Infiltration of the brain by pathogens causes Alzheimer’s disease

Itzhaki, Ruth F.; Wozniak, Matthew A.; Appelt, Denah M.; Balin, Brian J.

doi:10.1016/j.neurobiolaging.2003.12.021

Cited by 163 publications

(126 citation statements)

References 57 publications

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“…29 -32 Moreover, increased pathogen burdens of each of these infectious agents have been associated, albeit controversially so, with heightened risk for development of sporadic AD. 31,33 Such provocative findings raise the possibility that pathogen-induced IFN␥ expression, which could feasibly occur at subclinical levels over a lifetime due to intermittent waves of latency and re-activation phases of infection, may serve as an active participant in disease-exacerbating and/or disease-ameliorating cellular processes.…”

Section: Discussionmentioning

confidence: 99%

Interferon-γ Differentially Affects Alzheimer’s Disease Pathologies and Induces Neurogenesis in Triple Transgenic-AD Mice

Mastrangelo

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et al. 2009

The American Journal of Pathology

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Inflammatory processes, including the episodic and/ or chronic elaboration of cytokines , have been identified as playing key roles in a number of neurological disorders. Whether these activities impart a disease-resolving and/or contributory outcome depends at least in part on the disease context, stage of pathogenesis, and cellular milieu in which these factors are released. Interferon-␥ (IFN␥) is one such cytokine that produces pleiotropic effects in the brain. It is protective by ensuring maintenance of virus latency after infection, yet deleterious by recruiting and activating microglia that secrete potentially damaging factors at sites of brain injury. Using the triple-transgenic mouse model of Alzheimer's disease (3؋Tg-AD), which develops amyloid and tau pathologies in a pattern reminiscent of human Alzheimer's disease, we initiated chronic intrahippocampal expression of IFN␥ through delivery of a serotype-1 recombinant adeno-associated virus vector (rAAV1-IFN␥). Ten months of IFN␥ expression led to an increase in microglial activation, steady-state levels of proinflammatory cytokine and chemokine transcripts, and severity of amyloid-related pathology. In contrast, these rAAV1-IFN␥-treated 3؋Tg-AD mice also exhibited diminished phospho-tau pathology and evidence of increased neurogenesis. Overall, IFN␥ mediates what seem to be diametrically opposed functions in the setting of AD-related neurodegeneration. Gaining an understanding as to how these apparently divergent functions are interrelated and controlled could elucidate new therapeutic strategies designed to harness the neuroprotective activity of IFN␥. (Am J Pathol

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Section: Discussionmentioning

confidence: 99%

Interferon-γ Differentially Affects Alzheimer’s Disease Pathologies and Induces Neurogenesis in Triple Transgenic-AD Mice

Mastrangelo

Sudol

Narrow

et al. 2009

The American Journal of Pathology

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“…Adequate cell-mediated immunity is important for maintaining the virus in this chronic state (14,15). Importantly, CMV has been linked to inflammatory processes, cardiovascular disease, cognitive outcomes, and Alzheimer's disease (11,(16)(17)(18)(19)(20). For these reasons, it is important to examine the prevalence of CMV at various life stages within diverse socioeconomic and racial groups.…”

Section: Introductionmentioning

confidence: 99%

Socioeconomic disparities in the seroprevalence of cytomegalovirus infection in the US population: NHANES III

2008

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SummaryThere is a strong relationship between socioeconomic status (SES) and health outcomes in the U.S, though the mechanisms are poorly understood. Increasing evidence points to links between lifelong exposure to infectious disease and subsequent chronic disease. Exposure and susceptibility to infections may be one way SES affects long-term health, though little populationbased research to date has examined social patterning of infections in the U.S. This paper tests the relationship between income, education, race/ethnicity and seroprevalence of cytomegalovirus (CMV) infection at different ages in a representative sample of the U.S. population, and tests potential mediators for these relationships. The study finds significant racial and socioeconomic disparities in CMV seroprevalence beginning at early ages and persisting into middle age. Potential exposures do not explain the relationship between socioeconomic status and CMV positivity. Because reactivation of latent CMV infections may contribute to chronic disease and immune decline later in life, future research should determine the exposure or susceptibility pathways responsible for these disparities in the prevalence of CMV infection.

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“…Chlamydophila pneumoniae is an obligatory intracellular eubacterium that causes acute respiratory diseases and may be involved in chronic inflammatory processes, such as atherosclerosis (Rosenfeld et al, 2000), asthma (Hahn et al, 1991) and Alzheimer's disease (Itzhaki et al, 2004). Persistence of chlamydial infection has been thought to be important for chronic diseases and has been characterized using model animals and activation stimuli such as cytokines and antibiotics (Beatty et al, 1993;Belland et al, 2003;Malinverni et al, 1995;Mehta et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Chlamydial SET domain protein functions as a histone methyltransferase

et al. 2007

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SET domain genes have been identified in numbers of bacterial genomes based on similarity to SET domains of eukaryotic histone methyltransferases. Herein, a Chlamydophila pneumoniae SET domain gene was clarified to be coincidently expressed with hctA and hctB genes encoding chlamydial histone H1-like proteins, Hc1 and Hc2, respectively. The SET domain protein (cpnSET) is localized in chlamydial cells and interacts with Hc1 and Hc2 through the C-terminal SET domain. As expected from conservation of catalytic sites in cpnSET, it functions as a protein methyltransferase to murine histone H3 and Hc1. However, little is known about protein methylation in the molecular pathogenesis of chlamydial infection. cpnSET may play an important role in chlamydial cell maturation due to modification of chlamydial histone H1-like proteins. INTRODUCTIONChlamydophila pneumoniae is an obligatory intracellular eubacterium that causes acute respiratory diseases and may be involved in chronic inflammatory processes, such as atherosclerosis (Rosenfeld et al., 2000), asthma (Hahn et al., 1991) and Alzheimer's disease (Itzhaki et al., 2004). Persistence of chlamydial infection has been thought to be important for chronic diseases and has been characterized using model animals and activation stimuli such as cytokines and antibiotics (Beatty et al., 1993;Belland et al., 2003;Malinverni et al., 1995;Mehta et al., 1998). However, molecular-level relationships between chronic disease progression and persistent infection are not yet clear.Chlamydiae exhibit a unique life cycle in which they alternate morphologies between elementary bodies (EBs) and reticulate bodies (RBs). EBs are transcriptionally inactive electron-dense particles that are internalized into host cells by inducing phagocytosis. EB differentiation into RBs occurs with the development of phagosomes into inclusions. Transcriptionally active RBs multiply by binary fission with nutrients acquired from the host cell. At the end of the developmental cycle, RBs are converted into EBs and released from host cells for the next infection. Besides the developmental cycle, during persistent infection caused by exposure to interferon gamma (IFN-c) or antibiotics, RBs differentiate into aberrantly large and non-multiplying RBs (Belland et al., 2003). However, little is known about the switching mechanism whereby vegetative RBs convert into infectious EBs or aberrant RBs. Understanding this molecular system should be helpful for the prevention of persistent chlamydial infection.Two eukaryotic histone H1-like proteins of chlamydiae, Hc1 and Hc2, are present mainly in EBs, where those proteins bind DNA and promote genomic DNA condensation (Barry et al., 1992;Hackstadt et al., 1991;Perara et al., 1992;Tao et al., 1991). Recently a small regulatory RNA gene was identified as a suppressor of the lethal phenotype of hctA overexpression in Escherichia coli and it was shown to negatively regulate Hc1 synthesis at an early stage of infection (Grieshaber et al., 2006 HEp-2 cells (ATCC CCL-23) were used ...

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Infiltration of the brain by pathogens causes Alzheimer’s disease

Cited by 163 publications

References 57 publications

Interferon-γ Differentially Affects Alzheimer’s Disease Pathologies and Induces Neurogenesis in Triple Transgenic-AD Mice

Interferon-γ Differentially Affects Alzheimer’s Disease Pathologies and Induces Neurogenesis in Triple Transgenic-AD Mice

Socioeconomic disparities in the seroprevalence of cytomegalovirus infection in the US population: NHANES III

Chlamydial SET domain protein functions as a histone methyltransferase

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