Weight: 2.97 Paper Topics: pathways leading hundreds genes implicated alzheimer's disease grouped discrete signalling networks relevant various subpathologies risk factors biochemistry alzheimer's disease environmental risk factors associated alzheimer's disease including infectious agents herpes simplex chlamydia pneumonia borrelia burgdorferi vitamin deficiency hypercholesterolaemia hyperhomocysteinaemia folate deficiency oestrogen depletion cerebral nerve growth factor ngf deprivation diabetes cerebral hypoperfusion hypoxia hypoglycaemia able promote cerebral beta-amyloid deposition in absence particular gene variant animal models 1 kegg pathway analyses multiple genes implicated alzheimer's disease shown subsets susceptibility genes grouped networks relevant amyloidogenic pathways eg bacterial viral entry pathways 1 2 cholesterol/lipoprotein function 3 4 growth factor signalling
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MethodsThe 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/  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        and is a general clearance receptor for complement opsonised pathogens  . 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  . 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)  . 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  . CD59 is also incorporated into chlamydial inclusion bodies  . Complement component C3 binds to melanins derived from C. neoformans  and cryptococcal capsules bind to C3 and activate the alternative complement pathway  . Complement component C3 also binds to the bacterial surface of H. pylori, and the complement pathway is involved in bactericidal effects against this pathogen  . P. gingivalis also uses complement receptor 3 (an integrin complex of integrin, alpha M/integrin, beta 2 (ITGAM/ ITGB2)) for entry  , and herpes simplex glycoprotein C also binds to this complex  as does C. neoformans  , while ITGB2 is involved in C. pneumoniae entry in human coronary artery endothelial cells  . This macrophage complement receptor, also known as MAC-1, generally mediates the phagocytosis of pathogens coated with complement C3 derivatives  . 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  . 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] .
Clathrin-Mediated EndocytosisPICALM, 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)  , one used by Herpes simplex for entry and cellto-cell transmission  and by C. pneumoniae for cellular entry  . IGF2R is also a component of late endosomes disrupted by the Helicobacter pylori VacA cytotoxin  . 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  .
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  . CD2AP is also involved in the entry of the helicobacter vacuolating toxin VacA and connects the actin cytoskeleton to early endosomes containing VacA  . CD2 is cleaved by gingipain proteases from P. gingivalis  .
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  and binds to dynamins that regulate the clathrin network  including DNM1 and the herpes simplex binding partner DNM2  and to clathrins and the alpha adaptins, AP2A1 and AP2A2  . 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  . BIN1 also binds to a number of alpha integrins (ITGA1, ITGA3, and ITGA6)  : integrins are used for attachment by many viruses, bacteria, and fungi and may serve as pattern recognition receptors regulating the immune response  . 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  ), 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  . CD33 binds to alpha2-3-or alpha2-6-linked sialic acids (N-acetyl neuraminic acid)  . 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  . N-acetyl neuraminic acid is expressed by C. neoformans, is involved in fungal adhesion to macrophages  , and is also a component of the cell wall of B. burgdorferi  , while Helicobacter pylori adhesins also bind to this particular form of sialic acid [99, 100] as does P. gingivalis  .
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  . Mice immunised with inactivated herpes simplex develop IgE-specific antibodies to the virus  . High levels of IgE are also observed in man following recurrent herpes simplex infection  and human IgE antibodies are also known to interact with herpes family viruses including HSV-1 and 2 and the Epstein-Barr and cytomegalovirus  and also to C. pneumoniae, H. pylori, and B. burgdorferi [     . IgE-related allergic responses are also involved in C. neoformans infection  . 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  . SMURF2 is known to bind to the VP22 tegument protein of herpes simplex  and plays a role in clathrin-mediated endocytosis and the subsequent ubiquitin-related proteasomal degradation of TGF beta receptors, to which it binds  . Clusterin is a ligand for TGF beta receptors (TGFBR1/TGFBR2)  . TGF beta signalling exerts immunosuppressive effects and inhibits host immunosurveillance and the recruitment of immunocompetent cells by chemokines  . 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  . ALK is best characterised via its relationship with lymphomas, caused by ALK gene fusion with any of several other housekeeping genes  . 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  . However, cholesterol efflux to lipidladen APOE, but not to lipid free APOE, is increased by ABCA7 expression in HEK-293 cells  . 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  . Herpes viral infection leads to an increased incorporation of phosphate into membrane sphingomyelin of the host  . Inhibition of sphingomyelinase has also been shown to markedly reduce herpes simplex viral reproduction  and also inhibits the antifungal effects of neutrophils against C. neoformans infection. Sphingomyelin is a receptor for the Helicobacter toxin VacA  and is also incorporated into inclusion bodies in C. pneumoniae-infected cells  . 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  . Phosphatidylcholine is also able to trigger capsular enlargement in C. neoformans infection  .