key: cord-0948502-gux1bh9m
authors: Carter, Chris
title: Alzheimer's Disease: APP, Gamma Secretase, APOE, CLU, CR1, PICALM, ABCA7, BIN1, CD2AP, CD33, EPHA1, and MS4A2, and Their Relationships with Herpes Simplex, C. Pneumoniae, Other Suspect Pathogens, and the Immune System
date: 2011-12-29
journal: Int J Alzheimers Dis
DOI: 10.4061/2011/501862
sha: 5eeeb39d1eda252e3ba5fff3596679b8e3376f8d
doc_id: 948502
cord_uid: gux1bh9m

Alzheimer's disease susceptibility genes, APP and gamma-secretase, are involved in the herpes simplex life cycle, and that of other suspect pathogens (C. pneumoniae, H. pylori, C. neoformans, B. burgdorferri, P. gingivalis) or immune defence. Such pathogens promote beta-amyloid deposition and tau phosphorylation and may thus be causative agents, whose effects are conditioned by genes. The antimicrobial effects of beta-amyloid, the localisation of APP/gamma-secretase in immunocompetent dendritic cells, and gamma secretase cleavage of numerous pathogen receptors suggest that this network is concerned with pathogen disposal, effects which may be abrogated by the presence of beta-amyloid autoantibodies in the elderly. These autoantibodies, as well as those to nerve growth factor and tau, also observed in Alzheimer's disease, may well be antibodies to pathogens, due to homology between human autoantigens and pathogen proteins. NGF or tau antibodies promote beta-amyloid deposition, neurofibrillary tangles, or cholinergic neuronal loss, and, with other autoantibodies, such as anti-ATPase, are potential agents of destruction, whose formation is dictated by sequence homology between pathogen and human proteins, and thus by pathogen strain and human genes. Pathogen elimination in the ageing population and removal of culpable autoantibodies might reduce the incidence and offer hope for a cure in this affliction.

Hundreds of genes have been implicated in Alzheimer's disease, many of which can be grouped into discrete signalling networks and pathways relevant to the various subpathologies, risk factors, and biochemistry of Alzheimer's disease. Many of the environmental risk factors associated with Alzheimer's disease, including infectious agents (herpes simplex, chlamydia pneumonia, and Borrelia burgdorferi) as well as Vitamin A deficiency, hypercholesterolaemia, hyperhomocysteinaemia or folate deficiency, oestrogen depletion, cerebral nerve growth factor (NGF) deprivation, diabetes, cerebral hypoperfusion (leading to hypoxia and hypoglycaemia) or are able to promote cerebral beta-amyloid deposition (in the absence of any particular gene variant) in animal models [1] . KEGG pathway and other analyses of the multiple genes implicated in Alzheimer's disease have shown that subsets of susceptibility genes can be grouped into networks that are relevant to each of these amyloidogenic pathways (e.g., bacterial and viral entry pathways [1, 2] , cholesterol/lipoprotein function [3, 4] , growth factor signalling [5] , folate and homocysteine pathways [6] , insulin signalling [7] , and steroid or Vitamin A metabolism [8, 9] ). A large number of genes are also related to the immune network [10] (see http://www.polygenicpathways.co.uk/alzkegg.htm and a recent review for further details [1] ). These gene subsets are thus related to multiple external factors that are each able to promote beta-amyloid deposition, suggesting that certain genes are related to the causes of Alzheimer's disease, (agents able to provoke beta-amyloid deposition) rather than (and as well as) to the underlying pathology of the disease itself.

Several studies have implicated the herpes simplex virus in the aetiology of Alzheimer's disease [11] [12] [13] . Viral DNA is found in amyloid plaques [14] , which are also heavily enriched in proteins used by the virus during its life cycle, as well as in proteins related to the immune network [15] , and Immunoglobulin IgM, but not IgG seropositivity for herpes simplex is predictive of the subsequent development of Alzheimer's disease [16] . IgM seropositivity is indicative of viral reactivation which again can be induced by several of the risk factors relevant to Alzheimer's disease and its underlying genetic pathways (e.g., NGF deprivation, 17-beta oestradiol, hypoxia, or fever and interleukin 6 activation, with the latter being common and general consequences of infection [1] ).

Along with herpes simplex, a number of other pathogens have been implicated in Alzheimer's disease and its associated pathologies. The viral, bacterial, spirochete, and fungal pathogens implicated in dementia or Alzheimer's disease are referenced at (http://www.polygenicpathways.co.uk/alzenvrisk.htm) and include HHV-6, Chlamydia pneumoniae, Helicobacter pylori, periodontal pathogens involved in gum disease [17] , Borrelia burgdorferi, and Cryptococcus neoformans. HIV-1 is also able to provoke dementia with Alzheimer's disease pathology [18] . Of these, H. pylori eradication has been reported to improve performance and increase lifespan in Alzheimer's disease patients [19] , while two case reports indicated virtually complete recovery from long-term (3 years) misdiagnosed dementia/Alzheimer's disease following antifungal treatment for C. neoformans infection [20, 21] . Many of these pathogens including herpes simplex, HHV-6, C. Pneumoniae, H. pylori and the periodontal pathogen, P. Gingivalis, have also been implicated in atherosclerosis [22] [23] [24] [25] , while C. neoformans infection in rabbits induces an increase in neutrophil superoxide production, plasma lipid peroxidation, and an increase in inflammatory cells, forerunners of atherosclerosis [26] . Atherosclerosis of the carotid arteries, or of the circle of Willis and leptomeningeal arteries, is a significant predictor of risk in dementia or Alzheimer's disease and correlates with Alzheimer's disease pathology [27, 28] . Cerebral hypoperfusion (hypoglycaemia, hypoxia, ischaemia, or carotid occlusion) or other factors linked to atherosclerosis (e.g., high cholesterol or homocysteine levels) are also able, per se, to induce cerebral beta-amyloid deposition in animal models (see above).

Genomewide association studies (GWAS) have now identified a subset of genes which, along with APOE4 [29] , contribute a high proportion of genetic risk. These include clusterin (CLU), phosphatidylinositol-binding clathrin assembly protein (PICALM) and complement receptor 1 (CR1) as well as the ATP cassette transporter ABCA7, Bridging integrator BIN1, a CD2-associated protein (CD2AP), CD33, ephrin A1 (EPHA1), and a membrane-spanning 4domains, subfamily A (MS4A) cluster recently honed down to MS4A2, although other genes within this cluster may also be relevant [30, 31] .

As discussed below, the major Alzheimer's disease genes implicated by the recent GWAS data, as well as APP and gamma secretase, and previous GWAS results are majoritarily involved in pathogen entry and defence, particularly in relation to herpes simplex, but also to other relevant pathogens, and in the immune network. This suggests that genes, pathogens, and the immune system act together to cause Alzheimer's disease, and that a focus on pathogen detection and elimination should be a priority in the ageing at risk population.

The genes identified in a number of recent genomewide association studies are available at the GWAS repository at the National Human Genome Research Institute http://www .genome.gov/gwastudies/ [32] and, along with pre-GWAS genes and environmental risk factors, at http://www.polygenicpathways.co.uk/alzenvrisk.htm. The genes returned from very large sample sets (N > 10, 000) include ABCA7, APOE, BIN1, CD2AP, CD33, CLU, CR1, EPHA1, MS4A2, MS4A4A, MS4A4E, MS4A6A, and PICALM whose pro perties in relation to diverse pathogens were identified by literature survey. While it is recognised that such genes, particularly APOE, ABCA7, CR1, and clusterin, which are involved in lipoprotein function and/or amyloid processing (see below), may exert effects on other relevant branches of Alzheimer's disease pathophysiology, the focus of this paper is on pathogens and the immune system, which appear to be the common factors integrating this network. Throughout the text, these and other genes implicated in Alzheimer's disease from the GWAS and pre-GWAS era are highlighted in bold and appended to the various processes in which they are involved (derived from a KEGG pathway analysis of these genes http://www.polygenicpathways.co.uk/alzkegg.htm) Herpes simplex binding proteins, and key interactors, currently numbering over 450, are stocked and referenced at http:// www.polygenicpathways.co.uk/herpeshost.html. KEGG pathway analysis of this interactome is provided at http:www .polygenicpathways.co.uk//HERPESKEGG.htm. Expression data are provided in Figure 1 and are also hyperlinked to the BioGPS webserver http://www.biogps.gnf.org/, which provides general gene information and mRNA expression profiles for most human genes, based on custom arrays from 79 human issues [33, 34] . Predicted B-cell epitopes from human beta-amyloid Figure 1 : The mRNA distribution of the major genes derived from GWAS in Alzheimer's disease, as well as that of APP and gamma-secretase components. Data are from the BioGps website. Plasmodium falciparum [37] [38] [39] [40] [41] [42] [43] and is a general clearance receptor for complement opsonised pathogens [44] . Clusterin, predominantly expressed in brain, liver, and testis, (http://www.biogps.org/#goto=genereport&id=1191/) is a ligand for the lipoprotein receptor, megalin (LRP2) that is involved in beta-amyloid clearance, and also a complement inhibitor that prevents the formation of the membrane attack complex, a channel that is inserted into pathogen membranes, killing them by lysis [45] . This complex is also seen in Alzheimer's disease neurones [46, 47] . The herpes simplex virus interacts with other members of the complement cascade, by binding to the complement component and CR1 ligand, C3 and its derivatives and to CD59, a further inhibitor of the formation of the complement membrane attack complex (see review) [48] . C. pneumoniae interacts with this pathway by binding to properdin (CFP), a protein that stabilises the complement C3 and C5 convertase and contributes to the formation of the membrane attack complex [49] . CD59 is also incorporated into chlamydial inclusion bodies [50] . Complement component C3 binds to melanins derived from C. neoformans [51] and cryptococcal capsules bind to C3 and activate the alternative complement pathway [52] . Complement component C3 also binds to the bacterial surface of H. pylori, and the complement pathway is involved in bactericidal effects against this pathogen [53] . P. gingivalis also uses complement receptor 3 (an integrin complex of integrin, alpha M/integrin, beta 2 (ITGAM/ ITGB2)) for entry [54] , and herpes simplex glycoprotein C also binds to this complex [55] as does C. neoformans [56] , while ITGB2 is involved in C. pneumoniae entry in human coronary artery endothelial cells [57] . This macrophage complement receptor, also known as MAC-1, generally mediates the phagocytosis of pathogens coated with complement C3 derivatives [58] . T. C3 also binds to P. gingivalis although the pathogen has devised an elegant escape strategy involving digestion of complement components C3, C4, and C5 by bacterial secreted proteases, known as gingipains [59] . The complement inhibitor CD59 is also a ligand for CD2, and CD59 activation of this receptor, presumably involving CD2AP, activates T cell receptor signalling resulting in the secretion of interleukins (IL1A, IL2 and IL6) and granulocyte macrophage colony stimulating factor (CSF2) [60, 61] .

ABCA7 plays a role in the complement-mediated activation of phagocytosis in macrophages. Complement component C1q, which binds to IgM or IgG complexed antigens (relevant to most pathogens), binds to macrophage calreticulin and LRP1 and C1q binding to macrophages markedly increased the expression of both LRP1 and ABCA7, effects which enhance the phagocytic abilities of macrophages [62] . C1q also binds to complement receptor CR1, an effect involved in the immune clearance of opsonised pathogens [63] . C1q also binds to beta-amyloid and is involved in amyloid-related complement activation [64] . inter alia [65] . These processes are usurped by many viruses and other pathogens to gain access to cells and to various intracellular compartments, while the lysosomal or proteasomal pathways may be used to destroy pathogen proteins [66] . Clathrin-mediated endocytosis is one of several processes used by Helicobacter pylori, herpes simplex, and many other viral, bacterial and fungal pathogens to gain entry to cells [67] [68] [69] .

PICALM, expressed primarily in myeloid and dendritic cells of the immune network http://www.biogps.org/ #goto=genereport&id=8301/, plays a key role in clathrinrelated endocytosis, binding to clathrin heavy chains (CLTC and CLTCL1), and recruiting the clathrin and adaptor protein 2 (AP-2) to the plasma membrane. The AP-2 complex is a heterotetramer consisting of permutations of two large adaptins (alpha (AP2A1, AP2A2)) or beta (AP2B1), a medium adaptin (AP1M1, AP1M2), and a small adaptin (sigma AP2S1). PICALM controls the endocytosis of the cation-independent mannose-6-phosphate IGF2 receptor (IGF2R) [70] , one used by Herpes simplex for entry and cellto-cell transmission [71] and by C. pneumoniae for cellular entry [57] . IGF2R is also a component of late endosomes disrupted by the Helicobacter pylori VacA cytotoxin [72] . The mannose-6-phosphate receptor binds to clusterin. PICALM also binds to a nuclear exportin crm-1 (XPO1) used by the herpes simplex virus during its life cycle [48] .

Gamma-adaptins (GGA, GGA2, GGA3) bind to clathrins and mannose-6-phosphate receptors and regulate protein traffic between the Golgi network and the lysosome and the sorting of mannose-6-phosphate receptors (IGF2R and M6PR) at the trans-Golgi network [73] . This network is also related to important Alzheimer's disease susceptibility genes as the interactions culled from NCBI gene show that GGA1 binds to the sortilin-related receptor, SORL1, and the APP cleaving beta-secretase BACE2, while GGA2 binds to the beta-secretases BACE1 and BACE2, SORL1 and the prolylisomerase PIN1.

CD2AP, primarily expressed in dendritic cells and B lymphoblasts http://www.biogps.org/#goto=genereport&id= 23607/, is a scaffolding molecule that regulates the actin cytoskeleton and is primarily associated with the T-lymphocyte marker protein CD2. CD2 stimulates T cell activation and is involved in the creation of contacts between antigen presenting cells and T cells (the immunological synapse), effects mediated via CD2AP and clathrin [74] . CD2AP is also involved in the entry of the helicobacter vacuolating toxin VacA and connects the actin cytoskeleton to early endosomes containing VacA [75] . CD2 is cleaved by gingipain proteases from P. gingivalis [76] .

CD2AP also binds to the actin-bonding protein, cortactin (CTTN), a protein that is exploited by several bacteria (Escherichia coli, Shigella, Neisseria, Rickettsia, Chlamydia, Staphylococcus, Cryptosporidium, and Helicobacter pylori), fungi (Candida Albicans), and viruses (Vaccinia) enabling them to modify the actin cytoskeleton, which they use for transport [77] [78] [79] . CD2AP has not been specifically associated with herpes simplex, although the actin cytoskeleton is exploited by this and many other viruses [80] .

CD2AP also associated with E-Cadherin, (CDH1) [81] . The ectodomain of E-cadherin is involved in bacterial adherence to mammalian cells [82] . E-Cadherin binds to the H. pylori toxin CagA [83] and is also cleaved by the Helicobacter pylori protein HtRA allowing the pathogen to invade the intracellular compartment [84] . CDH1 and CDH5 expressions are increased by C. pneumoniae infection of human brain microvascular endothelial cells, contributing to vascular permeability changes and atherosclerosis [85] .

Bridging integrator 1 (BIN1), also known as amphiphysin 2, is primarily expressed in the pineal and skeletal muscle, or otherwise ubiquitously http://www.biogps.org/ #goto=genereport&id=274/. It is also involved in the clathrin-mediated endocytosis machinery [86] and binds to dynamins that regulate the clathrin network [87] including DNM1 and the herpes simplex binding partner DNM2 [88] and to clathrins and the alpha adaptins, AP2A1 and AP2A2 [89] . BIN1 also participates in phagocytosis in macrophages and is associated, but only transiently, with early phagosomes; however, it is retained on vacuoles containing Chlamydia pneumoniae, an effect that reduces the ability of the macrophage system to kill the bacteria via nitric oxide generation. Macrophages expressing a dominant negative BIN1 internalise C. pneumoniae, but do not allow their killing [90] . BIN1 also binds to a number of alpha integrins (ITGA1, ITGA3, and ITGA6) [91] : integrins are used for attachment by many viruses, bacteria, and fungi and may serve as pattern recognition receptors regulating the immune response [92] . Individual integrins bind to many others, forming heteromeric complexes; for example, ITGA1 binds to ITGA3 or ITGA6, while ITGA3 binds to ITGB1 (a receptor for the H. pylori protein CagA [93] ), ITGB4, or ITGB5, and ITGA6 binds to ITGB1 and ITGB4 (data from NCBI gene).

3.3. The Immune Network (APOE, BIN1, CD2AP, CD33, MS4A2) ( Figure 4) . CD33, mainly expressed in myeloid cells, monocytes, and dendritic cells (http://www.biogps.org/ #goto=genereport&id=945/), is a member of the sialic acid binding Immunoglobulin g-like lectin (SIGLEC) family. CD33-related SIGLECs regulate adaptive immune responses and are also important as macrophage pattern recognition receptors for sialylated pathogens, including enveloped viruses [94] . CD33 binds to alpha2-3-or alpha2-6-linked sialic acids (N-acetyl neuraminic acid) [95] . These particular sialic acids are expressed on the surface envelope glycoproteins (B, D, and H) of the herpes simplex virion, and these residues are required for viral entry into cells [96] . N-acetyl neuraminic acid is expressed by C. neoformans, is involved in fungal adhesion to macrophages [97] , and is also a component of the cell wall of B. burgdorferi [98] , while Helicobacter pylori adhesins also bind to this particular form of sialic acid [99, 100] as does P. gingivalis [101] .

BIN1, as well as its relationship to the clathrin mediated endocytosis machinery, also regulates the expression of indoleamine 2,3-dioxygenase (IDO1), an enzyme that catalyzes the first rate-limiting step in tryptophan metabolism to N-formyl-kynurenine [102] . IDO1 upregulation is an important defence mechanism against pathogenic bacteria, many of which are unable to synthesise tryptophan. Their survival is compromised by the diversion of tryptophan metabolism to kynurenines [103] . This IDO1 response is also deleterious to other pathogens and parasites, including T. gondii, and to a number of viruses, including herpes simplex and other herpes viruses [104] . IDO1 protein expression is localised to plaques and tangles in the Alzheimer's disease brain. IDO1 activation can lead to the production of toxic tryptophan derivatives such as 3-hydroxyanthranilic acid or the N-methyl-D aspartate receptor agonist and excitatory neurotoxin, quinolinic acid [105] (GRIN2B, GRIN3A). Plasma tryptophan levels are also lower in the ageing population and in Alzheimer's disease, a pattern accompanied by immune activation, and by increased concentrations of quinolinic acid [106, 107] .

MS4A2, expressed mainly in the tonsils, lymph nodes, B cells, and dendritic cells http://www.biogps.org/#goto= genereport&id=931/, is a component of the immunoglobulin E (IgE) receptor, which is involved in allergic responses in which allergens bound to receptor bound IgE result in the activation of allergic mediators such as histamine [108] . Mice immunised with inactivated herpes simplex develop IgE-specific antibodies to the virus [109] . High levels of IgE are also observed in man following recurrent herpes simplex infection [110] and human IgE antibodies are also known to interact with herpes family viruses including HSV-1 and 2 and the Epstein-Barr and cytomegalovirus [111] and also to C. pneumoniae, H. pylori, and B. burgdorferi [ [112] [113] [114] [115] . IgE-related allergic responses are also involved in C. neoformans infection [116] . Other members of this gene cluster (including MS4A4A, MS4A4E, and MS4A6A) are also structurally related to the immunoglobulin E receptor and to CD20 (MS4A1) and also regulate B cell and T cell proliferation and/or differentiation [117, 118] . EPHA1 is an ephrin receptor, primarily expressed in the liver and otherwise ubiquitously (http://www.biogps.org/ #goto=genereport&id=2041/). Only three protein/protein interactions for EPHA1 are reported in the NCBI gene interaction section, including its ligand EFNA1, the anaplastic lymphoma receptor tyrosine kinase (ALK), and a SMADspecific E3 ubiquitin protein ligase 2 (SMURF2). EFNA1 is one of several proteins identified as being important in the entry of C. pneumoniae into human coronary artery endothelial cells [57] . SMURF2 is known to bind to the VP22 tegument protein of herpes simplex [119] and plays a role in clathrin-mediated endocytosis and the subsequent ubiquitin-related proteasomal degradation of TGF beta receptors, to which it binds [120] . Clusterin is a ligand for TGF beta receptors (TGFBR1/TGFBR2) [121] . TGF beta signalling exerts immunosuppressive effects and inhibits host immunosurveillance and the recruitment of immunocompetent cells by chemokines [122] . ALK is ubiquitously expressed (http://www.biogps.org/#goto=gene-report&id=238/). It plays a role in neural development, and its expression decreases with age [123] . ALK is best characterised via its relationship with lymphomas, caused by ALK gene fusion with any of several other housekeeping genes [124] . Its key involvement in lymphoma suggests a role in the immune network although the function of the normal ALK protein is poorly understood. 5 ). ABCA7 is an ATP-binding cassette transporter, predominantly localised in the pineal gland and cells of the immune network (T cells, natural killer cells, and dendritic cells http://www.biogps.org/#goto=genereport&id=10347/). The lipoproteins APOA1 and APOE are substrates for ABCA7, and in cultured HEK-293 cells, plasma membrane-situated ABCA7 increases the efflux of phosphatidylcholine and sphingomyelin efflux to APOA1 and APOE, with no effect on cholesterol efflux [125] . However, cholesterol efflux to lipidladen APOE, but not to lipid free APOE, is increased by ABCA7 expression in HEK-293 cells [126] . Sphingomyelin is enriched in extracellular herpes simplex viral membranes: this sphingomyelin, together with phosphatidylserine, is collected by the viral envelope during viral passage from the nuclear membrane to the exocytosis pathway [127] . Herpes viral infection leads to an increased incorporation of phosphate into membrane sphingomyelin of the host [128] . Inhibition of sphingomyelinase has also been shown to markedly reduce herpes simplex viral reproduction [129] and also inhibits the antifungal effects of neutrophils against C. neoformans infection. Sphingomyelin is a receptor for the Helicobacter toxin VacA [130] and is also incorporated into inclusion bodies in C. pneumoniae-infected cells [131] . Phosphatidylcholine plays an important role in the fusion of herpes simplex glycoproteins B and H with the host cell lipid membrane, a process used in viral entry [132] . Phosphatidylcholine is also able to trigger capsular enlargement in C. neoformans infection [133] .

ABCA7 expression increases the extracellular surface deposition of ceramide (derived from sphingomyelin) [134] . Ceramide, a potent activator of apoptosis, as well as its downstream target, caspase 3 (CASP3) are both able to reactivate the herpes simplex virus from latency [135] . Ceramide is also incorporated into C. pneumoniae inclusions, an effect that may play a role in the antiapoptotic effects of this bacterium [136] . APOA1 exerts antiviral effects against herpes simplex and inhibits viral entry into cells as well as viral-induced cell fusion and intercellular spread [137] . In macrophages, ABCA7 is expressed intracellularly and does not participate in cholesterol or phospholipid efflux, instead playing a role in the phagocytosis of apoptotic cells, an important general defence mechanism against invading pathogens [62, 138] .

Possession of the APOE4 allele facilitates the entry and transmission of herpes simplex in mice models [139] . In man, APOE is also involved in hepatitis C, HIV-1, and herpes simplex infectivity [140] [141] [142] [143] , and APOE4 facilitates the binding of C. pneumoniae elementary bodies to host cells [144] .

APOE mRNA is primarily expressed in the liver, adipocytes; kidney and brain, with very low expression in the peripheral immune network (http://www.biogps.org/#goto= genereport&id=348/) but nevertheless plays an important role in the immune system. For example, the presence of the APOE4 allele is associated with an enhanced macrophage inflammatory response, and cytokine responses to the intracerebral injection of lipopolysaccharide are increased in APOE4 transgenic mice, which also exhibit increased microglial activation. The anti-inflammatory effects of 17beta-oeastradiol on microglia are also reduced in such animals [145, 146] . C-reactive protein (CRP) levels are also decreased in APOE4 carriers [145] [146] [147] . CRP is an acute phase protein that binds to phosphocholine on dead or dying cells and on bacteria, subsequently activating the complement pathway [148] . Resistance to infection (Klebsiella pneumoniae) or endotoxaemia is also decreased in APOE knockout mice [149] .

In addition, atherosclerosis is induced or worsened by infection with a number of relevant pathogens (Cytomegalovirus, herpes simplex, Helicobacter pylori, influenza, C. pneumoniae or P. gingivalis) in APOE knockout mice [150] [151] [152] [153] [154] [155] [156] . Helicobacter pylori is able to promote atherosclerosis in heterozygous APOE (+/−) LDLR (+/−) mice, which is associated with an immune response to the bacterial heat shock protein hsp60 [157] . (Figure 4) . Prior to the very large GWAS collaboration, several other genes had been identified in smaller genomewide studies (APOC1, CELF2, DISC1, FAM113B, GAB2, MTHFD1L, PAX2, PCDH11X, PVRL2 RFC3, SASH1, TOMM40, TTLL7, and ZNF224). PVRL2 is a receptor for herpes simplex (HSV-1 and HSV-2) [158] , and the mitochondrial translocator, TOMM40, a receptor for certain chlamydial species [159] . The replication factor RFC3 is part of a complex necessary for human DNA polymerase activity, a process exploited by many viruses including herpes simplex, whose virion component ICP34.5 binds to proliferating cell nuclear antigen (PCNA), an RFC3 binding partner and also a cofactor for DNA polymerase [160] . ZNF224 is a transcriptional repressor binding to the protein arginine methyltransferase, PRMT5 [161] . Protein arginine methylation is important in viral infection and replication, as well as in cytokine signalling, and a related arginine methyltransferase, PRMT1, regulates herpes simplex replication via methylation of the ICP27 viral gene [162] .

DISC1 is a component of the microtubule-associated dynein motor complex used in viral traffic [163] ; TTLL7 (tubulin tyrosine ligase-like family, member 7) also regulates tubulin phosphorylation [164] and can again be related to viral traffic along the microtubule network (see below). CELF2 (also known as CUGBP2) is a member of the APOBEC1 cytidine deaminase mRNA editing complex that also controls herpes simplex viral replication [165] . GAB2 13 is a member of the GRB2-associated binding protein family which act as adapter hubs transmitting signalling via cytokine and growth factor receptors, and T-and B-cell antigen receptors (definition from NCBI gene), while PAX2 inhibits the expression of the antimicrobial peptide beta defensin (DEFB1) [166] , a gene associated with HSV-1 and cytomegalovirus seropositivity in children with acute lymphoblastic leukaemia [167] , as well as with H. pylori or chlamydial infections [168, 169] , also endowed with antimicrobial activity against C. neoformans and other pathogens [170] . MTHD1L (methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-like) is involved in the mitochondrial synthesis of tetrahydrofolate which in turn is important in the de novo synthesis of purines and thymidylate and in the regeneration of methionine from homocysteine (definition from NCBI gene). Many pathogens, including herpes simplex, express thymidylate kinases, which are important for viral replication and a target for acyclovir [171] . Hyperhomocysteinaemia correlates with C. pneumoniae IgG immunoreactivity in carotid artery atherosclerosis [172] and is also associated with H. pylori infection in the context of atherosclerosis [173] . The apolipoprotein APOC1 is a component of high-density lipoprotein: herpes simplex is present in all lipoprotein blood fractions in blood (VLDL, LDL and HDL) and the lipid component of these lipoproteins binds to viral glycoprotein B [174] (c.f. APOA1, APOA4, APOA5, APOC1, APOC2, APOC3, APOC4, APOD, and APOE). No immediately apparent pathogen-relevant interactions were found for FAM113B (expressed exclusively in T cells, dendritic cells, and natural killer cells http:// www.biogps.org/#goto=genereport&id=91523/), PCDH11X (which is ubiquitously expressed http://www.biogps.org/ #goto=genereport&id=27328/), or SASH1 (primarily expressed in the brain and lung although also in other tissues, including the immune network http://www.biogps.org/#go-to=genereport&id=23328/) although the pathogen/immune theme is clearly carried through, particularly in relation to herpes simplex, in this second rank of Alzheimer's disease susceptibility genes. (Figure 2) . APOE, clusterin, and complement receptor 1 play key roles in beta amyloid clearance as do two further herpes simplex binding proteins APOA1, and alpha-2 macroglobulin (A2M). This is primarily mediated via lipoprotein receptors. A2M, or APOE-bound Aβ, is cleared by the lipoprotein receptor LRP1, while LRP2 (megalin) clears clusterin-bound Aβ. LRP8 is a receptor for both APOE and clusterin. APOA1 is also involved in beta-amyloid clearance via its transporter ABCA1. The role of ABCA7 has not been examined, although APOA1 is also a ligand for this transporter (see above). The Varicella Zoster and herpes simplex glycoprotein E binding protein, insulin-degrading enzyme, are also involved in beta-amyloid degradation, as is caspase-3 which is activated by the herpes simplex viral US3 kinase. The HSV-1 binding protein, complement C3 is also a ligand for LRP1 and LRP8, both of which play a role in C3 cellular uptake. Beta amyloid in the bloodstream is processed by its binding to complement C3, which subsequently binds to complement receptor 1 on erythrocytes. The effects above are referenced in a recent review [48] .

Clathrin-dependent endocytosis is also involved in the internalisation and recycling of neuronal APP, a procedure necessary for the subsequent cleavage of APP and the generation of beta-amyloid [175, 176] , and in the neuronal [177] , but not the microglial uptake of both soluble and aggregated beta-amyloids, the latter representing an important rout of disposal [178] . However, while knockdown of the clathrin assembly protein AP180 in a neuronal cell line does reduce beta-amyloid generation, PICALM knockdown does not [179] . The accumulation of beta-amyloid in the brain interstitial space, related to the prior endocytosis of APP, is clathrin dependent [180] . Clathrin-mediated endocytosis is relevant to many receptors, including members of the lipoprotein family (LRP1, LRP2, LRP8, LDLR, VLDLR) [181] , all of which are involved in beta-amyloid clearance, as well as in cholesterol and lipoprotein physiology [182] .

ABCA7 plays a role in beta-amyloid secretion, which is increased in Chinese hamster ovary cells expressing APP and ABCA7. This was related to an effect on APP intracellular retention, rather than on secretase-mediated proteolysis of APP [126] .

Gamma-secretase cleaves APP, and other gamma-secretase substrates also play key roles in APP processing (ADAM10) [183] , lipid and cholesterol function (LRP1, LDLR, VLDLR), and other processes relevant to Alzheimer's disease, for example, NOTCH signalling [184] .

No other immediately apparent relationships with betaamyloid could be found by literature survey for CD2AP, CD33, and EPHA1 or for MS4A-related proteins, although such are not precluded.

Many pathogens, including herpes simplex, helicobacter, chlamydiae, P. gingivalis, and C. neoformans [185] [186] [187] [188] , use the microtubule network that serves as a useful railway track between various cellular compartments, and may hijack dynein and kinesin motors for this purpose (see http://www .polygenicpathways.co.uk/herpeshost.html for herpes simplex). Tau (MAPT) stabilises microtubules by interacting with tubulins and promoting microtubule assembly [189] . When tau is phosphorylated, by any of several kinases, microtubules become disorganised. Tau hyperphosphorylation and neurofibrillary tangles are among the core pathologies of Alzheimer's disease [190] and can be promoted by herpes simplex infection [191] . In relation to viral/human protein homology, herpes simplex proteins are homologous to a number of kinases known to phosphorylate tau (GSK3A, GSK3B, MAPK1, and CAMK2B) suggesting that tau phosphorylation could be a direct result of a viral kinase [192] .

Secretase. APP plays a key role in the herpes simplex life cycle and is involved in its intracellular transport [193] , an effect likely related to the ability of both APP and the herpes simplex protein, US11, to bind to the APP and kinesin binding protein APPBP2 (also known as pat1) [194, 195] .

The AntiMicrobial Effects of Beta-Amyloid. Beta-amyloid is an antimicrobial peptide with broad spectrum activity against a variety of yeasts and bacteria, effects that were attenuated by anti-Aβ antibodies [196] , Beta-amyloid also has antiviral effects and, like acyclovir, attenuates the stimulatory effects of herpes simplex on miRNA-146a levels in neuronal cells [197] . Beta-amyloid also activates innate immune responses via the activation of pattern recognition receptors, such as Toll receptors (TLR2, TLR4) , which are also involved in beta-amyloid clearance [198, 199] . The antimicrobial, antiviral, and immunostimulant properties of beta amyloid are, however, likely to be abrogated by the presence of beta-amyloid autoantibodies in the sera of the ageing population and in Alzheimer's disease [200] . As immunogenic regions of beta-amyloid are homologous to similar regions within proteins expressed by all of the principal pathogens discussed in this paper, such antibodies are likely to be derived from antibodies raised to numerous pathogens (see below).

Gamma secretase is constituted of four components: the presenilins (PSEN1 or PSEN2), anterior pharynx-defective-1 (APH1A), the Presenilin enhancer-2 (PSENEN), and nicastrin (NCSTN) [201] . While all components are expressed in cerebral tissue, the major focus of distribution is within cells of the immune network; dendritic cells, myeloid cells, and monocytes for PSEN1 http://www .biogps.org/#goto=genereport&id=5663/; dendritic cells and natural killer cells for PSENEN http://www.biogps.org/#go-to=genereport&id=55851/, dendritic cells and myeloid cells for nicastrin http://www.biogps.org/#goto=genereport&id= 23385/ and B cells, dendritic cells, natural killer cells, and myeloid cells for APH1A. The substrate, APP, is the only gene in this set that appears to be preferentially distributed in brain compartments, but, as with gamma-secretase components, it is also highly expressed in dendritic cells of the immune system (http://www.biogps.org/#goto=gene-report&id=351/). The primary function of such cells is to process antigens and present them to B cells and T cells. They scout for and recognise pathogens via the agency of numerous pattern recognition receptors, for example, Toll receptors (TLR2, TLR4) , or viral DNA sensors, expressed on their surface [202, 203] .

As well as cleaving APP, gamma secretase is involved in the proteolysis of at least three herpes simplex receptors, nectin 1 alpha (PVRL1) [204] , and syndecans (SDC1, SDC2) [205] . SDC1 is also a receptor for HIV-1, Hepatitis E, and the human papillomavirus [206] [207] [208] [209] , while SDC3, also a gamma secretase substrate, is an HIV-1 and papillomavirus receptor [210, 211] .

Several other gamma secretase substrates (reviewed by Lleó and Saura [201] ) also function as viral/pathogen receptors, including ADAM10, a receptor for the cytotoxin Staphylococcus aureus alpha-haemolysin [212] , CD44, an entry receptor for C. neoformans [213] , CD46, a receptor for adenoviruses, measles virus, human herpes virus 6 (HHV-6), Streptococci, and Neisseria [214] : CD46 is also cleaved by a protease secreted by P. gingivalis [215] . Desmoglein-2 is an adenovirus receptor [216] , while rhinovirus receptors include the lipoprotein receptors LRP1, LDLR, and VLDLR [217, 218] . LDLR is also a hepatitis C receptor [219] . NOTCH1 and NOTCH4 are activated by the Epstein-Barr virus [220, 221] , while ERBB4 is a receptor for vaccinia and other pox viruses [222] . The low affinity nerve growth factor (NGFR) is a rabies virus receptor, [223] , Ephrin B2, (EFNB2) a Nipah virus and Hendra virus receptor [224] and sialophorin (SPN), a receptor for the influenza A, and both human and simian immunodeficiency viruses [225, 226] and for the C. neoformans virulence factor, galactoxylomannan [227] . Fractalkine (CX3CL1) binds to the cytomegalovirus chemokine receptor, US28 [228] , while the chemokine CXCL16 is a scavenger receptor for phosphatidylserine and oxidized low density lipoprotein [229] : phosphatidylserine is the major lipid membrane component in most bacteria [230] . Dystroglycan is a receptor for the Lymphocytic choriomeningitis and Lassa fever viruses [231, 232] and also for mycobacterium leprae (the Leprosy pathogen) [233] .

The antimicrobial and immunostimulant effects of betaamyloid, the cleavage of a number of pathogen receptors by gamma secretase, and the concentration of both APP and gamma-secretase components in dendritic cells suggest that a major function of this key group, implicated in both familial and late onset Alzheimer's disease, is dedicated to pathogen defence, and that increased beta-amyloid generation is primarily a defence mechanism to rid the body (and brain) of invading pathogens: This scenario is supported by the ability of herpes simplex, C. pneumoniae, and B. burgdorferi to increase beta-amyloid deposition [234] [235] [236] . One might expect many other pathogens to increase beta-amyloid deposition, and that, as has been noted in atherosclerosis, (a component of Alzheimer's disease pathology), the final extent of risk may depend upon the overall pathogen burden, rather than upon any specific pathogen [237] .

Causative Agents.. Viruses and bacteria express proteins containing short contiguous amino acid stretches (pentapeptides or more, or longer gapped consensi) that are identical to those in human proteins: these pathogen/human consensi number in millions and concern all human proteins [238] [239] [240] [241] .

Autoantibodies, which are observed in many, if not most human diseases, are often regarded as an epiphenomenon of little consequence. However, they can traverse the blood brain barrier [242] (which is compromised in Alzheimer's disease [243] ) and are also able to enter cells, essentially by hitching a ride on viruses, via high affinity IgG receptors (Fc gamma receptors) (FCER1G) in the case of the rhinovirus, or the SARS coronavirus, or via the tripartite motif protein, TRIM21, in the case of adenoviruses, where they are able to activate an intracellular immune attack. It would appear that the cellular entry of antibody laden viruses is diverted from their usually preferred receptors towards those used by antibodies [244] [245] [246] . This may be relevant to the MS4A family. Fc gamma receptors are localised in microglia and astrocytes in the brain and their expression is upregulated by blood brain barrier disruption [247] , while TRIM21 appears to be exclusively localised in peripheral immunocompetent cells (http://www.biogps.org/#goto=genereport&id=6737/). This ability places autoantibodies in a rather more sinister context, as their targeting of extracellular and intracellular human proteins would be expected to effect protein knockdown, a strictly immunopharmacological effect, as well as immune attack.

In multiple sclerosis, schizophrenia, and cystic fibrosis, as well as in Alzheimer's disease, numerous autoantigens targeted by the autoantibodies reported in these conditions, contain peptide sequences identical to those in the pathogens also implicated in the disease. Such regions of homology are focalised within epitope regions of the human autoantigen [192, [248] [249] [250] . In Parkinson's disease, antibodies to the Epstein-Barr virus, which has been implicated in postencephalitic adult and juvenile Parkinsonism, are also known to cross-react with synuclein, a key protein involved in neurodegeneration in this disorder [251] [252] [253] . In addition, 22 autoantigens reported in HIV-1/AIDS contain HIV-1/human matching sequences [254] , supporting the contention that autoantibodies are in many cases antibodies initially raised to pathogens, which because of this homology, then target their human homologues. It has been argued that slightly dissimilar, rather than exact matches, are the more malignant in terms of autoimmunity, being less likely to be regarded as self, while the antibodies would retain low affinity for human counterparts [254, 255] .

Autoantibody production would also be sustained, even after pathogen elimination, by continued encounter of the human homologue. The production of autoantibodies must be dependent upon the extent of pathogen/human matching, and thus by genes which determine human protein sequences. These pathogen/human matches are also highly and significantly enriched in the products of susceptibility genes implicated in Alzheimer's disease, multiple sclerosis, and schizophrenia [192, 248, 250] . Many genes related to Alzheimer's disease, including those described above, are involved in the immune network [10, 256] , and the propensity for developing autoantibodies to particular proteins is also genetically determined and inherited [257] . Thus, despite the fact that all human proteins likely possess pathogen homologues, whether or not autoantibodies will be produced will depend on the extent of human/pathogen matching (determined by human genes and the strain of pathogen encountered), on whether the pathogen protein is deemed as self or nonself (a factor determined soon after birth) and on other genetic factors related to the immune network, and autoimmunity. Somatic hypermutation, that drives the creation of multiple antibodies and which selects against those reacting to self, is disrupted in autoimmune disorders [258] . These links suggest an interplay, applicable to many diseases, where susceptibility gene products, risk promoting pathogens and autoimmunity can all be related via protein sequence homology.

It has also been noted that autoantigens have a tendency to relate to proteins known to bind to dermatan sulphate, a component of dead cells [259] and a constituent of glycosaminoglycan receptors for many bacteria and viruses [260] .

Proteins. All three of these proteins are autoantigens in Alzheimer's disease and were chosen for analysis because of the ability of their antibodies to promote features of Alzheimer's disease, in vivo. In mice, immunisation with neuronal tau produces neurofibrillary tanglelike structures, axonal damage, and gliosis, as in Alzheimer's disease [261] . In addition, in transgenic mice, initially expressing NGF antibodies only in lymphocytes, NGF antibodies subsequently enter the brain provoking extensive cortical degeneration, cholinergic neuronal loss, tau hyperphosphorylation, and beta-amyloid deposition [262] . Betaamyloid autoantibodies are also able to promote meningoencephalitis, both in laboratory models and in clinical trials [263, 264] . Beta-amyloid plaques contain numerous inflammatory proteins, and even without meningoencephalitis, these are commonly found within the walls of meningeal and medium-sized cortical arteries in Alzheimer's disease [265] .

Almost the entire length of the tau protein (638/776 amino acids = 82.2%) was predicted as immunogenic (B cell epitope), as defined by the server set cutoff index of 0.35. For the analysis in Table 1 , only regions of the tau protein with an immunogenicity index >2.5 were examined for homology. For other proteins (NGF and beta-amyloid), the analysis concerned immunogenic regions above the cutoff value of 0.35.

All pathogens express proteins with homology to each autoantigen, specifically within predicted B-cell epitope regions of the human autoantigen ( Table 1 ), suggesting that antibodies raised to any could be responsible for targeting these human proteins, under the appropriate circumstances. Perversely, the successful elimination of the pathogen via antibody production could set in motion the very autoimmune responses that may be crucial to the development of Alzheimer's disease, a Pyrrhic victory, which would also be promulgated by any further encounter with these very common pathogens, or by structurally related proteins from other pathogens, as well as by continual encounter of the human autoantigen homologue (see Section 3.6.5).

As well as autoantibodies to these three proteins, a number of autoantibodies targeting highly relevant proteins have been reported in Alzheimer's disease. These have functional effects on their target proteins and include antibodies that block the activity of ATP synthase, induce apoptosis, and increase the cellular uptake of high density lipoprotein [266, 267] , antibodies to cholinergic neurones that cause immunalysis of brain synaptosomes [268] , antibrain antibodies that enhance intraneuronal beta-amyloid deposition [269] as well as antibodies to the nicotinic receptor CHRNA7, that displace its ligand alpha-bungarotoxin [270] : autoantibodies to the receptor for advanced glycation products (AGER) [271] , to the antimicrobial peptide S100B, have also been reported [272] .

Cause of the Disease, rather than to the Disease Itself. Using Table 1 : Viral, bacterial, and fungal protein homology with beta-amyloid (top), NGF (middle), or tau (bottom); Predicted B cell epitope segments were compared with Borrelia burgdorferi, C. neoformans, C. pneumoniae, H. pylori, P. gingivalis and herpes viruses (HSV1, HHV6, and cytomegalovirus) proteomes by BLAST analysis. The B cell antigenicity indices are shown, and those above the server set threshold of 0.35 are in italics. The first column shows the amino acid number within the peptide or protein sequence, and the second shows the amino acid pertaining to that position. The alignments with pathogen proteins are shown. Spaces represent nonidentical amino acids and + signs amino acids with similar physicochemical properties. Only highly antigenic regions of pentapeptides or more were processed. The VGGVV sequence, antibodies to which label beta-amyloid in brain tissue, despite relatively low antigenicity, has already been reported to be identical to proteins expressed by 69 viruses including HSV-1, HSV-2, and HHV6. factor deficiency) are able to promote cerebral beta-amyloid deposition in animal models, without the aid of any gene variant. Subsets of susceptibility genes can be related to each of these amyloidogenic pathways [1] . In the case of genomewide association studies, the genes returned, as well as APP, beta amyloid, and gamma secretase, seem intimately concerned with pathogen life cycles and defence and the immune network. This suggests that the diverse microbial risk factors as well as other dietary and environmental factors implicated in Alzheimer's disease are in fact causative agents, whose deleterious effects are conditioned by susceptibility genes. As the environmental risk factors are amenable to therapy, while the susceptibility gene products have so far proved largely resistant, this suggests numerous ways with which to tackle the problem of Alzheimer's disease.

Herpes Simplex Reactivation. Alzheimer's disease plaques and tangles are highly enriched in human proteins used the herpes simplex during its life cycle, as well as in many immune-related proteins, suggesting that immune attack on a reactivated virus, diverted to neurones, which contain the complement membrane attack complex, may be ultimately responsible for the extensive neuronal destruction seen in Alzheimer's disease [15] . The herpes simplex virus establishes latency in neurones, existing as a dormant form where only the latency transcript is expressed. A number of factors again related to susceptibility genes and environmental risk factors in Alzheimer's disease can be related to herpes simplex latency and reactivation. The cerebral herpes simplex viral load is decreased in APOE knockout mice, while the viral load is much increased in APOE4 transgenic mice, compared to APOE3 mice, suggesting that APOE4 favours the establishment of a greater number of latent viruses in cerebral tissue [274] . In neuroblastoma cells, this latent form may even exert beneficial effects, blocking apoptosis and promoting neurite extension via AKT1 upregulation [275] . However, this latent form can be reactivated by NGF deprivation [276] , and NGF promotes viral latency via the TrkA receptor NTRK1 [277] , the expression of which is reduced in the Alzheimer's disease brain [278] . (Relevant pathways and genes: neurotrophin signalling (GSK3B, NTRK1, NTRK2, PIK3R1, and SOS2) . Vitamin A supplementation in rats increases the cerebral levels of both NGF and BDNF [279] , while oestrogen deficiency lowers cerebral NGF levels, an effect reversed by 17-beta oestradiol [280] , which is, however, also able to reactivate the virus, via oestrogen receptor alpha (ESR1) [281] . High levels of total oestradiol have been reported as a risk factor for Alzheimer's disease in both women and men [282, 283] . Vitamin A related gens include APOE4, the isoform least able to transport the vitamin A precursor retinyl palmitate, A2M ABCA1 ALB ALDH2 APOA1 CHD4 CLU CYP46A1 ESR1 GSTM1 GSTP1 HSPG2 KLF5 LIPA LPL LRAT LRP2 LRPAP1 MEF2A NPAS2 NR1H2 PARP1 PIN1 POU2F1 PPARA PPARG RXRA THRA TTR UBQLN1 VDR and many others controlled by retinoid receptor element (reviewed in [126] ). The virus can also be reactivated by heat [284] , IL6 [285] , or TNF [286] . IL6 plasma and CSF levels have been reported to be increased in Alzheimer's disease and the secretion of IL6 from monocytes is increased [287] [288] [289] . IL6 plasma levels are raised by infection with C. pneumoniae [290] or Helicobacter pylori [291] , and IL6 production in monocytes is stimulated by C. neoformans [292] . Stressactivated corticosterone is also able to reactivate the virus [293] (pathway = steroid hormone biosynthesis: COMT, CYP19A1, HSD11B1). Cortisol levels are increased in the ageing population and in Alzheimer's disease [294, 295] . A number of related stressors including adrenaline [296] , or downstream effectors such as cyclic AMP, protein kinase A, or C activation [297] are also able to reactivate the virus. Herpes simplex reactivation is blocked by betareceptor antagonism (ADRB1) [296, 298] . Glucocorticoids and prostaglandins are also able to reactivate the virus [299] : cyclooxygenase inhibitors (PTGS2), celecoxib and indomethacin block viral reactivation and nonsteroidal antiinflammatory use has been associated with a lower incidence of Alzheimer's disease. Lysophosphatidic acid is also able to reactivate the virus [300] (LPAR5). Hypoxia also increases the replication of herpes simplex [301] : transient cerebral ischaemia also lowers NGF levels [302] , and these effects are relevant to the cerebral hypoperfusion seen in ageing and in Alzheimer's disease [303] . Vitamin A and the retinoic acid isomers all-trans-, 9-cis-, and 13-cis-Retinoic Acid are all able to reduce viral replication [304] . Low Vitamin A levels are a problem in the ageing population and even in successfully ageing persons can be observed in 50% of the population over the age of 80-85 [305] . Low vitamin A levels are also a risk factor for Alzheimer's disease [306] . Mice deficient in the nitric oxide synthase NOS2 are also more susceptible to herpes virus infection, and reactivation occurs is stimulated by caspase 3 activation (CASP3) [135] .

Thus, fever or cytokine release induced by diverse infections might be expected to reactivate herpes simplex as would several of the conditions associated with Alzheimer's disease (cerebral hypoperfusion, low cerebral NGF levels, vitamin A deficiency, or high oestradiol levels).

3.6.6. The Microbiome in Alzheimer's Disease. These pathogens form a very small proportion of an extensive human microbiome comprising of trillions of bacteria, viruses, and other pathogens, whose influence on diseases is increasingly recognised [307] . Individual species may exert benevolent or malevolent effects which may well be dictated by the very extensive sequence homology between human and pathogen proteins which enables pathogens to intercalate with numerous important signalling networks, via competition with their human counterparts [239, 241, 248, 250, 254] . These networks are implicated in diseases, and their efficiency, as well as pathogen/host homology, is dictated by susceptibility genes. This host/pathogen matching covers the entire human proteome and is represented by millions of short consensi of pentapeptides or more, not counting the longer gapped consensi. Clearly, powerful algorithms are needed to trawl human and pathogen proteomes and to link these homologies to susceptibility genes and to epitopes and autoantigens.

The principles discussed here may apply to many other, if not most, human diseases.

Protective Agents in Alzheimer's Disease. Statins [308] , fish consumption [309] , omega-3 polyunsaturated fatty acids [310] , the Mediterranean diet [311] , nonsteroidal antiinflammatories [312] , or the generally healthy life-style of nuns living in convents [313] have all been associated with a reduced incidence or severity of Alzheimer's disease, while homocysteine lowering B vitamins and folate have been shown to slow the rate of brain atrophy in cognitively impaired elderly patients [314] . A rather pessimistic study [315] recently stated that no firm conclusions could be drawn on the association of any modifiable factors with risk of Alzheimer's disease. While this may be a justifiable statistical conclusion from meta-analysis, this is not to reckon with the diversity of the underlying genomic platform of each individual or with the profusion of diverse interacting risk and protective factors (epistasis, gene/environment, and environment/environment interactions).

As with the risk factors, protective agents can be linked to genetic and pathological pathways involved in cholesterol and lipid function (statins, fish, and diet, e.g., GSK3B, IL1A, IL1B, IL6, IL8, IL10, IL18, PLAU, SERPINA1 , SERPINE1, SERPINF2, PTGS2, TGFB1, TNF). As with the risk factors, the success of such protective agents is likely to be determined by genes and other confounding factors. In this genomic era, affordable whole genome sequencing will soon be achieved, ushering in an age of more effective treatments tailored to individual genetic profiles. Alzheimer's disease is clearly multifactorial with many related genetic and environmental risk factors, several underlying pathologies, and several available protective strategies. A recent study has also shown that many other seemingly benign factors (eyesight, hearing, denture wearing, stomach, kidney, bladder or bowel problems, coughs, and colds) as well as high blood pressure and diabetes, constituting a frailty index, combine to markedly increase both the incidence and severity of Alzheimer's disease [316] . A further study, identifying physical inactivity, depression, smoking, mid-life hypertension or obesity, low education, and diabetes as key risk factors, has estimated that ∼50% of Alzheimer's disease cases may be preventable [317] .

Elimination of the risk factors, including the regular detection and elimination of pathogens in the elderly, adherence to sensible dietary and vitamin supplement recommendations, and the genetically tailored use of certain drug regimens are together likely to be able to markedly reduce the incidence of Alzheimer's disease. Using phage display, it is now possible to express peptide fragments of the entire human proteome in a phage library, and to use this to trap autoantibodies in blood or other bodily fluid samples. The antigen expressed by the labelled phage can be identified by high throughput sequencing [318] . Such technology is likely to be extremely useful in characterising biomarkers and pathological immune processes as well as potential pathogen/human cross-reactivity.

Proteome-wide characterisation of the autoantibodies relevant to Alzheimer's disease (a move from GWAS to PWAS) would also be very informative as selective autoantibody removal via affinity dialysis might well be expected to influence the severity and progression of Alzheimer's disease.

Since the submission of this paper, Miklossy has reported a highly significant association between spirochete infection and Alzheimer's disease. As well as B. burgdorferi, several periodontal pathogen treponemas species were detected in brain samples and the pathological features of Alzheimer's disease were reproduced by infection in vitro [319] . In addition, two groups have reported a very extensive repertoire of autoantigens in Alzheimer's disease, which can be characterised with a high degree of accuracy by a definitive immunosignature [320, 321] . The principles outlined above could thus be tested by analysis of pathogen/autoantigen cross-reactivity.

The fox and the rabbits, environmental variables and population genetics. 1: replication problems in association studies and the untapped power of GWAS. 2: vitamin A deficiency, herpes simplex reactivation and other causes of Alzheimer's disease

Interactions between the products of the Herpes simplex genome and Alzheimer's disease susceptibility genes: relevance to pathological-signalling cascades

Convergence of genes implicated in Alzheimer's disease on the cerebral cholesterol shuttle: APP, cholesterol, lipoproteins, and atherosclerosis

A cluster of cholesterol-related genes confers susceptibility for Alzheimer's disease

Shared molecular and functional frameworks among five complex human disorders: a comparative study on interactomes linked to susceptibility genes

Dementia revealed: novel chromosome 6 locus for Late-onset alzheimer disease provides genetic evidence for Folate-pathway abnormalities

Genetic variability in the insulin signalling pathway may contribute to the risk of late onset Alzheimer's disease

Evidence for defective retinoid transport and function in late onset Alzheimer's disease

Comparative gene expression analysis in mouse models for multiple sclerosis, Alzheimer's disease and stroke for identifying commonly regulated and disease-specific gene changes

Implication of the immune system in Alzheimer's disease: evidence from genome-wide pathway analysis

HSV-1 infection of human brain cells induces miRNA-146a and Alzheimer-type inflammatory signaling

Herpes simplex virus type 1 in Alzheimer's disease: the enemy within

The association of herpes simplex virus and Alzheimer's disease: a potential synthesis of genetic and environmental factors

Herpes simplex virus type 1 DNA is located within Alzheimer's disease amyloid plaques

Alzheimer's disease plaques and tangles: cemeteries of a Pyrrhic victory of the immune defence network against herpes simplex infection at the expense of complement and inflammation-mediated neuronal destruction

Seropositivity to Herpes Simplex Virus antibodies and risk of Alzheimer's disease: a population-based cohort study

Inflammation and Alzheimer's disease: possible role of periodontal diseases

Prevalence of Alzheimer plaques in AIDS

Five-year survival after Helicobacter pylori eradication in Alzheimer disease patients

Reversible dementia: a case of cryptococcal meningitis masquerading as Alzheimer's disease

Cryptococcal meningitis misdiagnosed as alzheimer's disease: complete neurological and cognitive recovery with treatment

Detection of human herpesvirus 6 DNA but not human herpesvirus 7 or 8 DNA in atherosclerotic and nonatherosclerotic vascular tissues

The role of infection in carotid plaque pathogenesis and stability: the clinical evidence

The influence of persistent pathogens on circulating levels of inflammatory markers: a cross-sectional analysis from the Multi-Ethnic Study of Atherosclerosis

Porphyromonas gingivalis infection is associated with carotid atherosclerosis in non-obese Japanese type 2 diabetic patients

Cryptococcus neoformans causes lipid peroxidation; therefore it is a potential inducer of atherogenesis

Atherosclerosis of cerebral arteries in Alzheimer disease

Atherosclerosis and risk for dementia

Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families

The membrane-spanning 4-domains, subfamily A (MS4A) gene cluster contains a common variant associated with Alzheimer's disease

The three new pathways leading to Alzheimer's disease

A Catalog of Published Genome-Wide Association Studies

A gene atlas of the mouse and human protein-encoding transcriptomes

BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources

Improved method for predicting linear B-cell epitopes

Gapped BLAST and PSI-BLAST: a new generation of protein database search programs

Infection of human peripheral blood mononuclear cells by erythrocyte-bound HIV-1: effects of antibodies and complement

Human erythrocytes bind and inactivate type 5 adenovirus by presenting Coxsackie virus-adenovirus receptor and complement receptor 1

Staphylococcus aureus bound to complement receptor 1 on human erythrocytes by bispecific monoclonal antibodies is phagocytosed by acceptor macrophages

Phagocytosis of heat-killed Staphylococcus aureus by eosinophils: comparison with neutrophils

Complement receptor 1 expression on mouse erythrocytes mediates clearance of Streptococcus pneumoniae by immune adherence

Complement receptor 1 is a sialic acid-independent erythrocyte receptor of Plasmodium falciparum

Complementindependent binding of microorganisms to primate erythrocytes in vitro by cross-linked monoclonal antibodies via complement receptor 1

A transgenic mouse model for studying the clearance of blood-borne pathogens via human complement receptor 1 (CR1)

Functional and structural properties of lipid-associated apolipoprotein J (clusterin)

Ultrastructural localization of complement membrane attack complex (MAC)-like immunoreactivity in brains of patients with Alzheimer's disease

Activation of the classical complement pathway in brain tissue of Alzheimer patients

APP, APOE, complement receptor 1, clusterin and PICALM and their involvement in the herpes simplex life cycle

Native properdin binds to Chlamydia pneumoniae and promotes complement activation

Host complement regulatory protein CD59 is transported to the chlamydial inclusion by a golgi apparatus-independent pathway

Activation of the alternative complement pathway by fungal melanins

Phenotypic heterogeneity in expression of epitopes in the Cryptococcus neoformans capsule

Susceptibility of Helicobacter pylori to the bactericidal activity of human serum

Subversion of innate immunity by periodontopathic bacteria via exploitation of complement receptor-3

Structurally homologous ligand binding of integrin Mac-1 and viral glycoprotein C receptors

In contrast to anti-tumor activity, YT cell and primary NK cell cytotoxicity for Cryptococcus neoformans bypasses LFA-1

A systemic network for Chlamydia pneumoniae entry into human cells

Interaction of two phagocytic host defense systems: Fcγ receptors and complement receptor 3

Biphasic effect of gingipains from Porphyromonas gingivalis on the human complement system

The glycosylphosphatidylinositol-anchored CD59 protein stimulates both T cell receptor ζ/ZAP-70-dependent andindependent signaling pathways in T cells

CD2-mediated CD59 stimulation in keratinocytes results in secretion of IL-1α, IL-6, and GM-CSF: implications for the interaction of keratinocytes with intraepidermal T lymphocytes

ATP-binding cassette transporter A7 enhances phagocytosis of apoptotic cells and associated ERK signaling in macrophages

C1q and C4b bind simultaneously to CR1 and additively support erythrocyte adhesion

Inhibition of C1q-beta-amyloid binding protects hippocampal cells against complement mediated toxicity

Principles of Virology

Entry of herpes simplex virus mediated by chimeric forms of nectin1 retargeted to endosomes or to lipid rafts occurs through acidic endosomes

Uptake of Helicobacter pylori outer membrane vesicles by gastric epithelial cells

Clathrinmediated endocytosis: what works for small, also works for big

Clathrin assembly lymphoid myeloid leukemia (CALM) protein: localization in endocytic-coated pits, interactions with clathrin, and the impact of overexpression on clathrin-mediated traffic

Role of mannose-6-phosphate receptors in herpes simplex virus entry into cells and cellto-cell transmission

Vacuoles induced by Helicobacter pylori toxin contain both late endosomal and lysosomal markers

The structure and function of GGAs, the traffic controllers at the TGN sorting crossroads

Inhibition of T cell activation and adhesion functions by soluble CD2 protein

Early endosomes associated with dynamic F-actin structures are required for late trafficking of H. pylori VacA toxin

Binding of Porphyromonas gingivalis gingipains to human CD4 + T cells preferentially down-regulates surface CD2 and CD4 with little affect on co-stimulatory molecule expression

Candida albicans internalization by host cells is mediated by a clathrin-dependent mechanism

Cortactin: an Achilles' heel of the actin cytoskeleton targeted by pathogens

Serine phosphorylation of cortactin controls focal adhesion kinase activity and cell scattering induced by Helicobacter pylori

Viral manipulations of the actin cytoskeleton

CD2AP contributes to cell migration and adhesion in cultured gastric epithelium

A role for α-and β-catenins in bacterial uptake

The versatility of helicobacter pylori caga effector protein functions: the master key hypothesis

Helicobacter pylori HtrA is a new secreted virulence factor that cleaves E-cadherin to disrupt intercellular adhesion

Chlamydia pneumoniae infection alters the junctional complex proteins of human brain microvascular endothelial cells

A high precision survey of the molecular dynamics of mammalian clathrinmediated endocytosis

Mutations in amphiphysin 2 (BIN1) disrupt interaction with dynamin 2 and cause autosomal recessive centronuclear myopathy

Cellular internalization of green fluorescent protein fused with herpes simplex virus protein VP22 via a lipid raft-mediated endocytic pathway independent of caveolae and Rho family GTPases but dependent on dynamin and Arf6

Clathrin interacts specifically with amphiphysin and is displaced by dynamin

Amphiphysin IIm is required for survival of Chlamydia pneumoniae in macrophages

Identification of novel interaction partners for the conserved membrane proximal region of α-integrin cytoplasmic domains

The role of epithelial integrin receptors in recognition of pulmonary pathogens

Role of the cagpathogenicity island encoded type IV secretion system in Helicobacter pylori pathogenesis

Siglecs as positive and negative regulators of the immune system

New aspects of siglec binding specificities, including the significance of fucosylation and of the sialyl-Tn epitope. Sialic acid-binding immunoglobulin superfamily lectins

Sialic acid on herpes simplex virus type 1 envelope glycoproteins is required for efficient infection of cells

Identification of N-Acetylneuraminic acid and its 9-O-acetylated derivative on the cell surface of Cryptococcus neoformans. Influence on fungal phagocytosis

Characterization of Borrelia burgdorferi glycoconjugates and surface carbohydrates

SabA is the H. pylori hemagglutinin and is polymorphic in binding to sialylated glycans

Identification of a new sialic acid-binding protein in Helicobacter pylori

Binding of the periodontitis associated bacterium Porphyromonas gingivalis to glycoproteins from human epithelial cells

Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy

The missing link between indoleamine 2,3-dioxygenase mediated antibacterial and immunoregulatory effects

Role of indoleamine 2,3-dioxygenase in antimicrobial defence and immuno-regulation: tryptophan depletion versus production of toxic kynurenines

Immune system to brain signaling: neuropsychopharmacological implications

Kynurenine and its metabolites in Alzheimer's disease patients

Tryptophan degradation and immune activation in Alzheimer's disease

IgE antibody-specific activity in human allergic disease

Cell-bound and circulating IgE antibody to herpes simplex virus

High levels of IgE in patients suffering from frequent recurrent herpes simplex lesions

Patients with Meniere's disease possess IgE reacting with herpes family viruses

Basophil-bound and serum immunoglobulin E directed against Helicobacter pylori in patients with chronic gastritis

IgE anti-Borrelia burgdorferi components (p18, p31, p34, p41, p45, p60) and increased blood CD8 + CD60 + T cells in children with Lyme disease

Detection of anti-Chlamydia pneumoniae IgE in children with reactive airway disease

Extraction of ige-binding components of helicobacter pylori by immunoblotting analysis in chronic urticaria patients

Eosinophil-Cryptococcus neoformans interactions in vivo and in vitro

Identification of a new multigene four-transmembrane family (MS4A) related to CD20, HTm4 and β subunit of the high-affinity IgE receptor

MS4a4B, a CD20 Homologue in T Cells, Inhibits T Cell Propagation by Modulation of Cell Cycle

Host cell targets of tegument protein VP22 of herpes simplex virus 1

Distinct endocytic pathways regulate TGF-β receptor signalling and turnover

Interaction of transforming growth factor β receptors with apolipoprotein J/clusterin

TGF-β and immune cells: an important regulatory axis in the tumor microenvironment and progression

The ALK gene, an attractive target for inhibitor development

Nonmuscle myosin heavy chain (MYH9): a new partner fused to ALK in anaplastic large cell lymphoma

ATP-binding cassette transporter A7 (ABCA7) binds apolipoprotein A-I and mediates cellular phospholipid but not cholesterol efflux

ATP-binding cassette transporter A7 regulates processing of amyloid precursor protein in vitro

The phospholipid composition of extracellular herpes simplex virions differs from that of host cell nuclei

Incorporation of 32P-phosphate into membrane phospholipids during infection of cultured human fibroblasts by herpes 28 International Journal of Alzheimer's Disease simplex virus type 1

Sphingolipid metabolism during infection of human fibroblasts by herpes simplex virus type 1

Sphingomyelin is important for the cellular entry and intracellular localization of Helicobacter pylori VacA

Sphingomyelin trafficking in Chlamydia pneumoniae-infected cells

Role of membranotropic sequences from herpes simplex virus type I glycoproteins B and H in the fusion process

Phospholipids trigger Cryptococcus neoformans capsular enlargement during interactions with amoebae and macrophages

Adenosine triphosphate binding cassette (ABC) transporters are expressed and regulated during terminal keratinocyte differentiation: a potential role for ABCA7 in epidermal lipid reorganization

Caspase-3-dependent reactivation of latent herpes simplez virus type 1 in sensory neuronal cultures

Chlamydophila pneumoniae derived from inclusions late in the infectious cycle induce aponecrosis in human aortic endothelial cells

Inhibition of virus-induced cell fusion by apolipoprotein A-I and its amphipathic peptide analogs

Roles of ATP-binding cassette transporter A7 in cholesterol homeostasis and host defense system

Apolipoprotein E genotype influences vertical transmission of herpes simplex virus type 1 in a gender specific manner

The C-terminal α-helix domain of apolipoprotein E is required for interaction with nonstructural protein 5A and assembly of hepatitis C virus

Infectivity of hepatitis C virus is influenced by association with apolipoprotein E isoforms

Increased vulnerability of ApoE4 neurons to HIV proteins and opiates: protection by diosgenin and l-deprenyl

Herpes simplex encephalitis: involvement of apolipoprotein E genotype

Apolipoprotein E4 enhances attachment of Chlamydophila (Chlamydia) pneumoniae elementary bodies to host cells

The APOE4 genotype alters the response of microglia and macrophages to 17β-estradiol

APOE genotype-specific differences in the innate immune response

Creactive protein and rate of dementia in carriers and non carriers of Apolipoprotein APOE4 genotype

The physiological structure of human C-reactive protein and its complex with phosphocholine

Apolipoprotein E knock-out mice are highly susceptible to endotoxemia and Klebsiella pneumoniae infection

Herpesvirus infection accelerates atherosclerosis in the apolipoprotein E-deficient mouse

Chronic infections and atherosclerosis

Chlamydia pneumoniae infection induces an unstable atherosclerotic plaque phenotype in LDL-receptor, ApoE double knockout mice

Cytomegalovirus infection increases development of atherosclerosis in Apolipoprotein-E knockout mice

Porphyromonas gingivalis infection accelerates the progression of atherosclerosis in a heterozygous apolipoprotein Edeficient murine model

Influenza infection exerts prominent inflammatory and thrombotic effects on the atherosclerotic plaques of apolipoprotein E-deficient mice

Infection with Toxoplasma gondii increases atherosclerotic lesion in ApoE-deficient mice

Regulation of cellular immunity prevents Helicobacter pylori-induced atherosclerosis

A cell surface protein with herpesvirus entry activity (Hveb) confers susceptibility to infection by mutants of herpes simplex virus type 1, herpes simplex virus type 2, and pseudorabies virus

RNAi screen in Drosophila cells reveals the involvement of the tom complex in Chlamydia infection

The herpes simplex virus (HSV) protein ICP34.5 is a virion component that forms a DNA-binding complex with proliferating cell nuclear antigen and HSV replication proteins

ZNF224: structure and role of a multifunctional KRAB-ZFP protein

Protein arginine methyltransferase 1 regulates herpes simplex virus replication through ICP27 RGG-box methylation

A schizophreniaassociated mutation of DISC1 perturbs cerebral cortex development

Biochemistry: tubulin polyglutamylase enzymes are members of the TTL domain protein family

APOBEC1-mediated editing and attenuation of HSV-1 DNA implicates an antiviral role in neurons during encephalitis

PAX2 oncogene negatively regulates the expression of the host defense peptide human beta defensin-1 in prostate cancer

Association between defb1 gene haplotype and herpes viruses seroprevalence in children with acute lymphoblastic leukemia

Potential role of human beta-defensin 1 in Helicobacter pylori-induced gastritis

HBD-1 and hBD-2 are expressed in cervico-vaginal lavage in female genital tract due to microbial infections

Structural and functional characterization of hBD-1(Ser35), a peptide deduced from a DEFB1 polymorphism

Structural basis for the specificity of thymidylate kinases from human pathogens: implications for nucleotide analogues activation

Association of hyperhomocysteinemia and Chlamydia pneumoniae infection with carotid atherosclerosis and coronary artery disease in Japanese patients

Helicobacter pylori and Arteriosclerosis

Herpes simplex virus binds to human serum lipoprotein

Retrieval of the Alzheimer's amyloid precursor protein from the endosome to the TGN is S655 phosphorylation state-dependent and retromer-mediated

Trafficking of cell-surface β-amyloid precursor protein: evidence that a sorting intermediate participates in synaptic vesicle recycling

Inhibition of beta-amyloid1-42 internalization attenuates neuronal death by stabilizing the endosomal-lysosomal system in rat cortical cultured neurons

Microglia mediate the clearance of soluble aβ through fluid phase macropinocytosis

The clathrin assembly protein AP180 regulates the generation of amyloid-β peptide

Endocytosis is required for synaptic activity-dependent release of amyloid-β in vivo

Structural, biochemical and signaling properties of the low-density lipoprotein receptor gene family

Lipoprotein receptors-an evolutionarily ancient multifunctional receptor family

Part-time α-secretases: the functional biology of ADAM 9

An overview of notch signaling in adult tissue renewal and maintenance

The temperaturesensitive role of Cryptococcus neoformans ROM2 in cell morphogenesis

Diverse requirements for SRCfamily tyrosine kinases distinguish chlamydial species

Helicobacter pylori vacuolating cytotoxin (VacA) disorganizes the cytoskeletal architecture of gastric epithelial cells

Exit of intracellular Porphyromonas gingivalis from gingival epithelial cells is mediated by endocytic recycling pathway

A protein factor essential for microtubule assembly

The role of tau kinases in Alzheimer's disease

Neuronal cytoskeletal dynamic modification and neurodegeneration induced by infection with herpes simplex virus type 1

Alzheimer's disease: a pathogenetic autoimmune disorder caused by herpes simplex in a gene-dependent manner

Herpes simplex virus dances with amyloid precursor protein while exiting the cell

Association of the herpes simplex virus type 1

Us11 gene product with the cellular kinesin light-chainrelated protein PAT1 results in the redistribution of both polypeptides

PAT1, a microtubule-interacting protein, recognizes the basolateral sorting signal of amyloid precursor protein

The Alzheimer's disease-associated amyloid β-protein is an antimicrobial peptide

Acyclovir or Aβ42 peptides attenuate HSV-1-induced miRNA-146a levels in human primary brain cells

Inflammation in Alzheimer's disease: amyloidβ oligomers trigger innate immunity defence via pattern recognition receptors

Role of toll-like receptor signalling in Aβ uptake and clearance

Identification of autoantibody against beta-amyloid peptide in the serum of elderly

γ-secretase substrates and their implications for drug development in Alzheimer's disease

Innate immunity to virus infection

Regulation of antigen uptake, migration, and lifespan of dendritic cell by Toll-like receptors

Nectin-1α, an immunoglobulin-like receptor involved in the formation of synapses, is a substrate for presenilin/γ-secretase-like cleavage

Proteomic profiling of gamma-secretase substrates and mapping of substrate requirements

Syndecan-1 and syndecan-2 play key roles in herpes simplex virus type-1 infection

Heparan sulfate proteoglycans are required for cellular binding of the hepatitis E virus ORF2 capsid protein and for viral infection

Different heparan sulfate proteoglycans serve as cellular receptors for human papillomaviruses

A role for syndecan-1 and claudin-2 in microbial translocation during HIV-1 infection

Syndecan-3 is a dendritic cell-specific attachment receptor for HIV-1

Binding of human papilloma virus L1 virus-like particles to dendritic cells is mediated through heparan sulfates and induces immune activation

Role of a disintegrin and metalloprotease 10 in Staphylococcus aureus α-hemolysin-mediated cellular injury

Involvement of human CD44 during Cryptococcus neoformans infection of brain microvascular endothelial cells

Structure of the extracellular portion of CD46 provides insights into its interactions with complement proteins and pathogens

Porphyromonas gingivalis mediates the shedding and proteolysis of complement regulatory protein CD46 expressed by oral epithelial cells

Desmoglein 2 is a receptor for adenovirus serotypes 3, 7, 11 and 14

Members of the low density lipoprotein receptor family mediate cell entry of a minor-group common cold virus

Expression and folding of human very-low-density lipoprotein receptor fragments: neutralization capacity toward human rhinovirus HRV2

Effect of combined siRNA of HCV E2 gene and HCV receptors against HCV

Epstein-Barr virus latent membrane protein 2A exploits Notch1 to alter B-cell identity in vivo

An Epstein-Barr virus protein interacts with Notch

Pathogenic poxviruses reveal viral strategies to exploit the ErbB signaling network

Low-affinity nerve-growth factor receptor (P75NTR) can serve as a receptor for rabies virus

Structural basis of Nipah and Hendra virus attachment to their cell-surface receptor ephrin-B2

Association of host cell surface adhesion receptors and other membrane proteins with HIV and SIV

Characterization of influenza A virus binding sites on human neutrophils

Involvement of glycoreceptors in galactoxylomannan-induced T cell death

Differential ligand binding to a human cytomegalovirus chemokine receptor determines cell type-specific motility

Expression of SR-PSOX, a novel cell-surface scavenger receptor for phosphatidylserine and oxidized LDL in human atherosclerotic lesions

Amino acid-containing membrane lipids in bacteria

Identification of αdystroglycan as a receptor for lymphocytic choriomeningitis virus and Lassa fever virus

Immunosuppression and resultant viral persistence by specific viral targeting of dendritic cells

Mycobacterium leprae and leprosy: a compendium

Detection of amyloid beta aggregates in the brain of BALB/c mice after Chlamydia pneumoniae infection

β-amyloid deposition and Alzheimer's type changes induced by Borrelia spirochetes

HSV-1 promotes Ca2 + -mediated APP phosphorylation and Aβ accumulation in rat cortical neurons

Infectious burden: a new risk factor and treatment target for atherosclerosis

Describing the hexapeptide identity platform between the influenza A H5N1 and Homo sapiens proteomes

Massive peptide sharing between viral and human proteomes

Hepatitis B virus and Homo sapiens proteome-wide analysis: a profusion of viral peptide overlaps in neuron-specific human proteins

No human protein is exempt from bacterial motifs, not even one

Re-engineering biopharmaceuticals for delivery to brain with molecular Trojan horses

Cerebral microvascular endothelium and the pathogenesis of neurodegenerative diseases

Human Rhinovirus Type 2-Antibody Complexes Enter and Infect Cells via Fc-γ Receptor IIB1

Antibodies mediate intracellular immunity through tripartite motif-containing 21 (TRIM21)

Anti-severe acute respiratory syndrome coronavirus spike antibodies trigger infection of human immune cells via a pH-and cysteine protease-independent FcγR pathway

Alterations of Fc γ receptor I and Toll-like receptor 4 mediate the antiinflammatory actions of microglia and astrocytes after adrenaline-induced blood-brain barrier opening in rats

Epstein-Barr and other viral mimicry of autoantigens, myelin and vitamin D related proteins, and of EIF2B, the cause of vanishing white matter disease: massive mimicry of multiple sclerosis relevant proteins by the Synechococcus phage

Pathogen and autoantigen homologous regions within the cystic fibrosis transmembrane conductance regulator (CFTR) protein suggest an autoimmune treatable component of cystic fibrosis

Schizophrenia: a pathogenetic autoimmune disease caused by viruses and pathogens and dependent on genes

Postencephalitic parkinsonism and basal ganglia necrosis due to Epstein-Barr virus infection

Reversible Parkinsonian syndrome associated with anti-neuronal antibodies in acute EBV encephalitis: a case report

Monoclonal antibodies against Epstein-Barr virus cross-react with alpha-synuclein in human brain

Extensive viral mimicry of 22 AIDS-related autoantigens by HIV-1 proteins and pathway analysis of 561 viral/human homologues suggest an initial treatable autoimmune component of AIDS

The self/nonself issue a confrontation between proteomes

Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease

Autosomal dominant inheritance of autoantibodies to thyroid peroxidase and thyroglobulin-studies in families not selected for autoimmune thyroid disease

Somatic hypermutation and antigen-driven selection of B cells are altered in autoimmune diseases

Human proteins with affinity for dermatan sulfate have the propensity to become autoantigens

Glycosaminoglycan-binding microbial proteins in tissue adhesion and invasion: key events in microbial pathogenicity

Tauopathy-like abnormalities and neurologic deficits in mice immunized with neuronal tau protein

Alzheimer-like neurodegeneration in aged antinerve growth factor transgenic mice

Neuropathology and pathogenesis of encephalitis following amyloid-β immunization in Alzheimer's disease

Vaccination with amyloid-β peptide induces autoimmune encephalomyelitis in C57/BL6 mice

The neuroinflammatory response in plaques and amyloid angiopathy in Alzheimer's disease: therapeutic implications

Anti-ATP synthase autoantibodies from patients with Alzheimer's disease reduce extracellular HDL level

Autoantibodies to the adenosine triphosphate synthase play a pathogenetic role in Alzheimer's disease

Evidence for the presence of antibodies to cholinergic neurons in the serum of patients with Alzheimer's disease

Brain-reactive autoantibodies prevalent in human sera increase intraneuronal amyloid-γ1-42 deposition

The presence and origin of autoantibodies against α4 and α7 nicotinic acetylcholine receptors in the human blood: possible relevance to Alzheimer's pathology

Autoimmunity in Alzheimer's disease: increased levels of circulating IgGs binding Aβ and RAGE peptides

Differential neuroimmune markers to the onset of Alzheimer's disease neurodegeneration and dementia: autoantibodies to Aβ(25-35) oligomers, S100b and neurotransmitters

Selection experimants on industrial melanism in the Lepidoptera

Effect of apolipoprotein E on the cerebral load of latent herpes simplex virus type 1 DNA

Herpes simplex virus type 1 latency-associated transcript inhibits apoptosis and promotes neurite sprouting in neuroblastoma cells following serum starvation by maintaining protein kinase B (AKT) levels

Nerve growth factor deprivation results in the reactivation of latent herpes simplex virus in vitro

Nature and duration of growth factor signaling through receptor tyrosine kinases regulates HSV-1 latency in neurons

Reduction of cortical TrkA but not p75NTR protein in early-stage Alzheimer's disease

Highdose dietary supplementation of vitamin A induces brainderived neurotrophic factor and nerve growth factor production in mice with simultaneous deficiency of vitamin A and zinc

Effects of long-term replacement therapy of compound nylestriol tablet or low-dose 17 beta-estradiol on the expression of nerve growth factor in OVX rat hippocampal formation

17-β estradiol promotion of herpes simplex virus type 1 reactivation is estrogen receptor dependent

Endogenous estradiol and risk of dementia in women and men: the Rotterdam study

Endogenous sex hormones as risk factors for dementia in elderly men and women

Heat-induced reactivation of HSV-1 in latent mice: upregulation in the TG of CD83 and other immune response genes and their LAT-ICP0 locus

Neuronal reactivation of herpes simplex virus may involve interleukin-6

Enhancement by TNFalpha of reactivation and replication of latent herpes simplex virus from trigeminal ganglia of mice

Serum interleukin-6 levels correlate with the severity of dementia in down syndrome and in Alzheimer's disease

Elevated interleukin-6 secretion levels by mononuclear cells of Alzheimer's patients

Inflammatory markers in matched plasma and cerebrospinal fluid from patients with Alzheimer's disease

Cytokine responses in patients with pneumonia caused by Chlamydia or Mycoplasma

Serum and gastric fluid levels of cytokines and nitrates in gastric diseases infected with Helicobacter pylori

Interleukin-6 production by human monocytes stimulated with Cryptococcus neoformans components

Role of the hypothalamic pituitary adrenal axis and IL-6 in stressinduced reactivation of latent herpes simplex virus type 1

Cortisol and Alzheimer's disease. I: basal studies

Elevated basal cortisol level predicts lower hippocampal volume and cognitive decline in Alzheimer's disease

The role of cyclic nucleotide mediators in latency and reactivation of HSV-1 infected neuroblastoma cells

Activation of second-messenger pathways reactivates latent herpes simplex virus in neuronal cultures

Propranolol suppresses reactivation of herpesvirus

Stress-associated immunomodulation and herpes simplex virus infections

Iontophoresis of lysophosphatidic acid into rabbit cornea induces HSV-1 reactivation: evidence that neuronal signaling changes after infection

Hypoxia enhances the replication of oncolytic herpes simplex virus

Significance of nerve growth factor content levels after transient forebrain ischemia in gerbils

The vascular hypothesis of Alzheimer's disease: bench to bedside and beyond

Inhibition of herpes simplex virus replication by retinoic acid

Ten-year trends in vitamin intake in free-living healthy elderly people: the risk of subclinical malnutrition

Serum levels of β-carotene, α-carotene and vitamin A in patients with Alzheimer's disease

Investigating the biological and clinical significance of human dysbioses

Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors

Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease

High dietary and plasma levels of the omega-3 fatty acid docosahexaenoic acid are associated with decreased dementia risk: the Rancho Bernardo study

The role of diet in cognitive decline

Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studies

Healthy aging and dementia: findings from the nun study

Homocysteine-lowering by b vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial

Risk factors and preventive interventions for Alzheimer disease: state of the science

Nontraditional risk factors combine to predict Alzheimer disease and dementia

The projected effect of risk factor reduction on Alzheimer's disease prevalence

Autoantigen discovery with a synthetic human peptidome

Analysis of the evidence following Koch's and Hill's criteria

Diagnosis of Alzheimer's disease based on disease-specific autoantibody profiles in human sera

Application of immunosignatures to the assessment of Alzheimer's disease