene for apolipoprotein E (APOE-4). Indirect support comes from studies indicating the role of APOE in several diverse diseases of known pathogen cause. A second putative risk factor is the bacterium, Chlamydia pneumoniae. This pathogen has been identified and localized in AD brain. Current studies aimed at "proof of principle" address the entry of the organism into the CNS, the neuroinflammatory response to the organism, and the role that the organism plays in triggering AD pathology. An infection-based animal model demonstrates that following intranasal inoculation of BALB/c mice with C. pneumoniae, amyloid plaques/deposits consistent with those observed in the AD brain develop, thus implicating this infection in the etiology of AD.

This paper critically reviews the possibility that infiltration of the brain by pathogens (e.g. Herpes simplex virus type 1 (HSV1) or Chlamydophila pneumoniae (Cp)) acts as a trigger or co-factor for Alzheimer's disease (AD). The evidence currently available is limited and in some cases inconsistent, but it does justify the need for more vigorous investigation of this hypothesis. An issue of particular concern is the paucity of experimental evidence showing that pathogens can elicit the neuropathological changes and cognitive deficits that characterise AD. Other weaknesses include a failure to obtain independent confirmation of Cp in AD brains, and a lack of evidence for HSV1 proteins or intact virions in AD brain tissue. Future avenues of investigation that might prove fruitful include epidemiological investigations of the incidence of AD in individuals who are either immunosuppressed or have received chronic antiviral or antibiotic therapy. There is also a need to consider systemic infections as potential contributors to the pathogenesis of AD.

Amyloid deposits resembling plaques found in Alzheimer's disease (AD) brains were formed in the brains of non-transgenic BALB/c mice following intranasal infection with Chlamydia pneumoniae. The mice were infected at 3 months of age with C. pneumoniae isolated from an AD brain. Infection was confirmed by light and electron microscopy in olfactory tissues of the mice. C. pneumoniae was still evident in these tissues 3 months after the initial infection indicating that a persistent infection had been established. Amyloid beta (Abeta) 1-42 immunoreactive deposits were identified in the brains of infected BALB/c mice up to 3 months post-infection with the density, size, and number of deposits increasing as the infection progressed. A subset of deposits exhibited thioflavin-s labeling. Intracellular Abeta1-42 labeling was observed in neuronal cells. Experimental induction of amyloid deposition in brains of non-transgenic BALB/c mice following infection with C. pneumoniae may be a useful model for furthering our understanding of mechanisms, linked to infection, involved in the initiation of the pathogenesis of sporadic AD.

Our previous studies found that experimental infection of BALB/c mice with the Gram-positive bacterium Nocardia asteroides induced a parkinsonian-type syndrome with levodopa-responsive movement abnormalities, loss of nigrostriatal dopaminergic neurons, depletion of striatal dopamine, and intraneuronal inclusions in the substantia nigra (SN) with an appearance similar to Lewy bodies. In the present study, an in situ hybridization technique was developed to detect nocardial 16S ribosomal RNA (rRNA), using a Nocardia-specific probe (B77). Cerebral cortical specimens from cynomolgus monkeys were examined for the presence of nocardial RNA 48 h, 3.5 months, and 1 year after experimental infection with N. asteroides. Hybridization reactions were detected within Nocardia-like structures 48 h after infection and within intracellular inclusion bodies (immunoreactive for alpha-synuclein and ubiquitin) in one of two 3.5-month-infected monkeys. The in situ hybridization procedure was then applied in a blinded fashion to 24 human SN specimens with Lewy bodies and 11 human SN specimens without Lewy bodies (including five normal controls). Hybridization reactions were detected in nine Lewy body-containing specimens and none of the others. Reactivity was limited to inclusions with the appearance of Lewy bodies, with the exception of one specimen in which intracellular reactivity was also observed in Nocardia-like structures. These results suggest a possible association between Nocardia and neurodegenerative disorders in which Lewy bodies are present.

Chlamydia pneumoniae is a common respiratory pathogen that is now being incriminated in a number of chronic diseases. The ability of C. pneumoniae to infect and persist in macrophages makes it a likely candidate to disseminate in a number of different tissues, including those of the central nervous system. This review addresses the potential and the underlying mechanisms by which C. pneumoniae infections can play a role in such diverse neurological diseases as multiple sclerosis and Alzheimer's disease.

We recently detected cytomegalovirus (CMV) in brains of 83% of vascular dementia (VaD) patients and 34% of age-matched normal people. Since CMV and also Chlamydia pneumoniae (Cpn) have been found in some studies to be associated with coronary artery disease (which shares several risk factors with VaD), we sought Cpn DNA in VaD brain DNA. We examined brain specimens from 19 VaD patients, 16 elderly normal people and four Alzheimer's disease (AD) patients for the presence of a sequence in the Cpn gene for rRNA, using polymerase chain reaction (PCR) and taking stringent precautions against contamination. We did not detect Cpn DNA in any of the brain specimens, the sensitivity of detection being 10 copies or fewer bacterial DNA sequences per tube or, in terms of infectious units (IFU), 0.025 IFU. Our results do not support a role for Cpn in the aetiology of VaD, either in the 83% of patients in whose brains we detected CMV, or in the remaining 17% without CMV in brain.