• =?UTF-8?Q?Pathogenic_microbes=2C_the_microbiome=2C_and_Alzheimer?= =?UT

    From =?UTF-8?B?4oqZ77y/4oqZ?=@21:1/5 to All on Tue Mar 7 14:54:54 2017
    Pathogenic microbes, the microbiome, and Alzheimer’s disease (AD)

    http://journal.frontiersin.org/article/10.3389/fnagi.2014.00127/full

    James M. Hill1,2,3, Christian Clement3, Aileen I. Pogue4, Surjyadipta Bhattacharjee2, Yuhai Zhao2 and Walter J. Lukiw2,3,4,5*
    1Department of Microbiology, Immunology & Parasitology, Louisiana State University Health Sciences Center, New Orleans, USA
    2LSU Neuroscience Center, Louisiana State University Health Sciences Center, New Orleans, USA
    3Department of Ophthalmology, Louisiana State University Health Sciences Center, New Orleans, USA
    4Alchem Biotek, Toronto, ON, Canada
    5Department of Neurology, Louisiana State University Health Sciences Center, New Orleans, USA
    Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of cognitive and behavioral impairment in industrialized societies. The cause of AD is unknown and the major risk factor for AD is age. About 5% of all AD cases
    have a genetic or familial cause however the vast majority of all AD cases (~95%) are of sporadic origin. Both the familial and the sporadic forms of AD share a common disease phenotype involving at least eight characteristic features including (i)
    evidence of uncontrolled oxidative stress; (ii) up-regulated pro-inflammatory signaling; (iii) changes in innate-immune signaling; (iv) the progressive accumulation of lesions including neurofibrillary tangles (NFT) and amyloid beta (Aβ)-containing
    senile plaques (SP); (v) significant synaptic signaling deficits; (vi) neurite and brain cell atrophy; (vii) progressively altered gene expression patterns that are different from healthy brain aging; and (viii) progressive cognitive impairment and
    dementia in the host. There is currently no cure or adequate clinical treatment for AD, and it remains unclear how AD originates and propagates throughout the brain and central nervous system (CNS). Results from recent genome-wide association studies (
    GWAS) indicate that a significant portion of AD-relevant gene signals are not located within gene coding regions suggesting the contribution of epigenetic or environmental factors to AD risk. The potential contribution of pathogenic microbes to aging and
    AD is becoming increasingly recognized (Miklossy, 2011; Cho and Blaser, 2012; Bhattacharjee and Lukiw, 2013; Poole et al., 2013; Heintz and Mair, 2014; Huang et al., 2014; Mancuso et al., 2014). Importantly, most of the changes seen in AD, such as
    inflammation, brain cell atrophy, immunological aberrations, amyloidogenesis, altered gene expression and cognitive deficits are also seen as a consequence of microbial infection (Cho and Blaser, 2012; Yatsunenko et al., 2012; Bhattacharjee and Lukiw,
    2013; Foster and McVey Neufeld, 2013; Kim et al., 2013; Heintz and Mair, 2014; Mancuso et al., 2014). This brief communication will review some recent observations on the potential contribution of pathogens to neurological dysfunction, with specific
    reference to AD wherever possible.

    Firstly, humans contain a complex and dynamic community of microbes called the microbiome that forms a “metaorganism” with symbiotic or commensal benefit to the host (Cho and Blaser, 2012; Bhattacharjee and Lukiw, 2013; Heintz and Mair, 2014). The
    microbiome of the human gastrointestinal (GI) tract contains the largest reservoir of microbes, containing about 1014 microbes from at least 1000 distinct microbial species, and outnumbering human host cells by about 100 to 1 (Whitman et al., 1998; Kim
    et al., 2013). The GI tract microbiome has been estimated to encode about 4 × 106 genes so the quantity of the microbiome genes outnumbers host genes by about 150 to 1 (Bhattacharjee and Lukiw, 2013). Over 99% of GI tract microbiota are anaerobic
    bacteria, with fungi, protozoa, archaebacteria and other microorganisms making up the remainder; interestingly only two bacterial divisions are prominent in GI tract microbiota, including Firmicutes (~51%) and Bacteroidetes (~48%), with the remaining 1%
    of phylotypes distributed amongst the Cyanobacteria, Fusobacteria, Proteobacteria, Spirochaetes, and Verrucomicrobia, with various species of fungi, protozoa, viruses and other microorganisms making up the remainder (http://www.genome.gov/pages/research/
    sequencing/seqproposals/hgmiseq.pdf). Of all human GI tract microbiota, bacterial densities of up to 1012 per ml are the highest recorded density in any known microbial ecosystem (Whitman et al., 1998; Bhattacharjee and Lukiw, 2013; Kim et al., 2013).
    Interestingly, the microorganisms making up the smallest 1% of the microbiome have a disproportionately large effect on disease, and it is a major function of the healthy GI tract microbiome to keep under control the proliferation of any potentially
    pathogenic microbes contained within (Hornig, 2013; Kim et al., 2013; Heintz and Mair, 2014; see below).

    Recent interest in the role of the microbiome in human health and disease has rapidly expanded over the last several years with the advent of new sequencing and bioinformatics technologies for interrogating the genetics of complex microbial communities
    and microbial-host interactions. There is currently much interest in the ability of GI tract bacteria to influence host innate-immune, neuroinflammatory-, neuromodulatory- and neurotransmission-functions (Bravo et al., 2012; Bhattacharjee and Lukiw, 2013;
    Boutajangout and Wisniewski, 2013; Brenner, 2013; Douglas-Escobar et al., 2013; Heintz and Mair, 2014; Mancuso et al., 2014). While potentially pathogenic GI tract microbes are kept in check by a homeostatic commensalism, their increased abundance has
    been associated with diseases that include anxiety, autoimmune-disease, diabetes, metabolic-syndrome, obesity, and stress-induced and progressive neuropsychiatric diseases including autism, schizophrenia and AD (Bravo et al., 2012; Bhattacharjee and
    Lukiw, 2013; Boutajangout and Wisniewski, 2013; Foster and McVey Neufeld, 2013; Hornig, 2013; Heintz and Mair, 2014).

    Here we list 10 recent, highly specific and illustrative insights into the potential contribution of pathogenic microbes, altered microbiome signaling and other disease-inducing agents to the development of AD:

    (1) Fungal infection of the CNS: AD is characterized in part by amyloid-containing senile plaques (SPs) and neurofibrillary tangles (NFTs) that induce microglial cell activation, neuroinflammation and brain and neurovascular cell dysfunction. Recently
    yeast and fungal proteins including (1,3)-β-glucan, high levels of fungal polysaccharides and disseminated and diffuse mycoses in the peripheral blood of AD patients suggests that chronic fungal infections may increase AD risk (Prusiner, 2013; Alonso et
    al., 2014; Heintz and Mair, 2014). It is interesting that amyloids are associated with the surface structures of fungi which may aid in their organization and promote higher order assembly of amyloid (Liu et al., 2008; Asti and Gioglio, 2014).
    (2) HSV-1 is associated with AD: Abundant evidence suggests that the double-stranded DNA (dsDNA) herpes simplex virus-1 (HSV-1), a neurotrophic, neuroinvasive member of the family Herpesviridae can establish lifelong latency in CNS tissues and contribute
    to AD (Jamieson et al., 1991; Kammerman et al., 2006; Itzhaki and Wozniak, 2008; Toma et al., 2008; Lukiw et al., 2010; Ball et al., 2012; Agostini et al., 2014; Mancuso et al., 2014). A particularly interesting observation is that when human brain cells
    are infected with HSV-1, there is a significant and selective up-regulation in the expression of a small non-coding single-stranded RNA (ssRNA) known as miRNA-146a. This pro-inflammatory miRNA is also significantly up-regulated in anatomical areas of the
    human brain affected with AD and in human prion diseases where it contributes to altered innate-immune responses (Lukiw et al., 2010; Prusiner, 2013). It is noteworthy that of all ~2000 known miRNAs the same inducible, pro-inflammatory miRNA-146a is
    specifically up-regulated in both AD and in HSV-1 infected brain cells (Hill and Lukiw, 2014). Besides host-encoded miRNAs, ~200 virally encoded miRNAs have been discovered in dsDNA viruses (mainly HSV-1 and polyomoviruses)—these regulate fundamental
    biological processes including immune recognition, promotion of cell survival, angiogenesis, cell proliferation and differentiation, but their contribution to the AD process is not well understood (Plaisance-Bonstaff and Renne, 2011).
    (3) Prion diseases: driven by an unusual type of self-replicating “microbe,” prion diseases are sporadic, inherited or acquired and ultimately fatal neurological disorders highly similar to AD (Lukiw et al., 2011; Prusiner, 2013). Aβ peptide “
    prion-like” aggregates induce widespread amyloidogenesis after inoculation into susceptible animal hosts (Stöhr et al., 2012; Prusiner, 2013). The recent discovery that prions can serve as Aβ receptors to relay amyloid neurotoxicity, and that
    peripherally administrated prions reach the brain, has engendered renewed interest in this self-replicating protein and its involvement in AD-like signaling processes that include neuroinflammation, synaptic degeneration and amyloidogenesis (Prusiner,
    2013; Chen et al., 2014; Hernandez-Rapp et al., 2014).
    (4) Chlamydophila pneumoniae, other pathogenic bacteria and AD: The association of the gram negative, obligate intracellular bacteria and pneumonia-causing C. pneumoniae of the family Chlamydiaceae with diseases such as coronary artery disease, arthritis,
    multiple sclerosis, meningoencephalitis, and AD has recently gained serious attention (Balin and Hudson, 2014; Wunderink and Waterer, 2014). Atypical extracellular C. pneumoniae antigens in the neocortex of AD brain and their association with SP and NFT
    suggest the contribution of C. pneumoniae infection to AD pathology (Hammond et al., 2010; Choroszy-Król et al., 2014). It is interesting to note that virtually all AD patients expire from pneumonia as a cause of death and not as a direct consequence of
    AD itself (Choroszy-Król et al., 2014; Huston et al., 2014). Interestingly, other recent studies have further implicated Borrelia species, Helicobacter pylori, the periodontopathic spirochaete Treponema denticola, Tannerella forsythia, Porphyromonas
    gingivalis and other bacteria with increased incidence of age-related dementias including AD (Miklossy, 2011; Poole et al., 2013; Huang et al., 2014).
    (5) HIV-1 and AD: Human immunodeficiency virus (HIV), a lentivirus of the family Retroviridae, is a slowly replicating virion containing a 9749 nucleotide ssRNA genome that causes acquired immunodeficiency syndrome (AIDS)—a condition in which
    progressive failure of the immune system allows opportunistic infection (Borjabad and Volsky, 2012; Risacher and Saykin, 2013). HIV-associated neurocognitive disorders (HAND) is a common manifestation of HIV infection and encompasses a variety of
    neurological disorders including AIDS dementia complex, HIV-associated encephalopathy and AIDS-associated cognitive decline (Borjabad and Volsky, 2012; Widera et al., 2014). Histopathologically HIV-infected brains exhibit atrophy of neurites and neuronal
    loss in anatomical areas identical to what is seen in AD (Widera et al., 2014). Recent comparative meta-analysis further indicate that brains of patients with HAND and AD share common mis-regulated gene expression profiles implicating altered neuroimmune
    responses and progressive deficits in synaptic transmission (Borjabad and Volsky, 2012). Conversely, Aβ42 peptides appear to enhance HIV-1 attachment and entry to promote productive infection in susceptible cells of the CNS (Widera et al., 2014).
    (6) Toxoplasma and neurodegeneration: Toxoplasma species such as Toxoplasma gondii are intracellular protozoan parasites that can cause encephalitis and neurological dysfunction by promoting chronic inflammation of the brain and CNS. Recently AD has been
    associated with significantly increased anti-T. gondii antibodies suggesting a possible mechanistic link between T. gondii infection and AD (Prandota, 2014).
    (7) Viroids, miRNAs and AD: viroids are minimalist plant pathogens that consist of a viroid-specific ssRNA that are remarkably similar to miRNAs in their mode of generation, processing, structure and function, mobility and ability to spread disease
    within the host (Hill et al., 2009; Hill and Lukiw, 2014; Pogue et al., 2014). Abundant research evidence now strongly links miRNA dysregulation with AD and represents a new class of biomarkers which may be diagnostic for AD (Alexandrov et al., 2012;
    Danborg et al., 2014; Maffioletti et al., 2014). We may be able to gain insight on the mechanism of AD neuropathology driven by miRNA from what is already known about plant viroids and their ability to spread systemic degenerative disease (Navarro et al.,
    2012; Hill et al., 2014; Pogue et al., 2014).
    (8) Hepatitis and AD: Hepatitis C virus (HCV) is a small, enveloped ssRNA virus of the family Flaviviridae containing a ~9600 nucleotide genome that causes a chronic infectious disease of the liver and is associated with neuroimmune disorders (Monaco et
    al., 2012). HCV infection has recently been shown to significantly increase the risk for AD, especially in the aged (Chiu et al., 2013; Karim et al., 2014).
    (9) Cytomegalovirus and AD: A growing number of common viruses and latent viral infections involving Herpesviridae have been linked to the development of AD, and one of these is the human cytomegalovirus (HCMV). HCMV infection is often unnoticed in
    healthy people, but can be life-threatening for immune-compromised, HIV-infected or organ transplant patients. Recently blood serum, cerebrospinal fluid, and cryopreserved lymphocytes from AD patients were analyzed for associations between CMV infection
    and AD and it was found (i) that CMV antibody levels were positively associated with the number of NFT; (ii) that the percentage of senescent T cells was significantly higher for CMV-seropositive as compared to CMV-seronegative subjects, and (iii) that
    this was associated with the pathologic diagnosis of AD (Lurain et al., 2013). (10) GI tract and blood-brain barrier permeability: Lastly and importantly, the GI tract epithelial barrier and the blood brain barrier both become significantly more permeable over the course of aging (Brenner, 2013; Tran and Greenwood-Van Meerveld,
    2013). This may make the CNS more susceptible to potential neurotoxins generated by microbiome-resident or environmental pathogens. Environmental and dietary influences, including chronic bacterial or viral infections can progressively alter blood-brain
    barrier permeability and thereby facilitate cerebral colonization by opportunistic pathogens as we age (Welling et al., 2014).

    Taken together, it is clear that the human CNS is under constant assault by a wide array of extrinsic and intrinsic neurotrophic microbes and pathogens including bacteria, virus, fungus, nucleic-acid free prions, or small non-coding RNAs found both in
    the environment and contained within the microbiome. Virtually every type of microbe known has been implicated in contributing to the susceptibility and pathogenesis of the AD process. This may be especially important over the course of aging because
    innate-immune and physiological barriers are often compromised with age, enabling microbes and/or their ‘neurotoxic secretions’ to gain easier access to CNS compartments (Brenner, 2013; Tran and Greenwood-Van Meerveld, 2013; Welling et al., 2014).
    Because AD is clearly a multifactorial disease, and there are multiple biological pathways by which brain cells can dysfunction, perhaps it is not too surprising that multiple and complex microbial insults could contribute to AD, including the spreading
    of pathological signals throughout the CNS (Alexandrov et al., 2012; Bhattacharjee and Lukiw, 2013). The contributions of microbes to multiple aspects of human physiology and neurobiology in health and disease have up until now not been fully appreciated.
    Interestingly, both the entorhinal cortex-hippocampal axis and the olfactory system have been suggested as the earliest anatomical regions targeted by AD, indicating that perhaps primary as well as opportunistic infections might contribute to AD
    pathogenesis (Lazarov and Marr, 2010; Bhattacharjee and Lukiw, 2013; Cross et al., 2013; Balin and Hudson, 2014). What is currently known is (i) that most neurological disorders have a progressive, age-related and geographical character; (ii) that the
    composition of the human microbiome and exposure to pathogens changes with age, diet, lifestyle, and biological environment; and (iii) that microbial exposure, microbiome complexity and AD incidence are highly variable in different human populations (
    Yatsunenko et al., 2012; Lukiw, 2013; Danborg et al., 2014; Heintz and Mair, 2014). Intelligent pharmacological approaches including anti-bacterial, anti-viral and/or anti-inflammatory drugs in combination, or drug strategies more effectively directed
    toward the health and homeostasis of the holobiome should be useful in the future clinical management of AD and related degenerative disorders with an immune and inflammatory component.

    Conflict of Interest Statement
    The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

    Acknowledgments
    This work was presented in part at the Society for Neuroscience (SFN) Annual Conference 9–13 November 2013, San Diego CA. Sincere thanks are extended to Drs. L. Carver, E. Head, W. Poon, H. LeBlanc, F. Culicchia, C. Eicken, S. Bhattacharjee, and C.
    Hebel for short post-mortem interval (PMI) human brain tissues or extracts, miRNA array work and initial data interpretation, and to D Guillot and AI Pogue for expert technical assistance. Thanks are also extended to the many neuropathologists,
    physicians and Alzheimer researchers who have provided high quality, short post-mortem interval (PMI) human brain tissues for scientific study; additional human temporal lobe and other control and AD brain tissues were provided by the Memory Impairments
    and Neurological Disorders (MIND) Institute and the University of California, Irvine Alzheimer’s Disease Research Center (UCI-ADRC; NIA P50 AG16573). Research on miRNA in the Lukiw laboratory involving the innate-immune response in AD and in retinal
    disease, amyloidogenesis and neuroinflammation was supported through a COBRE III Pilot Project NIH/NIGMS Grant P30-GM103340, an unrestricted grant to the LSU Eye Center from Research to Prevent Blindness (RPB); the Louisiana Biotechnology Research
    Network (LBRN) and NIH grants NEI EY006311, NIA AG18031 and NIA AG038834.

    References
    Agostini, S., Clerici, M., and Mancuso, R. (2014). How plausible is a link between HSV-1 and AD? Expert Rev. Anti. Infect. Ther. 12, 275–278. doi: 10.1586/14787210.2014.887442

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Alexandrov, P. N., Dua, P., Hill, J. M., Bhattacharjee, S., Zhao, Y., and Lukiw, W. J. (2012). microRNA (miRNA) speciation in Alzheimer’s disease (AD) cerebrospinal fluid (CSF) and extracellular fluid (ECF). Int. J. Biochem. Mol. Biol. 3, 365–373.

    Pubmed Abstract | Pubmed Full Text

    Alonso, R., Pisa, D., Marina, A. I., Morato, E., Rábano, A., and Carrasco, L. (2014). Fungal infection in patients with Alzheimer’s disease. J. Alzheimers Dis. 41, 301–311. doi: 10.3233/JAD-132681

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Asti, A., and Gioglio, L. (2014). Can a bacterial endotoxin be a key factor in the kinetics of amyloid fibril formation? J. Alzheimers. Dis. 39, 169–179. doi: 10.3233/JAD-131394

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Balin, B. J., and Hudson, A. P. (2014). Etiology and pathogenesis of AD. Curr. Allergy Asthma Rep. 14, 417. doi: 10.1007/s11882-013-0417-1

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Ball, M. J., Lukiw, W. J., Kammerman, E. M., and Hill, J. M. (2012). Intracerebral propagation of AD: strengthening evidence of an HSV-1 etiology. Alzheimers Dement. 9, 169–175. doi: 10.1016/j.jalz.2012.07.005

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Bhattacharjee, S., and Lukiw, W. J. (2013). Alzheimer’s disease and the microbiome. Front. Cell. Neurosci. 7:153. doi: 10.3389/fncel.2013.00153

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Borjabad, A., and Volsky, D. J. (2012). Common transcriptional signatures in brain from patients with HIV-associated neurocognitive disorders, Alzheimer’s, and multiple sclerosis. J. Neuroimmune. Pharmacol. 7, 914–926. doi: 10.1007/s11481-012-9409-5

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Boutajangout, A., and Wisniewski, T. (2013). The innate immune system in AD. Int. J. Cell. Biol. 2013:576383. doi: 10.1155/2013/576383

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Bravo, J. A., Julio-Pieper, M., Forsythe, P., Kunze, W., Dinan, T. G., Bienenstock, J., et al. (2012). Communication between gastrointestinal bacteria and the nervous system. Curr. Opin. Pharmacol. 12, 667–672. doi: 10.1016/j.coph.2012.09.010

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Brenner, S. R. (2013). Blue-green algae or cyanobacteria in the intestinal micro-flora my produce neurotoxins such as beta-N-methylamino-L-alanine which may be related to development of amyotrophic lateral sclerosis, AD and Parkinsons-dementia-complex.
    Med. Hypotheses. 80, 103–108. doi: 10.1016/j.mehy.2012.10.010

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Chen, B., Soto, C., and Morales, R. (2014). Peripherally administrated prions reach the brain at sub-infectious quantities. FEBS Lett. 588, 795–800. doi: 10.1016/j.febslet.2014.01.038

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Chiu, W. C., Tsan, Y. T., Tsai, S. L., Chang, C. J., Wang, J. D., Chen, P. C., et al. (2013). Hepatitis C viral infection and the risk of dementia. Eur. J. Neurol. doi: 10.1111/ene.12317. [Epub ahead of print].

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Cho, I., and Blaser, M. J. (2012). The human microbiome: at the interface of health and disease. Nat. Rev. Genet. 13, 260–270. doi: 10.1038/nrg3182

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Choroszy-Król, I., Frej-Mądrzak, M., Hober, M., Sarowska, J., and Jama-Kmiecik, A. (2014). Infections caused by Chlamydophila pneumoniae. Adv. Clin. Exp. Med. 23, 123–126.

    Pubmed Abstract | Pubmed Full Text

    Cross, D. J., Anzai, Y., Petrie, E. C., Martin, N., Richards, T. L., Maravilla, K. R., et al. (2013). Loss of olfactory tract integrity affects cortical metabolism in the brain and olfactory regions in aging and mild cognitive impairment. J. Nucl. Med.
    54, 1278–1284. doi: 10.2967/jnumed.112.116558

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Danborg, P. B., Simonsen, A. H., Waldemar, G., and Heegaard, N. H. (2014). The potential of microRNAs as biofluid markers of neurodegenerative diseases—a systematic review. Biomarkers 19, 259–268. doi: 10.3109/1354750X.2014.904001

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Douglas-Escobar, M., Elliott, E., and Neu, J. (2013). Effect of intestinal microbial ecology on the developing brain. JAMA Pediatr. 167, 374–379. doi: 10.1001/jamapediatrics.2013.497

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Foster, J. A., and McVey Neufeld, K. A. (2013). Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 36, 305–312. doi: 10.1016/j.tins.2013.01.005

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Hammond, C. J., Hallock, L. R., Howanski, R. J., Appelt, D. M., Little, C. S., and Balin B. (2010). Immunohistological detection of Chlamydia pneumoniae in Alzheimer’s disease. BMC Neurosci. 11:121. doi: 10.1186/1471-2202-11-121

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Heintz, C., and Mair, W. (2014). You are what you host: microbiome modulation of the aging process. Cell 156, 408–411. doi: 10.1016/j.cell.2014.01.025

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Hernandez-Rapp, J., Martin-Lannerée, S., Hirsch, T. Z., Launay, J. M., and Mouillet-Richard, S. (2014). Hijacking PrP(c)-dependent signal transduction: when prions impair Aβ clearance Front. Aging Neurosci. 6:25. doi: 10.3389/fnagi.2014.00025

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Hill, J. M., and Lukiw, W. J. (2014). Comparing miRNAs and viroids; highly conserved molecular mechanisms for the transmission of genetic information. Front. Cell Neurosci. 8:45. doi: 10.3389/fncel.2014.00045

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Hill, J. M., Zhao, Y., Bhattacharjee, S., and Lukiw, W. J. (2014). miRNAs and viroids utilize common strategies in genetic signal transfer. Front. Mol. Neurosci. 7:10. doi: 10.3389/fnmol.2014.00010

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Hill, J. M., Zhao, Y., Clement, C., Neumann, D. M., and Lukiw, W. J. (2009). HSV-1 infection of human brain cells induces miRNA-146a and Alzheimer-type inflammatory signaling. Neuroreport 20, 1500–1505. doi: 10.1097/WNR.0b013e3283329c05

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Hornig, M. (2013). The role of microbes and autoimmunity in the pathogenesis of neuropsychiatric illness. Curr. Opin. Rheumatol. 25, 488–795. doi: 10.1097/BOR.0b013e32836208de

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Huang, W. S., Yang, T. Y., Shen, W. C., Lin, C. L., Lin, M. C., and Kao, C. H. (2014). Association between Helicobacter pylori infection and dementia. J. Clin. Neurosci. doi: 10.1016/j.jocn.2013.11.018. [Epub ahead of print].

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Huston, W. M., Barker, C. J., Chacko, A., and Timms, P. (2014). Evolution to a chronic disease niche correlates with increased sensitivity to tryptophan availability for the obligate intracellular bacterium Chlamydia pneumoniae. J. Bacteriol. 196, 1915–
    1924. doi: 10.1128/JB.01476-14

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Itzhaki, R. F., and Wozniak, M. A. (2008). Herpes simplex virus type 1 in Alzheimer’s disease: the enemy within. J. Alzheimers Dis. 13, 393–405.

    Pubmed Abstract | Pubmed Full Text

    Jamieson, G. A., Maitland, N. J., Craske, J., Wilcock, G. K., and Itzhaki, R. F. (1991). Detection of HSV-1 DNA sequences in normal and Alzheimer’s disease brain using polymerase chain reaction. Biochem. Soc Trans. 19:122S.

    Pubmed Abstract | Pubmed Full Text

    Kammerman, E. M., Neumann, D. M., Ball, M. J., Lukiw, W., and Hill, J. M. (2006). Senile plaques in Alzheimer’s disease: possible association of beta-amyloid with HSV-1 L-particles. Med. Hypotheses. 66, 294–299. doi: 10.1016/j.mehy.2005.07.033

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Karim, S., Mirza, Z., Kamal, M. A., Abuzenadah, A. M., Azhar, E. I., Al-Qahtani, M. H., et al. (2014). An association of virus infection with type 2 diabetes and Alzheimer’s disease. CNS Neurol. Disord. Drug Targets 13, 429–439. doi: 10.2174/
    18715273113126660164

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Kim, B. S., Jeon, Y. S., and Chun, J. (2013). Current status and future promise of the human microbiome. Pediatr. Gastroentero.l Hepatol. Nutr. 16, 71–79. doi: 10.5223/pghn.2013.16.2.71

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Lazarov, O., and Marr, R. A. (2010). Neurogenesis and Alzheimer’s disease: at the crossroads. Exp. Neurol. 223, 267–281. doi: 10.1016/j.expneurol.2009.08.009

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Liu, W. T., Lin, S. C., Chou, W. I., Liu, T. H., Pan, R. L., Tzou, D. L., et al. (2008). Identification and characterization of a novel fibril forming peptide in fungal starch binding domain. Biochem. Biophys. Res. Commun. 377, 966–970. doi: 10.1016/j.
    bbrc.2008.10.085

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Lukiw, W. J., Cui, J. G., Yuan, L. Y., Bhattacharjee, P. S., Corkern, M., Clement, C., et al. (2010). Acyclovir or Aβ 42 peptides attenuate HSV-1-induced miRNA-146a levels in human primary brain cells. Neuroreport 21, 922–927. doi: 10.1097/WNR.
    0b013e32833da51a

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Lukiw, W. J., Dua, P., Pogue, A. I., Eicken, C., and Hill, J. M. (2011). Upregulation of miRNA-146a, a marker for inflammatory neurodegeneration, in sporadic Creutzfeldt-Jakob disease and Gerstmann-Straussler-syndrome. J. Toxicol. Environ. Health 74,
    1460–1468. doi: 10.1080/15287394.2011.618973

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Lukiw, W. J. (2013). Variability in miRNA abundance, speciation and complexity amongst different human populations and potential relevance to AD. Front. Cell Neurosci. 7:133. doi: 10.3389/fncel.2013.00133

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Lurain, N. S., Hanson, B. A., Martinson, J., Leurgans, S. E., Landay, A. L., Bennett, D. A., et al. (2013). Virological and immunological characteristics of human cytomegalovirus infection associated with AD. J. Infect. Dis. 208, 564–572. doi: 10.1093/
    infdis/jit210

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Maffioletti, E., Tardito, D., Gennarelli, M., and Bocchio-Chiavetto, L. (2014). Micro spies from the brain to the periphery: new clues from studies on miRNAs in neuropsychiatric disorders. Front. Cell. Neurosci. 8:75. doi: 10.3389/fncel.2014.00075

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Mancuso, R., Baglio, F., Cabinio, M., Calabrese, E., Hernis, A., Nemni, R., et al. (2014). Titers of HSV-1 antibodies correlate with grey matter volumes in AD. J. Alzheimers Dis. 38, 741–745 doi: 10.3233/JAD-130977

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Miklossy, J. (2011). Emerging roles of pathogens in AD. Expert Rev. Mol. Med. 13:e30. doi: 10.1017/S1462399411002006

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Monaco, S., Ferrari, S., Gajofatto, A., Zanusso, G., and Mariotto, S. (2012). HCV-related nervous system disorders. Clin. Dev. Immunol. 2012:236148. doi: 10.1155/2012/236148

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Navarro, B., Gisel, A., Rodio, M. E., Delgado, S., Flores, R., and Di Serio, F. (2012). Viroids: how to infect a host and cause disease without encoding proteins. Biochimie 94, 1474–1480. doi: 10.1016/j.biochi.2012.02.020

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Plaisance-Bonstaff, K., and Renne, R. (2011). Viral miRNAs. Methods Mol. Biol. 721, 43–66. doi: 10.1007/978-1-61779-037-9_3

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Pogue, A. I., Hill, J. M., and Lukiw, W. J. (2014). MicroRNA (miRNA): sequence and stability, viroid-like properties, and disease association in the CNS. Brain Res. doi: 10.1016/j.brainres.2014.03.042. [Epub ahead of print].

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Poole, S., Singhrao, S. K., Kesavalu, L., Curtis, M. A., and Crean, S. (2013). Determining the presence of periodontopathic virulence factors in short-term postmortem Alzheimer’s disease brain tissue. J. Alzheimers Dis. 36, 665–677. doi: 10.3233/JAD-
    121918

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Prandota, J. (2014). Possible link between Toxoplasma gondii and the anosmia associated with neurodegenerative diseases. Am. J. Alzheimers Dis. Other Demen. 29, 205–214. doi: 10.1177/1533317513517049

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

    Prusiner, S. B. (2013). Biology and genetics of prions causing neurodegeneration. Annu. Rev. Genet. 47, 601–623. doi: 10.1146/annurev-genet-110711-155524

    Pubmed Abstract | Pubmed Full Text | CrossRef Full Text


    [continued in next message]

    --- SoupGate-Win32 v1.05
    * Origin: fsxNet Usenet Gateway (21:1/5)