AlzGenes

ALZHEIMER'S DISEASE SUSCEPTIBILITY GENES Kegg pathway analysis of over 400 susceptibility genes: Herpes simplex related genes included : Diverse Kegg pathways of GWAS and other networks

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Enhanced links to genes are provided by Last update: July 28, 2011	PolygenicBlog on the relationships between genes and risk factors
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Genes associated with both atherosclerosis/hypercholesterolaemia and Alzheimer's Cholesterol/lipoprotein pathways Red genes have been implicated in AD: Yellow genes have beeen implicated in AD and atherosclerosis

Family	Gene
Cholesterol and lipoprotein-related	A2M, ABCA1, APOA1, APOA4, APOC1, APOC2, APOC3, APOE, CD36, CETP, HMGCR, LDLR, LIPA, LRP1, LRP6, LPA, LPL, OLR1, SREBF1
Cytokines	CCL2, CCR2, IL1B, IL1RN, IL6,IL18, TGFB1, TNF
Oxidative stress	ALDH2, GSTM1, GSTT1, HFE, HMOX1, MPO, NOS3, PON1, PON2
Nuclear receptor and related	CYP19A1, ESR1, PPARA
Proteases	ACE, CST3, MMP1, MMP3, SERPINE1
Miscellaneous	AGER, BCHE, CBS, CD14, CFH, CR1, CRP, GNB3, HLA-A2, HTR6, ICAM1, MEF2A, MTHFR, NGB, PTGS2, TLR4

GWAS studies catalogued by the National Human Genome Research Institute

Major genes (see below)

Corder et al, 1993 Harold et al, 2009, Lambert et al, 2009

Apolipoprotein E (APOE), Clusterin (CLU), Complement receptor 1 (CR1), phosphatidylinositol binding clathrin assembly protein (PICALM) Note that APOE and CR1 have also been associated with atherosclerosis

Classes of Genes

Acetyl Choline Glucose	Adhesion	Blood/Serum	Channels	Cholesterol	DNA Repair/ replication	Folate Homocysteine	Growth factors	Heat shock	Immune	Kinases	Mitochondria
Monoamine	Nuclear	Oxidative stress	Peptides	Protease	Proteoglycan/Viral receptors	Spliceosome	Structural	Ubiquitin	Miscellany	Orphans

Table 1: Components of the cholesterol shuttle and cholesterol and lipoprotein related genes that have been associated with Alzheimer's disease. Cholesterol/lipoprotein pathways Red genes have been implicated in AD: Yellow genes have beeen implicated in AD and atherosclerosis

Gene	Alzheimer's disease	Atherosclerosis/ hypercholesterolemia	Modifications in AD	Relationships with other gene products	HSV-1
ACAD8 acyl-Coenzyme A dehydrogenase family, member 8 GeneCards 11q25	Wollmer et al, 2007
DHCR24 24-dehydrocholesterol (desmosterol) reductase (seladin) GeneCards Metabolome 1p33-p31.1	Lamsa et al, 2007		Downregulated in AD temporal cortex Livonen et al, 2002 Relatively high proportion of desmosterol in AD brain Wender et al, 1994
FDPS farnesyl diphosphate synthase) GeneCards 1q22	Wollmer et al, 2007
HMGCR 3-hydroxy-3-methylglutaryl-Coenzyme A reductase BIOGRID GeneCards 5q13-q14	Licastro et al 2006	Hubacek et al, 1999	No mRNA change Yasojima et al, 2002	Rate limiting enzyme for cholesterol biosynthesis. Transcription controlled by SREBF1 and PPARA Narce and Poisson 2002.Transcription/activityrepressed by 24 and 25-OHcholesterol (CYP46A1, CH25H)Saucier etal ,1989 Nishimura et al,2005. Induced by homocysteine in endothelial cells Li et al, 2002 (cf MTHFR, MTR, MTRR)	HSV-1 entry into Vero cells is lipid raft dependent and is blocked by nystatin Bender et al, 2003
HMGCS2 3-hydroxy-3-methylglutaryl-Coenzyme A synthase 1 mitochondrial GeneCard 1p13-p12	Wollmer et al, 2007			Provides the substrate for HMGCR
A2M alpha-2-macroglobulin Biogrid 12p13.3	(Zappia et al. 2002)	Related to atherosclerosis in circle of Willis Larionov et al, 2006 a risk factor for Alzheimer's disease Roher et al, 2003	No change in CSF protein (Blennow et al. 2000)	Ligand for LRP1 (Strickland et al. 1990. ). Binds to APOE (Krimbou et al. 1998)Binds to growth factors including BDNF (Wolf and Gonias 1994); Binds to beta amyloid and mediates degradation and transport of amyloid beta peptides via A2M associated proteases and LRP (Fabrizi et al. 2001). Binds to lecithin cholesterol acyl transcerase (LCAT) (Krimbou et al. 2001)	Binds to HSV-1 Alonso et al, 2001
LPA lipoprotein, Lp(a) BIOGRID GeneCards 6q23-27	(Compton et al. 2002)	(Kronenberg et al. 1999)	Increased serum levels(Kuriyama et al. 1992) Lp(a) serum levels are associated with an increased risk for AD, independently of apolipoprotein E genotypes (Solfrizzi et al. 2002)	Binds to APOE (Bard et al. 1992)Binds to LDLR, LRP1, VLDLR and gp330 lipoprotein receptors (Niemeier et al. 1999;Reblin et al. 1997)
APOA1 BIOGRID GeneCards 11q23-q24	(Vollbach et al. 2005)	(Spiridonova et al. 2001b)		Promotes cholesterol efflux from tissues to the liver for excretion, and it is a cofactor for lecithin cholesterolacyltransferase (LCAT) which is responsible for the formation of most plasma cholesteryl esters.	Inhibits HSV-1 induced cell fusion Srinivas et al, 1991 The Herpes simplex virus binds to all classes of lipoprotein (LDL, HDL, VLDL), via glycoprotein B (UL27) Huemer et al, 1988, the use of individual lipoproteins or lipoprotein receptors for herpes viral entry has not been closely examined.
APOA4 Biogrid GeneCards 11q23	(Csaszar et al. 1997)	(Ganan et al. 2004)		Potent activator of LCAT(Emmanuel et al. 1994) Substrate for ABCA1(Remaley et al. 2001)
APOA5 apolipoprotein A-V 11q23	Barbosa et al, 2006			regulates plasma triglyceride levels,
APOC1 apolipoprotein C-I Biogrid GeneCards 19q13.2	(Ki et al. 2002)	(Hubacek et al. 2004)	Astrocytic protein levels increased in Alzheimer's disease frontal cortex and hippocampus: mRNA decreased (Petit-Turcotte et al. 2001)	Activates LCAT, inhibits CETP (Shachter 2001):Elevated serum cholesterol, triglycerides and free fatty acids in transgenic mice expressing hAPOC1(Jong et al. 1998;Shachter et al. 1996)Transported by ABCA1 (Remaley et al. 2001). Inhibits APOE mediated binding of VLDL to LRP1 and VLDLR (Jong et al. 1999b)
APOC2 apolipoprotein C-II Biogrid GeneCards 19q13.2	(Schellenberg et al. 1987)	(Kawano et al. 2002),	No change in blood APOC2 levels (Adunsky et al. 2002)	Transported by ABCA1 (Remaley et al. 2001). Binds to and activates LPL (Shen et al. 2002;MacPhee et al. 2000)Reduces APOB binding to LDLR (Clavey et al. 1995)
APOC3 Apolipoprotein C III Biogrid GeneCards 11q23.1-q23	(Sun et al. 2005b)	(Waterworth et al. 2000)	No change in blood APOC3 levels(Adunsky et al. 2002)	Transported by ABCA1 (Remaley et al. 2001). Binds to LDLR, inhibits LPL (Jong et al. 1999a).
APOC4 apolipoprotein C-IV 19q13.2	Grupe at al, 2007
APOD Apolipoprotein D Biogrid GeneCards 3q26	(Desai et al. 2003)		Localised in amyloid deposits (Navarro et al. 2003)Increased protein levels in hippocampus frontal cortex and CSF (Glockner and Ohm 2003;Thomas et al. 2003;Terrisse et al. 1998)	Role in Cholesteryl ester exchange: Binds to and activates LCAT(Holmquist 1989). Release from astrocytes stimulated by 25-hydroxycholesterol (CH25H) (Patel et al. 1995). Binds cholesterol, progesterone, arachidonic acid, bilirubin (Nakagawa et al. 2002)
APOE apolipoprotein E Biogrid GeneCards 19q13.2	(Rubinsztein and Easton 1999)	(Horejsi and Ceska 2000)	Reduced CSF levels with evidence for increased oxidation of lipoproteins (of which APOE is the major constituent)(Neely and Montine 2002; Schippling et al. 2000;Yamauchi et al. 1999)	Major Cholesterol carrier (Swertfeger and Hui 2001). Ligand for LDLR, LRP1 (Raussens et al. 2002), (Myklebost et al. 1989), LRP8(APOER2) (Kim et al. 1996), LDLR and and VLDLR (Liu et al. 2002): Amyloid beta binds to APOE (Strittmatter et al. 1993)	APOE4 and HSV-1 infection combine to increase AD risk Itzhaki and Wozniak,2006APOE-derived peptides have anti infective activity(HSV-1 and 2) Dobson et al, 2006. APOE4 favours HSV-1 cerebral entry Burgos et al, 2003 APOE isoforforms modify HSV-1 viral latency and immediate early gene expressionMiller and Federoff, 2008
CLU Clusterin Apolipoprotein J 8p21-p12	Two independent GWAS studies Harold et al, 2009, Lambert et al, 2009		Plaque constituent Choi-Miura et al, 1992	Binds to LRP2, LRP8, VLDLR: Important role in beta-amyloid clearance. Hammad et al, 1997
ABCA1 ATP-binding cassette, sub-family A (ABC1), member 1 Biogrid GeneCards 9q31.1	(Wollmer et al. 2003a)	(Lutucuta et al. 2001),	Increased hippocampal mRNA(Blalock et al. 2004)	ABCA1 induction reduces beta and gamma secretase activity (Sun et al. 2003) and increases the secretion of amyloid beta ₄₀ and ₄₂. (Fukumoto et al. 2002b) Transports cholesterol (Knight 2004). Transports lipoproteins APOA-II, APOA4, APOC1, APOC2, APOC3, APOE (Remaley et al. 2001)
ABCA2 ATP-binding cassette, sub-family A (ABC2), member 2 Biogrid GeneCards 9q34	(Mace et al. 2005)			Expression in CHO cells increases LDLR expression (Chen et al. 2004)
ABCG1 ATP-binding cassette, sub-family G (WHITE), member 1 Biogrid GeneCards 21q22.3	Wollmer et al, 2007			Involved in macrophage cholesterol and phospholipid transport. Transports 7-beta-hydroxycholesterol Engel et al, 2007, a product of APP
NPC1 Niemann-Pick disease, type C1 18q11-q12	Erickson et al, 2008			Mediates intracellular cholesterol trafficking
NPC2 Niemann-Pick disease, type C2 Biogrid GeneCards	Wollmer et al, 2007			regulates the transport of cholesterol through the late endosomal /lysosomal system
OPRS1 Sigma receptor 1Biogrid GeneCard 9p13.3s	(Uchida et al. 2005)			Sigma 1 ligand inhibits cholesterol biosyntheis at the sterol isomerase step (Labit-Le Bouteiller et al. 1998) Regulates lipid transport from endoplasmic reticulum to plasma membrane Hayashi and Su,2003
APP Amyloid beta (A4) precursor protein Biogrid GeneCards 21q21.3 OMIM # 104760	(Goate et al. 1989) APP AICD Abeta1-42 Abeta1-40	APP cholesterol APP lipoprotein	Major component of senile plaques	Abeta40 reduces cholesterol synthesis via HMGCR inhibition Grimm et al, 2005 Oxidises cholesterol to 7beta-Hydroxycholesterol Nelson and Alkon, 2005, a substrate of HSDB11. Binds to LRP1 via interactions with LRPAP1 and APBB1 Kinoshita et al, 2001. Cleaved by BACE and gamma secretase. Binds to APBB1, APBB2, APBB3, APOE,MAPK8IP1, SNCA, TGFB1,(see gene info). C-terminal AICD induces GSK3B via APBB1 and TFCP2 Kim et al, 2004	Abeta fibrils stimulate the entry of HSV-1 and other enveloped viruses Wojtowicz et al, 2002. APP is involved in the anteroggrade transport of HSV-1 Satpute-Krishnan et al, 2003. HSV-1 infection increases intracellular beta-amyloid productionWozniak et al, 2007
LDLR Low density lipoprotein receptor Biogrid GeneCards 19p13.3	Poduslo et al. 2004)	(Bertolini et al. 2004)	Increased hippocampal mRNA(Blalock et al. 2004)	Binds to LPA(Reblin et al. 1997), APOB, APOE (Defesche 2004). Mediates the increase in the astrocytic expression of APOE induced by beta-amyloid (LaDu et al. 2000). AICD interacts with ARH an adaptor protein for LDLR(Noviello et al. 2003) Major role in cholesterol uptake via binding to APOB and APOE containing particles (Defesche 2004)	HSV-1 infection increases LDLR expression and transcription in arterial smooth muscle cells Hsu et al, 1995
LRP2 low density lipoprotein receptor-related protein 2 gp330, megalin 2q24.31	Vargas et al, 2010			Clusterin receptor. Binds to APOB, APOE, APOH, LRPAP1, LPA and LPL
LRP6 low density lipoprotein receptor-related protein 6 Biogrid GeneCards 12p11-p13	DeFerrari et al, 2007	Mani et al, 2007		Cleaved by gamma-secretase-like activity releasing an intracellular fragment that inhibits GSK3B Mi and Johnson, 2007
LRP8 (APOER2) Biogrid GeneCards 1p34	(Ma et al. 2002)		Decreased hippocampal mRNA(Blalock et al. 2004)	Cleaved by gamma secretase (Kinoshita et al. 2003). Brain localised APOE receptor(Kim et al. 1996)Associated with LRPAP1 (Andersen et al. 2003)
LRPAP1: Low density lipoprotein receptor-related protein associated protein 1 (RAP) Biogrid GeneCards 4p16.3	(Sanchez et al. 2001)	-		Universal low density lipoprotein receptor antagonist and chaperone (LDLR, LRP1,LRP8, VLDLR) (Bu 1998;Bu 2001;Medh et al. 1995) Controls APP/LRP1 association (Goto and Tanzi 2002)
LRP1 low density lipoprotein-related protein 1 (alpha-2-macroglobulin receptor) Biogrid GeneCards 12q13-q14	(Bi et al. 2001)	(Schulz et al. 2002)	Associated with senile plaques(Arelin et al. 2002)Increased protein levels in frontal cortex(Qiu et al. 2001)	APOE receptor (Myklebost et al. 1989)Binds A2M, LPL and VLDL (Nykjaer et al. 1993). Associated with APP(Rebeck et al. 2001) Exports amyloid/A2M complexes(Shibata et al. 2000) Cleaved by gamma secretase and BACE1 (Lleo et al. 2005;May et al. 2003;von Arnim et al. 2005)
LRP1B low density lipoprotein receptor-related protein 1B 2q21.2	Associated with succesful ageing without AD Poduslo et al, 2010			Retains APP at the cell surface and prevents abeta formation Cam et al, 2004 Binds to PLAU, PLAT and SERPINE1 Liu et al, 2001 and to LRPAP1Liu et al, 2001
OLR1 oxidised low density lipoprotein (lectin-like) receptor 1 (LOX1; SCARE1) Biogrid GeneCards	(Lambert et al. 2003)	(Chen et al. 2003)	Decreased expression in lymphocytes in individulals with the Alzheimer's associated polymorphism (Lambert et al. 2003)	Oxidised LDL Receptor (Moriwaki et al. 1998;Yamada et al. 1998)	HSV-1 increases OLR1 expression in endothelial cells Chirathaworn et al, 2004
RFTN1 Raftlin lipid raft linker 1 GeneCards	Wollmer et al, 2007			Involved in lipid rafts and BCR signallingSaeki et al, 2003
SORL1 sortilin-related receptor, (LDLR class) A repeats-containing OMIM Biogrid GeneCards	Rogaeva et al, 2007		Reduced expression in lymphocytes and cerebral tissue Scherzer et al, 2004	Mediates the uptake of APOE-enriched lipoproteins Taira et al, 2001. Binds to LRPAP1 Jacobsen et al, 1996 and BACE1 Spoelgen et al, 2006.Regulates APP processing Andersen et al, 2005 Gamma-secretase substrate Nyborg et al, 2006 Binds to PLAUR and PAI-1 (SERPINE1)Gliemann et al, 2004
VLDLR very low density lipoprotein receptor Biogrid GeneCards	(Yamanaka et al. 1998)		Localised in senile plaques (Vassar et al. 1999) Decreased hippocampal mRNA(Blalock et al. 2004)	Binds APOE, Lipoprotein (a) (LPA), LPL, and serpin/protease complexes. Also binds to LRPAP1 (Rettenberger et al. 1999)and APOC1 (Jong et al. 1999b)
DAB1 disabled homolog 1	GWAS study: Harold et al, 2009			Adaptor protein for APP, LRP1, LRP2, LRP8, LDLR, VLDLR
LPL lipoprotein lipase Biogrid GeneCards	(Baum et al. 1999)	(Peacock et al. 1992)	Increased hippocampal mRNA(Blalock et al. 2004)	Bridging factor for lipoprotein receptor mediated lipoprotein uptake. Binds to LRP1 (Williams et al. 1994)and gp330 (Kounnas et al. 1993)Activated by APOC2 (Fitzharris et al. 1981)Inhibited by APOE(Jong et al. 1997). Cholesterol prevents APOC2 binding to LPL (Arimoto et al. 1998)Increases the capture of HDL cholesteryl esters in the liver via binding to heparan sulphate proteoglycans (Rinninger et al. 1998a;Rinninger et al. 2001;Rinninger et al. 1998b) Localised to astrocytes , microglia and hippocampal pyramidal neurones (Blain et al. 2004;Yacoub et al. 1990)
CH25H cholesterol 25 hydroxylase Biogrid GeneCards Metabolome	(Papassotiropoulos et al. 2004)		Increased hippocampal mRNA(Blalock et al. 2004)	25-hydroxycholesterol stimulates APOD secretion from astrocytes (Patel et al. 1995) and of APOE in a human astrocytoma cell line (Gueguen et al. 2001). 25-hydroxycholesterol suppresses transcription of cholesterol synthetic enzymes and increases HMGCR degradation (Taylor 1992).
CYP46A1 cytochrome P450, family 46, subfamily A, polypeptide 1 Biogrid GeneCards Metabolome	(Papassotiropoulos et al. 2003)	24-(s)hydroxycholesterol and atherosclerosis	Shift of localisation from neurones to glia in AD brain (Bogdanovic et al. 2001)Increased CSF levels of the product 24S-hydroxycholesterol (Schonknecht et al. 2002)	Major cholesterol metabolising enzyme in brain (Lund et al. 2003). The CYP46 polymorphism is associated with increased brain beta-amyloid load and increased CSF levels(Papassotiropoulos et al. 2003)
HSD11B1 11-beta-Hydroxysteroid Dehydrogenase Type 1 Biogrid GeneCards	(de Quervain et al. 2004)			7-beta-hydroxycholesterol, the product of cholesterol oxidation by APP is metabolised by type 1 11-hydroxysteroid dehydrogenase(s) (HSD11B1) to the corresponding keto derivative (Hult et al. 2004)
LIPA lipase A, lysosomal acid, cholesterol esterase Biogrid GeneCards	(Li et al. 2004a)	(Bian et al. 2004) ,		Catalyzes the hydrolysis of cholesteryl esters and triglycerides
LIPC Hepatic lipase	Zhu et al, 2008			Binds to APOB and carried by LRP1
CETP cholesteryl ester transfer protein Biogrid GeneCards	(Rodriguez et al. 2005)	(Boekholdt et al. 2004)Tsai et al, 2008	High astrocytic expression in white and gray matter (Yamada et al. 1995)	Expression controlled by SREBF1 (Gauthier et al 1999)
SOAT1: sterol O-acyltransferase (acyl-Coenzyme A: cholesterol acyltransferase) 1 Biogrid GeneCards	(Wollmer et al. 2003b)			Modulates Abeta production via control of cholesterol/cholesteryl ester ratio (Puglielli et al. 2001): Metabolises cholesterol and oxysterols to esters (Cases et al. 1998;Zhang et al. 2003): Inhibitors reduce plasma cholesterol levels (Miyazaki et al. 2003)
PPP1R3A protein phosphatase 1, regulatory (inhibitor) subunit 3A (glycogen and sarcoplasmic reticulum binding subunit, skeletal muscle) (PP1G; PPP1R3) Biogrid GeneCards	(Liolitsa et al. 2002)			Dephosphorylates HMG CoA reductase? and glycogen synthase (Schelling et al. 1988): Not tested for recombinant protein.
MAPK8IP1 mitogen-activated protein kinase 8 interacting protein 1 Biogrid GeneCards	(Helbecque et al. 2003)		Decreased hippocampal mRNA(Blalock et al. 2004)	Associated with cytoplasmic domain of LRP1 and VLDLR(Stockinger et al. 2000). Binds to cytoplasmic domain of APP(Matsuda et al. 2001)	HSV-1 infection activates c-jun N-terminal kinase, an effect that enhances viral replication. MAPK8IP1 , a JNK inhibitor reduces viral yield McLean and Bachenheimer, 1999
APBA1 amyloid beta (A4) precursor protein-binding, family A, member 1 (X11) Biogrid GeneCards	Bertram et al, 2005			Stabilises APP and prevents proteolysis by gamma-secretase
APBB1: amyloid beta (A4) precursor protein-binding, family B, member 1 (Fe65) Biogrid GeneCards	(Hu et al. 1998)		No modification in cortex, increased immunoreactivity in hippocampus: Associated with paired helical filaments and not with APP or amyloid deposits (Delatour et al. 2001).	Linked to APP, LRP1 and LDLR (Trommsdorff et al. 1998). Repression of thymidylate synthase via interaction with TFCP2 (Bruni et al. 2002).Binds to ESR1 Bao et al, 2006
APBB2 amyloid beta (A4) precursor protein-binding, family B, member 2 (Fe65-like) Biogrid GeneCards	(Li et al. 2005)			Binds to cytoplasmic domain of APP (Guenette et al. 1996).Transfection decreases expression of LRP1 (Guenette et al. 2002)
APBB3 amyloid beta (A4) precursor protein-binding, family B, member 3 (Fe65L2) Biogrid GeneCards	(Tanahashi et al. 2002)			Repression of of thymidylate synthase probably via TFCP2 (Bruni et al. 2002;Zambrano et al. 1998). Linked to LRP1 (Tanahashi and Tabira 2002) and APP (Tanahashi and Tabira 1999)
CLSTN2 Calsyntenin 2 (alcadein) GeneCards	Liu et al, 2007			Cleaved by gamma-secretase liberating an intracellular fragment that inhibits FE65-dependent gene transactivation activity of the APP intracellular domain fragment Araki ey al, 2004
TFCP2 Transcription factor CP2 (CP2; LSF; LBP-1C; TFCP2C) Biogrid GeneCards	(Taylor et al. 2001)			Linked to LRP1 via LRPICD effects on FE65 mediated transcription (Kinoshita et al. 2003). Linked to APP effects via APBB's (Fe65 proteins) and AICD (Zambrano et al. 1998;Cao and Sudhof 2004)	Binds to HSV-1 origin of replication site Dabrowski et al, 1994
APH1A anterior pharynx defective 1 homolog A	Wang et al, 2009			Component of gamma secretase
APH1B anterior pharynx defective 1 homolog B GeneCards	Poli et al, 2007		Interacts with PSEN1 and NCSTN	Component of gamma secretase
PSEN1 Presenilin 1 Biogrid GeneCards	(Goate et al. 1989)		Primarily neuronally localised: No change in mRNA message in AD brain (Page et al. 1996): Overall protein expression similar in control and AD brains (Mathews et al. 2000): Strong expression in reactive astrocytes and tangles (Huynh et al. 1997) in AD. Immunoreactivity in neuritic components of plaques (Levey et al. 1997).	Part of gamma secretase complex (Kimberly and Wolfe 2003;Kimberly et al. 2003) involved in degradation of APP to cytotoxic peptides Gamma secretase is involved in APP, LRP1 and LRP8 processing (Kinoshita et al. 2003)	Gamma secretase cleaves the herpes viral receptor PVRL1 Kim et al, 2002
PSEN2 Presenilin 2 BiogridGeneCards	(Levy-Lahad et al. 1995)		Strong expression in reactive astrocytes and tangles –not in senile plaques (Huynh et al. 1997)	Mutation in familial AD (see OMIM) (OMIM 2004b) .
NCSTN Nicastrin Biogrid GeneCards	(Dermaut et al. 2002)		Increased hippocampal mRNA (Blalock et al. 2004)	Part of gamma secretase complex (Kimberly et al. 2003)	HSV-1 infection increases Bace1 and NCSTN expression in cells Wozniak et al, 2007
PSENEN presenilin enhancer 2 homolog (PEN2) GeneCards	Jia et al, 2007			Component of the gamma secretase complex
BACE1 beta-site APP-cleaving enzyme 1 Biogrid GeneCards	(Shi et al. 2004)		Similar mRNA expression in normal and AD brain (Preece et al. 2003; Gatta et al. 2002). Increased cortical protein expression and activity (Fukumoto et al. 2002a;Holsinger et al. 2002).	Cleaves APP and LRP1 (von Arnim et al. 2005). Binds to and is inhibited by NCSTN (Hattori et al 2002	HSV-1 infection increases Bace1 and NCSTN expression in cells Wozniak et al, 2007
BACE2 Biogrid GeneCards	(Myllykangas et al. 2005)			APP processing (does not generate beta-amyloid) (Sun et al. 2005a)
SREBF1 sterol regulatory element binding transcription factor 1 Biogrid GeneCards	(Spell et al. 2004)	(Rios et al. 2003)	Increased hippocampal mRNA(Blalock et al. 2004)	Major transcription factor controlling cholesterol synthesis and metabolism (Shimano 2002). Controls APO-AII and LDLR expression (Zannis et al. 2001)
CD36 CD36 antigen (collagen type I receptor, thrombospondin receptor) Biogrid GeneCards	(Taguchi et al. 2005)	(Lepretre et al. 2004)	Expressed on microglia in Alzheimer’s disease (Coraci et al. 2002): MRNA downregulated in hippocampus (Taguchi et al. 2005)	Scavenger receptor for oxidised lipoproteins and beta amyloid (Bamberger et al. 2003;Boullier et al. 2001): Also translocates long chain fatty acids.

Folate and homocysteine metabolism

Gene	Alzheimer's	Atherosclerosis	Changes in AD	Related to other genes	Herpes simplex
MTHFD1L methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-like	Beecham et al, 2009
CBS Cystathione beta synthase GeneCards	Beyer et al, 2004	Kelly et al, 2003		Homocysteine stimulates HMG CoA reductase HMGCR activity and cholesterol synthesis and secretion in hepatic cells and expression of HMGCR, SREBF1 and SREBF2, FDPS and IDI1 (Werstuck et al. 2001;O K et al. 1998) Plasma homocysteine is transported by lipoproteins (Ventura et al. 2003): Homocysteine promotes iron dependent oxidation of LDL (Alul et al. 2003), stimulates the secretion of APOB in hepatic cells (O K et al. 1998), increases the expression of LPL in macrophages (Beauchamp and Renier 2002)nd OLR1 in aortic endothelial cells (Nagase et al. 2001).
MTHFR 5,10-methylenetetrahydrofolate reductase (NADPH) Biogrid GeneCards	(Regland et al. 1999)	(Inamoto et al. 2003)	Decreased folate and increased homocysteine levels in Alzheimers disease plasma (McCaddon et al. 2002)
MTR methionine synthase Biogrid GeneCards	(Bosco et al. 2004)
MTRR 5-methyltetrahydrofolate-homocysteine methyltransferase reductase Biogrid GeneCards	(Beyer et al. 2003)
NAT2 N-acetyltransferase 2 (arylamine N-acetyltransferase) Biogrid GeneCards	(Rocha et al. 1999)		The endogenous substrate for NAT2 is the folate catabolite p-aminobenzoylglutamate (PABG) which is acetylated by the enzyme (Payton et al, 1999, Estrada-Rodgers at al, 1998). PABG is derived from 7,8 dihydrofolate, the substrate of hymidylate synthase (TS), the target of TFCP2.

Table 2. Growth factors and growth factor signalling

Gene	Alzheimer's disease	Atherosclerosis/ hypercholesterolemia	Modifications in AD	Relationships with other gene products	HSV-1
BDNF Brain derived neurotrophic factor Biogrid GeneCards 11p13	(Riemenschneider et al. 2002)		Reduced protein and mRNA levels in AD brain (Hock et al. 2000)	Systemic injection lowers total serum cholesterol in mice (Tsuchida et al. 2002). Binds to A2M, the ligand of LRP1(Wolf and Gonias 1994). Stimulates APP expression (Ruiz-Leon and Pascual 2004;Ruiz-Leon and Pascual 2001): Induced by icv infusion of beta amyloid (Tang et al. 2000). BDNF reglutaion of cholesterol synthesis in lipid rafts plays an importnat role in synapse development Suzuki et al, 2007
NTRK2 neurotrophic tyrosine kinase, receptor, type 2 GeneCards	Chen et al, 2007			BDNF receptor
CCL2 chemokine (C-C motif) ligand 2 GDCF-2, HC11, HSMCR30, MCAF, MCP-1, SCYA2, SMC-CF Biogrid GeneCards17q11.2-q12	Pola et al, 2004	Brenner et al, 2006		Implicated in the pathogenesis of diseases characterized by monocytic infiltrates, like psoriasis, rheumatoid arthritis and atherosclerosis. Binds to chemokine receptors CCR2 and CCR4.	The U83 gene of HHV-6 encodes a CCL2 mimic acting via CCR2 Luttichau et al, 2003. CCL2 enhances HSV-1 infectivity in mice Nakijama et al, 2001.
CCL3 chemokine (C-C motif) ligand 3 Mip-1 aplha17q11-q21	Li et al, 2008
CCR2 chemokine (C-C motif) receptor 2 Biogrid GeneCards3p21.31	Galimberti et al, 2004	Pai et al, 2006		Receptor for CCl2
FGF1 Fibroblast growth factor 1 Biogrid GeneCards 5q31	(Yamagata et al. 2004)		Expressed in reactive astrocytes around senile plaques (Kimura et al. 1994); Increased hippocampal mRNA(Blalock et al. 2004)	Increases APOE expression and release in astrocytes (Tada et al. 2004): Oxidised LDL complexes FGF1 and inhibits its activity (Ananyeva et al. 2003); Increases cholesterol synthesis in astrocytes (Ueno et al. 2002)
GRN (Pro)Granulin 17q21.32	Brouwers et al, 2008			Binds to HSPG2 Gonzalez et al, 2003
IGF1 insulin-like growth factor 1 (somatomedin C) 12q22-q23	Giedratis et al, 2009
NTRK1 neurotrophic tyrosine kinase, receptor, type 1 1q21-q22	Cozza et al, 2008			NGF receptor
TRPC4AP transient receptor potential cation channel, subfamily C, member 4 associated protein GeneCards20q11.22	Poduslo et al,2008 (WGA in late-onset pedigree)			Scaffolding potein for TNF receptors, binding to TRAD and TRAF2 Soond et al, 2003
TRAF2 TNF receptor-associated factor 2 GeneCards9q34	Culpan et al, 2007			Mediates signaling from numerous TNF receptors. Binds to TRPC4AP	Binds to many TNF receptors including the Herpes Viral entry mediator TNFRSF14
TGFB1 transforming growth factor, beta 1 Biogrid GeneCards 19q13.1 19q13 reviewed by (Bertram and Tanzi 2004)	(Luedecking et al. 2000)	(Andreotti et al. 2002)	Decreased plasma levels (De Servi et al. 2002)Elevated protein an AD brain microvessels (Grammas and Ovase 2002) intrathecal space (Tarkowski et al. 2002),CSF and serum levels (Chao et al. 1994) . Increased mRNA in entorhinal cortex and temporal gyrus (Luterman et al. 2000)Increased protein staining in tangle-bearing neurones (Flanders et al. 1995).	Decreases expression of OLR1 (Minami et al. 2000). Stimulates LDLR expression (Ruan et al. 1998). Oxidised LDL increases expression (Ding et al. 1997): Sequesterd by lipoproteins (Grainger et al. 1997).Binds to A2M (Arandjelovic et al. 2003). Stimulates release of APOE in macrophages(Zuckerman et al. 1992). Decreases expression of CYP11A1 (Naaman-Reperant et al. 1996), LCAT (Skretting et al. 1995), STAR (Brand et al. 1998). Increases expression of ABCA1 (Panousis et al. 2001). Expression increased by oxysterols (Leonarduzzi et al. 2001); Stimulates APP expression (Ge and Lahiri 2002): Potentiates amyloid beta generation (Lesne et al. 2003) and accelerates microglial beta amyloid clearance	The HSV-1 latency-associated transcript encodes a microrna for TGFB1 with anti-apoptotic functions Gupta et al, 2006.
VEGFA Biogrid GeneCards6p12.	Chiapelli et al, 2006			Regulates Zhou et al, 2004and is regulated by SREBF1 Motoyama et al, 2006	Herpes simplex viral DNA promotes angiogenesis by increasing the expression of VEGF, an effect attributed to a direct effect of unmethylated cPG motifs in the viral DNA Zheng et al, 2002.
GAB2 GRB2-associated binding protein 2 Biogrid ) GeneCards 11q14.1	Reiman et al, 2007			adapter protein acting downstream of cytokine and growth factor receptors and T- and B-cell antigen receptors FCER1G.
GSK3B Glycogen synthase kinase 3 beta Biogrid GeneCards 3q13.3	(Mateo et al. 2006)		Associated with hyperphosphorylated tau (MAPT)in alzheimers disease , Picks disease and other tauopathies (Ferrer et al. 2002)	Growth factor and related signalling. GSK3B expression (tau kinase) is controlled by TFCP2 (Lau et al. 1999) and thus by FE65 proteins associated with APP. Phosphorylates MAPT
PIK3R1 phosphoinositide-3-kinase, regulatory subunit, polypeptide 1 (p85 alpha) Biogrid GeneCards 5q13.1	(Liolitsa et al. 2002)	PIK3R1 cholesterol	Reduced activity of soluble form in fontal cortex (Zubenko et al. 1999)	Cytokine and growth factor signalling. Lipoprotein receptor signaling (Mineo et al. 2003). Involved in the anti-apoptotic effects of APP (Kashour et al. 2003) .PI3 kinase activation by insulin increases the secretion of soluble APP (Solano et al. 2000)	HSV-1 infection produces a transient phosphorylation of ser473 of the AKT1 kinase, an effect that is PI3K dependendent.Activation of this survival pathway may act to prevent apoptosis. The particular isoform of PI3K was not specified.Benetti and Roizmann, 2006 : HSV-1 toxicity is increased in PIK3R1 knockout fibroblasts Prejean et al, 2001
SOS2 guanine nucleotide exchange factor; guanine nucleotide releasing factor; son of sevenless homolog 2 GeneCards14q21	Hamilton et al, 2007			SOS couples tyrosine kinases to Ras activation

Table 3 Nuclear receptors and transcription factors associated with Alzheimer’s disease

Nuclear receptors	Alzheimer's disease	Atherosclerosis/ hypercholesterolemia	Modifications in AD	Relationships with other gene products	HSV-1
AR androgen receptor (dihydrotestosterone receptor Biogrid GeneCards	(Lehmann et al. 2004)		Decreased cytoplasmic staining in nucleus basalis and diagonal band of Broca in AD women but not men (Ishunina et al. 2002). Decreased testosterone levels in male AD patients are associated with risk (Okun et al. 2004;Moffat et al. 2004) and with increased plasma levels of beta amyloid (Gillett et al. 2003)	Regulation of cholesterol synthetic machinery in the periphery via the control of SREBF1 and sterol regulatory element-binding protein cleavage-activating protein (SCAP) (Heemers et al. 2004;Heemers et al. 2006). Both estrogen and androgens protect neurones from beta-amyloid toxicity via steroid receptor activation (Zhang et al. 2004b).
ESR1 estrogen receptor 1 (ER; ESR; Era; ESRA; NR3A1) Biogrid GeneCards	(Mattila et al. 2000)	(Lehtimaki et al. 2002)	Increased expression in diagonal band of Broca neurones (Ishunina and Swaab 2003)and hippocampal astrocytes (Lu et al. 2003)	Estrogen response elements or control of transcription by estrogen have ben observed for ABCA1(Srivastava 2002), APOE, LDLR (Levin-Allerhand et al. 2001) (Bruning et al. 2003). HMG CoA reductase (Di Croce et al. 1999) a high-density lipoprotein receptor (SCARB1) (Lopez et al. 2002) (inter alia). An ESR1 selective ligand reduces plasma cholesterol levels in rats (Harris et al. 2002). Binds to APBB1 Bao et al, 2006
ESR2 estrogen receptor 2 (ER beta) Biogrid GeneCards	(Pirskanen et al. 2005)			APOE is deposited along cerebral vessels and beta-amyloid1-42 accumulates in cortical and limbic regions in ESR2 knockout mice (Zhang et al. 2004a).
CYP19A1 (Aromatase: estrogen synthesis cf ESR1, ESR2). Biogrid GeneCards	(Iivonen et al. 2004) .	(Maffei et al. 2004)	Reduced CSF levels of 17beta-estradiol (E2) in female patients (Schonknecht et al. 2001)	Estrogen increases alpha-secterase activity (Hooper and Turner 2002) and protects against beta amyloid neurotoxicity (Marin et al. 2003)
NR1H2 Liver X receptor beta Biogrid GeneCards	(Adighibe et al. 2005)			LXR receptors positively control the transcription of many genes related to fatty acid and cholesterol function including ABCA1 and many lipoproteins including the APOE, APOC1, APOC2, APOC4 gene cluster and APOD (Mak et al. 2002;Hummasti et al. 2004;Tang et al. 2004;Liang et al. 2004).
POU2F1 Pou domain Class 2, transcription factor1 Biogrid GeneCards	(Taguchi et al. 2005)		MRNA downregulated in hippocampus (Taguchi et al. 2005)	Regulates the transcription of OLR1 Chen et al, 2006 LPLPreviato et al,1991) . Binding site in promoter region of BACE2 ( (Maloney et al, 2006)	HSV-1 VP16 incorporates POU2F1 and HCF1 which activates the transcription of viral genes Wysocka and Herr, 2003
PPARA peroxisome proliferative activated receptor, alpha Biogrid GeneCards	(Brune et al. 2003)	(Flavell et al. 2002), PPAR and atherosclerosis		Major regulator of lipid and lipoprotein metabolism (Gervois et al. 2000). LPL generated lipoprotein metabolites are PPARA ligands (Ziouzenkova et al. 2003). In peripheral cells activation increases expression of ABCA1 (Kok et al. 2003)HMGCS(Cullingford et al. 2002)HSD17B4 (Corton et al. 1996), CYP8B1(Hunt et al. 2000)Downregulates CYP7a1 (Marrapodi and Chiang 2000)Reduces SOAT1 activity(Chinetti et al. 2003). Polyunsaturated fatty acids are potent PPARA activators (Forman et al. 1997). Low levels of polyunsaturated fatty acids have been associated with an increased incidence of Alzheimer’s disease (Kyle et al. 1999;Tully et al. 2003) and fish diets rich in these compounds (n3-omega fatty acids) have been reported to reduce the incidence of Alzheimer’s disease (Morris et al. 2003). A selective PPARA agonist increased the levels of HDL-cholesterol (“good cholesterol”) in mice.
PPARG peroxisome proliferative activated receptor, gamma Biogrid GeneCards	Modifies age of onset (Koivisto et al 2006)			NSAIDS, whose use may delay the onset of AD (Mcgeer et al, 2006)aree PPARG agonists (Townsend and Pratico, 2005). Promotes ABCA1, CD36 Hodginson and Ye 2003) APOE (Lahiri, 2004), BACE1 (Sastre et al, 2006)LIPA Ghosh , 2001) LPL(Schoonjans et al,1996) POU2F21 (Bruemmer at al, 2003) Represses CYP19A1(Fan et al, 2002).
RXRA retinoid X receptor, alpha GeneCards	Kolsch et al 2008			Interacts with POU2F1,PARP1, PPARA, PPARG and VDR (see gene data)Important role in glucose, fatty acid and cholesterol metabolism Ahuja et al, 2003
VDR vitamin D (1,25- dihydroxyvitamin D3) receptor GeneCards	Gezen-Ak et al, 2007			Role in mineral physiology and also in immune system and growth

Table 4: Oxidative stress genes

Peroxidases, free radical	Alzheimer’s disease	Atherosclerosis	Modifications in AD	Relationships with other gene products	HSV-1
GSTM1 glutathione S-transferase M1 Biogrid GeneCards	Bernardini et al, 2005	De Waart et al, 2001			HSV infection results in a large and rapid reduction in cellular glutathione levels in host cells. Glutathione has a dramatic inhibitory effect on Herpes viral replication in vitro, while S-acetylglutathione, a prodrug that increases cellular glutathione levels is effective following systemic injection in mice Palamara et al, 1995. Vogel et al, 2005
GSTM3 glutathione S-transferase M3 (brain) GeneCards	Hong et al, 2007
GSTO1 glutathione S-transferase omega1 GeneCards	Li et al 2003
GSTP1 glutathione S-transferase pi 1	Bernardini et al, 2005
GSTT1 glutathione S-transferase theta 1 GeneCards	(Stroombergen and Waring 1999)	(Olshan et al. 2003)
HMOX1 heme oxygenase (decycling) 1	Infante at al, 2010	Schillinger et al, 2002		Cleaves heme to form biliverdin
IREB2 iron-responsive element binding protein 2 Biogrid GeneCards	Coon et al 2006		Associated with damaged neurones and tangles (Smith et al, 1998)
MPO Myeloperoxidase GeneCards	(Reynolds et al. 2000)	(Inamoto et al. 2003)	Reduced activity in Alzheimer's disease neutrophils (Davydova et al. 2003)Increased protein levels in brain (Green et al. 2004)	Lipoprotein oxidation, particularly APOE (Jolivalt et al. 1996). Peroxidation of beta amyloid may be involved in cross linking and fibre formation(Galeazzi et al. 1999)
NFE2L2 nuclear factor (erythroid-derived 2)-like 2	Influences disease progression Van Otter et al, 2010
NOS1 Biogrid GeneCards	(Galimberti et al. 2005)			See below	Activation of neuronal NOS inhibits HSV-1 replication in neurones Komatsu et al, 1996. Nitric oxide inhibits viral replication Torre et al, 2002, possibly by S-nitrosylation of viral proteins Colasanti et al, 1999
NOS2 nitric oxide synthase 2, inducible	Beecham et al, 2009
NOS3 nitric oxide synthase 3 (endothelial cell, eNOS) OMIM 163729 Biogrid GeneCards	(Dahiyat et al. 1999)	(Spiridonova et al. 2001a)	Increased astrocytic expression (Luth et al. 2001)	Nitric oxide: Lipoprotein pro- or antioxidant depending on oxidative statusBloodsworth et al. 2000)Stimulated by HDL (Mineo and Shaul 2003) and inhibited by LDL) (Balligand 2002)and oxidized lipoproteins (Balligand 2002;Mukherjee et al. 2001). NO downregulates LPL (Uchida et al. 1997)
NQO1 NAD(P)H dehydrogenase, quinone 1 (Also involved in Vitamin K (phylloquinone) metabolism) Biogrid GeneCards	(Ma et al. 2003)		Activity increased in the Alzheimer's disease brain (SantaCruz et al. 2004;Wang et al. 2000;Raina et al. 1999)	Vitamin K binds to APOE (Lamon-Fava et al. 1998) and stimulates pregnane X receptors leading to CYP3A4 activation and LXR activation.(Landes et al. 2003). Vitamin K reduces cholesterol levels (Kawashima et al. 1997).
PON1 paraoxonase 1 Biogrid GeneCards	(Scacchi et al. 2003)	(Oliveira et al. 2004)	Reduced serum paraoxonase activity (Paragh et al. 2002).	Protects against Lipoprotein Oxidation (Aviram et al. 1998). Hydrolyses oxidized cholesterol in oxidized LDL (Josse and Masson 2001;Oda et al. 2002;Navab et al. 2000;Mackness et al. 2000)Inhibits cholesterol biosynthesis in macrophages (Rozenberg et al. 2003)
PON2 paraoxonase 2 GeneCards	(Janka et al. 2002)	(Janka et al. 2002)	Decreased hippocampal mRNA(Blalock et al. 2004)	Protects Lipoprotein Oxidation (Ng et al. 2001)
PON3 paraoxonase 3	Erlich et al, 2006			Associates with HDL and inhibits LDL oxidation
SOD2 superoxide dismutase 2, mitochondrialBiogrid GeneCards	Wiener et al, 2007
STH saitohin GeneCards	Combarros et al, 2003			Unknown function but interaction with peroxiredoxin 6 suggests a role in antioxidant function Gao et al, 2005.
TF: Transferrin Biogrid GeneCards	(Hussain et al. 2002)		Decreased protein in cortical white matter (Connor et al. 1992b) localised to glial fibrillary tangles (Nishimura et al. 1995). Found in astrocytes in AD and oligodendrocytes in normal brain (Connor et al. 1992a).	Lipoprotein oxidation by iron released from transferrin in acidic conditions (Lamb and Leake 1994;Leake 1997).
HFE: hemochromatosis Biogrid GeneCards	(Pulliam et al. 2003)	(Finsterer et al. 2004)	Increased hippocampal mRNA(Blalock et al. 2004)
ALDH2 aldehyde dehydrogenase 2 family (mitochondrial) Biogrid GeneCards	(Kamino et al. 2000)	(Narita et al. 2003)	Aldehyde dehydrogenase activity is increased in the temporal cortex (Picklo et al. 2001) although it is not clear which form is concerned. Decreased hippocampal mRNA(Blalock et al. 2004)	Lipoprotein oxidation ALDH2 polymorphisms influence the amount of lipoprotein-acetaldehyde adducts (Nagata et al. 1999).

Table 5: Proteases and protease inhibitors and activators associated with Alzheime's disease. (See Table 1 for PSEN1, PSEN2, BACE, NCSTN)

Gene	Alzheimer's disease	Atherosclerosis/ hypercholesterolemia	Modifications in AD	Relationships with other gene products	HSV-1
ACE angiotensin I converting enzyme (peptidyl-dipeptidase A) 1 (DCP; ACE1; DCP1; CD143;) Biogrid GeneCards	(Elkins et al. 2004) (Meta-analysis )	(Cambien and Evans 1995)	Inverse association between the use of ACEinhibitors and the incidence of Alzheimer's disease(Broe et al. 2000). Increased immunoreactivity for ACE in AD parietal cortex (Savaskan et al. 2001), increased ACE density measured by inhibitor binding in temporal cortex (Barnes et al. 1991). Increased ACEactivity in frontal cortex, hippocampus and caudate (Arregui et al. 1982). Decreased CSF levels (Zubenko et al. 1985)	Degrades amyloid beta peptide (Hu et al. 2001)ATII regulates the expression of HMGCR (Keidar et al. 1999) and activates cholesteryl ester hydrolase (Cherradi et al. 2003): Hypercholesterolemia upregulates ATII (Niebauer et al. 2001). ATII reduces blood cholesterol levels in dogs (Singh et al. 1977), and decreases cholesterol efflux from macrophages in mice (Kaplan et al. 2002). Angiotensin II increases OLR1 (Mehta and Li 2002) and scavenger receptor (SCARB1) expression (Cherradi et al. 2001).AT II is bound to LDL (Osman et al. 2002) and increases the uptake and oxidation of LDL by macrophages (Keidar and Attias 1997). OLR1 activation increases ACE expression (Li et al. 2003).
AGT angiotensinogen (serpin peptidase inhibitor, clade A, member 8)	Taylor et al, 2001 weak
ADAM9 ADAM metallopeptidase domain 9 (meltrin gamma)	Cong et al, 2009			Alpha secretase activityHotoda et al, 2002
ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) Biogrid GeneCards	Harold et al, 2007		Reduced cortical protein expression Malinin et al, 2005	Binds to and activates PIK3R1Kang et al, 2001 Plays a role in beta-amyloid toxicity with SH3PXD2A Malinin et al, 2005
SH3PXD2A SH3 and PX domains 2A (FISH, SH3MD1) GeneCards	Harold et al, 2007			Binds to ADAM12 and involved in Abeta toxicity Malinin et al, 2005
BLMH Bleomycin hydrolase Biogrid GeneCards	(Papassotiropoulos et al. 2000a)		Localised in senile plaques: No significant change in mRNA expression in brain (Malherbe et al. 2000;Namba et al. 1999).	Increases APP degradation (Lefterov et al. 2000).
CARD8 caspase recruitment domain family, member 8	Fontalba et al, 2009			Caspase activator
CST3 cystatin C (amyloid angiopathy and cerebral hemorrhage) (Cathepsin S inhibitor) Biogrid GeneCards	(Beyer et al. 2001)	(Eriksson et al. 2004)	Increased cystatin immunostaining in vulnerable neurones (Deng et al. 2001;Malherbe et al. 2000)	Inhibits cathepsin S which is involved in APP processing and degradation of beta amyloid (Liuzzo et al. 1999;Munger et al. 1995). Binds to C4A Ghiso et al, 1990	Blocks HSV-1 replication Blorck et al, 1990
CTSS cathepsin S Biogrid	Grupe et al, 2007		Cathepsin S immunoreactivity is increased in cortical and hippocampal neurones and glia (Lemere et al. 1995).	Cathepsin S inhibits cholesterol efflux from mouse macrophages (Lindstedt et al. 2003). Cathepsin S degrades APOA-I (Lindstedt et al. 2003). Cathepsin S knockouts reduce atherosclerosis in LDL receptor knockout mice (Sukhova et al. 2003)
CTSD cathepsin D (lysosomal aspartyl protease) Biogrid GeneCards	(Crawford et al. 2000) (Papassotiropoulos et al. 2000b;Poduslo et al. 2004)		Increased expression in reactive astrocytes (Diedrich et al. 1991) RNA and immunoreactivity increased in neurones(Haas and Sparks 1996;Cataldo et al. 1995;Nakamura et al. 1991), localised to plaques (Bernstein et al. 1989); Increased levels in CSF(Schwagerl et al. 1995)	Lipoprotein and apolipoprotein degradation (Dekroon and Armati 2001;Schneider 1992;Tertov and Orekhov 1997;Van Lenten and Fogelman 1990).APP processing (Chevallier et al. 1997)
ECE1 endothelin converting enzyme 1 GeneCards	Scacchi et al, 2008			Involved in the production of active endothelin. Degrades beta-amyloidEckman et al, 2001. Expression increased by LDL and oxidised lipoproteins in endothelial cells Niemann et al, 2005
IDE. Insulin degrading enzyme Biogrid GeneCards	(Clarimon et al. 2003b)		Reduced activity in cytosolic extracts and reduced expression in hippocampus (Perez et al. 2000)	Degrades beta amyloid and AICD (Edbauer et al. 2002) Binds to AR (see biogrid)	Receptor for varicella :also binds HSV-1 glycoprotein E Li et al, 2006
MME membrane metallo-endopeptidase-like 2 (neprilysin) (NEP; CD10; CALLA) Biogrid GeneCards	(Clarimon et al. 2003b)	Neprilysin/ cholesterol	Expressed in senile plaques. Reduced expression in hippocampal neurones and cerebral vasculature: Evidence for oxidative damage to Neprilysin in AD brain (Wang et al. 2003;Carpentier et al. 2002;Akiyama et al. 2001)	Beta amyloid catabolism(Evin and Weidemann 2002). SREBP processing (Yamaguchi et al. 1999) . Interacts with PIK3R1 (see Biogrid)
MMP1 matrix metallopeptidase 1 (interstitial collagenase) Biogrid GeneCards	Flex et al, 2006	Pearce et al 2005
MMP3 stromelysin Biogrid GeneCards	(Saarela et al. 2004)	(Humphries and Morgan 2004)	Component of senile plaques (Yoshiyama et al. 2000)	Reduces cholesterol induced HDL efflux from foam cells by degrading APOA1 (Lindstedt et al. 1999)
PLAT (tPA) plasminogen activator, tissue Biogrid GeneCards	Shibata et al, 2006			Converts plasminogen to plasmin. PLAT/SERPINE1complexes are internalised by LRP1 Orth et al, 1992	Pai-1 and TPA levels are decreased in endothelial cells by HSV-1 infection Bok et al, 1993
PLAU plasminogen activator, urokinase Biogrid GeneCards	(Finckh et al. 2003).		Plasmin levels are decreased in the Alzheimer's disease brain (Ledesma et al. 2000).	Activates Plasmin which is involved in APP processing and beta amyloid degradation (Ledesma et al. 2000) . Plasmin reduces HDL-induced cholesterol efflux from foam cells(Lindstedt and Kovanen 2000). Plasmin degrades APOAI (Lijnen and Collen 1981) and LDL (Kruth 2002). PLAU/plasminogen activator inhibitor complexes bind to (VLDLR) which mediates their endocytosis (Kasza et al. 1997)
PRSS7 enterokinase Biogrid GeneCards	Grupe et al, 2007			Converts trypsinogen to trypsin
SERPINA1serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 1	Kowalska et al, 1996			Targets include elastase, plasmin, thrombin, trypsin, chymotrypsin, and plasminogen activator.
SERPINA3 (ACT; AACT) alpha-1-antichymotrypsin Biogrid GeneCards	(Jiang et al. 1999)		Increased plasma levels (Licastro et al. 2000): Increased serum and CSF levels correlated with disease severity (DeKosky et al. 2003): Localised increases in plaques and in reactive astrocytes (Hwang et al. 1999;Licastro et al. 1998;Abraham et al. 1988) Increased hippocampal mRNA(Blalock et al. 2004)	Binds to Beta amyloid: Inhibits chymotrypsin which degrades APP and amyloid beta (Matsubara et al. 1996). Chymotrypsin degrades APOAI (Stoffel and Niedel 1985), APOE (Harris et al. 2003;Clement-Collin et al. 1999)and lipoprotein lipase (Lookene and Bengtsson-Olivecrona 1993). Beta-amyloid SERPINA3 comlexes bind to PPARG and activate genes involved in cholesterol metabolism and transport including LDLR and HMGCR (Sun et al. 2002a;Sun et al. 2002b) .
SERPINE1 serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1)PAI-1 Biogrid GeneCards	Shibata et al, 2006	Gardemann et al, 1999		Binds to LRP1, inhibits PLAU: PLAT/SERPINE1 complexes are internalised by LRP1 Orth et al, 1992	Pai-1 and TPA levels are decreased in endothelial cells by HSV-1 infection Bok et al, 1993
SERPINF2 serine (or cysteine) proteinase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 2 Biogrid GeneCards	Shibata et al, 2006

Genes involved in glucose metabolism, acetyl CoA shuttling and acetylcholine metabolism associated with Alzheimer's disease. Cholinergic receptors

Cholinergic	Alzheimer's disease	Atherosclerosis/ hypercholesterolemia	Modifications in AD	Relationships with other gene products	HSV-1
CHAT choline acetyltransferase Biogrid GeneCards	(Kim et al. 2004)		Massive loss of cholinergic neurones and CHAT activity (Bowen and Davison 1980)		HSV1 infection reduces choline acetyltransferase (CHAT) and acetylcholinesterase ACHE acivity in PC12 cell Rubenstein and Price, 1984
BCHE Butyrylcholinesterase GeneCards	(Tilley et al. 1999)	(Nassar et al. 2002)	Localised to plaques and tangles in AD (Wright et al. 1993)
CHRFAM7A CHRNA7 (cholinergic receptor, nicotinic, alpha 7, exons 5-10) and FAM7A	Feher et al, 2009
CHRNA7 cholinergic receptor, nicotinic, alpha 7	Barabash et al, 2007
DLD Dihydrolipoamide dehydrogenase Biogrid GeneCards	Brown et al, 2004		See below	Component of the pyruvate dehydrogenase complex, the alpha-ketoglutarate dehydrogenase complex, and the branched-chain alpha-keto acide dehydrogenase complex
DLST dihydrolipoamide S-succinyltransferase (E2 component of 2-oxo-glutarate complex) Biogrid GeneCards	(Cruts et al. 1995)		Marked reduction in peripheral and central activity of the alpha-ketoglutarate complex in Alzheimer's disease (Kish 1997;Ko et al. 2001;Gibson et al. 1998;Mastrogiacomo et al. 1993;Sheu et al. 1994)MIRTD mRNA expression is decreased in the Alzheimer's disease brain (Kanamori et al. 2003) (MIRTD is a gene within DLST).	Both cholesterol and acetyl choline are synthesised from acetyl CoA. If derived from glycolysis, this may entail a loss of Krebs cycle intermediates and problems in Coenzyme A recycling . Within the mitochondrial Krebs cycle, two enzyme complexes, the pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase complex are able to reincorporate coenzyme A into acetylCoA and Succinyl-CoA respectively. DLST forms a part of the alpha-ketoglutarate dehydrogenase complex which is enriched in cholinergic neurones in the brain (Calingasan et al. 1994) suggesting that it is central to the energetic problems of cholinergic neurones.
GAPD : Glyceraldehyde-3-phosphate dehydrogenase Biogrid GeneCards	(Li et al. 2004b) .		Reduced activity in fibroblasts (Mazzola and Sirover 2003). Nuclear accumulation in prefrontal cortex (Tsuchiya et al. 2004). Decreased hippocampal mRNA(Blalock et al. 2004)	Glycolytic enzyme whose activity will affect pyruvate and acetyl CoA availability.Binds to C-terminus APP (Schulze et al. 1993). Binds to oct-1 (POU2F1) which controls H2B (Zheng et al. 2003) and LPL (Arca-Sedda et al. 1996)expression. Binds to macrophage scavenger receptor (Nakamura et al. 2002)
GAPDH glyceraldehyde-3-phosphate dehydrogenase	Li et al, 2004
GAPDHS glyceraldehyde-3-phosphate dehydrogenase, spermatogenic	Li et al, 2004
PCK1 phosphoenolpyruvate carboxykinase 1 (soluble) GeneCards	Grupe et al, 2007
SNCA synuclein, alpha (non A4 component of amyloid precursor) Biogrid GeneCards	(Matsubara et al. 2001).	Synuclein/cholesterol	Abnormal accumulation in Alzheimer's disease brain: Component of plaques(Kaplan et al. 2003;Arai et al. 2001)Decreased hippocampal mRNA(Blalock et al. 2004)	Binds to PLD2 whose substrate Lecithin binds to APOE and APOA1(Jonas 1984). Binds to and inhibits PLD2 (Jenco et al. 1998) whose substrate Lecithin reacts with cholesterol to form cholesterol ester via LCAT: potential role in acetylcholine metabolism via links with lecithin. Interacts with APP, MAPK8IP1. MAPT and UCHL1 (see Biogrid)
CHRNA3 Nicotinic receptor subunit alpha 3 GeneCards	(Kawamata and Shimohama 2002).
CHRNA4 Nicotinic receptor subunit alpha 4 Biogrid GeneCards	(Kawamata and Shimohama 2002).		Loss of alpha 4 but not alpha 3 subunits in AD temporal cortex (Martin-Ruiz et al. 1999)
CHRNB2 cholinergic receptor, nicotinic, beta 2 (neuronal) Biogrid GeneCards	Cook et al, 2004

Table 7: Monoamine related genes associated with Alzheime's disease.

Gene	Alzheimer's disease	Atherosclerosis/ hypercholesterolemia	Modifications in AD	Relationships with other gene products
COMT catechol-O-methyltransferase	Martinez et al, 2009
HTR6 5-hydroxytryptamine (serotonin) receptor 6 Biogrid GeneCards	(Tsai et al. 1999).	(Comings et al. 1999)
HTR7 5-hydroxytryptamine (serotonin) receptor 7 (adenylate cyclase-coupled) GeneCards	Liu et al, 2007
SLC6A4 solute carrier family 6 (neurotransmitter transporter, serotonin), member 4 Biogrid GeneCards	(Tsai et al. 2001)	Polymorphism associated with high cholesterol levels in man (Comings et al. 1999)	Decreased serotonin transporter sites in dorsal raphe hippocampus and entorhinal cortex possibly related to serotonergic neuronal loss (Tejani-Butt et al. 1995)
MAOA Monoamine oxidase A GeneCards	(Takehashi et al. 2002)		Increased activity in occipital cortex, caudate nucleus, thalamus and white matter(Sherif et al. 1992)nucleus basalis of Meynert and temporal cortex(Sparks et al. 1991)	Regulation of cholesterol metabolism and atherogenesis by sympathomimetic amines(Kaplan and Manuck 1994;Yamauchi et al. 1998;Ablad et al. 1988;Kaplan et al. 1987;Pauletto et al. 1991) Noradrenaline induces PPARG in astrocytes and neurones (Klotz et al. 2003)
PNMT phenylethanolamine N-methyltransferase GeneCards	(Mann et al. 2001)		Decreased activity in hippocampus (Burke et al. 1987)Increased activity in cell bodies of epinephrine cell groups in, the medulla pssibly related to reduced PNMT transport and degeneration of these neurones (Burke et al. 1990)
ADRB1 Adrenergic receptor Beta 1 Biogrid GeneCards	(Bullido et al. 2004)			Increases APP expression (Bullido et al. 2004)
ADRB2 adrenergic, beta-2-, receptor, surface GeneCards	Yu et al, 2008
GNB3 Biogrid GeneCards	(Bullido et al. 2004)	(Ishikawa et al. 2000)		Increases APP expression (Bullido et al. 2004)

Table 8 Immune-system and related

Gene	Alzheimer's disease	Atherosclerosis/ hypercholesterolemia	Modifications in AD	Relationships with other gene products	HSV-1
AGER advanced glycosylation end product-specific receptor (RAGE)	Li et al, 2010	Falcone et al, 2005		Recetor for beta-amyloid
C4A complement component 4A (Rodgers blood group) eneCards	Nerl et al, 1984			Binds to CR1
C4B complement component 4B (Childo blood group)GeneCards	Nerl et al, 1984
CD33 CD33 molecule	Bertram et al, 2008
CFH Complement factor H GeneCards	Zetterberg et al, 2008	Jylhava et al, 2009		Binds to CRP Laine et al, 2007	Glycoprotein C of HSV-1 inhibits CFH binding to complement C3B Huemer et al, 1993
CD14 CD14 molecule GeneCards	Rodriguez-Rodriguez et al, 2007	Risley at al, 2003		Lipopolysaccharide binding protein on monocytes and macrophages
CD86 CD86 molecule	Beecham et al, 2009
CR1 Complement receptor 1	Two independent GWAS studies Harold et al, 2009, Lambert et al, 2009	Boiocchi et al, 2009		Binds to C4A and complexes with CR2
CRP C-reactive protein Biogrid GeneCards	Van Oijen et al, 2006	Chen et al 2005		Bind to LDL (Nunomura et al, 1999). Increases CCL2, OLR1,SERPINE1, SORL1 expression in endothelial cells Li et al, 2004; Wang et al, 2005	CRP levels are a general reflection of pathogen burden (HSV-1 and others) Zhu et al, 2000
CSF1 colony stimulating factor 1 (macrophage)	Beecham et al, 2009
DEFB122 defensin, beta 122	Beecham et al, 2009
EIF2AK2 PKR eukaryotic translation initiation factor 2-alpha kinase 2 Biogrid GeneCards	Bullido et al, 2007		Increased levels of phosphorylated PKR in AD brain Onuki et al,2004	Viral activated kinase. Linked to Toll receptor signalling (TLR4) via TIRAP Horng et al, 2001	Like many viruses, HSV-1 activates PKR, but has evolved various defensive strategies to combat its effects. One viral gene product (ICP34.5) is highly homologous to the host GADD34 (PPP1R15A) and dephosphorylates the PKR target eif2alpha,Cassady et al, 1998 while another, US11, prevents PKR activation by inhibiting the PKR activator PACT (PRKRA) Peters et al, 2001. US11 also binds to PKR Cassady and Gross, 2002
EBF3 Early B-cell factor 3 GeneCards	Grupe et al, 2007			Regulates microtubule assembly Bu and Su 2001 and cell cycle arrest and apoptosis Zhao et al, 2006
FAS Fas (TNF receptor superfamily, member 6) Biogrid GeneCards	Chiappelli et al, 2006			Activates LCK Schottmann et al, 1996 Involved in the toxic effects of oxidised LDL Meier et al, 2007 and APP Millett et al, 2005
FCER1G Fc fragment of IgE, high affinity I, receptor for; gamma polypeptide Biogrid GeneCards	(Taguchi et al. 2005)		MRNA upregulated in hippocampus (Taguchi et al. 2005)		Two herpes simplex proteins, glycoproteins E and L (US8, UL1) form a decoy heterodimeric Fc receptor. This is expressed on the surface of virions and infected cells and binds to host immunoglobulin G. IgG is released from this receptor by the acidic conditions present in lysosomes and this receptor may thus promote the degradation of antiviral antibodies bound to IgG. It has also been suggested that the entrapment of antiviral antigens by this viral Fc receptor may divert their binding to host Fc receptors Sprague et al, 2006 (eg FCER1G).
GBP2 guanylate binding protein 2, interferon-inducible GeneCards	(Taguchi et al. 2005)		MRNA upregulated in hippocampus (Taguchi et al. 2005)
HLA-A major histocompatibility complex, class I, A	Guerini et al, 2009
HLA-A2 major histocompatibility complex, class I, A	(Small and Matsuyama 1986)	(Dogan et al. 2001)		Cleaved by gamma-secretase Carey et al, 2007
HLA-DRB1 major histocompatibility complex, class II, DR beta 1	Neill et al, 1999
IL1A: Interleukin 1alpha Biogrid GeneCards 2q14		Increased plasma levels (Licastro et al. 2000)	IL1 stimulates APP expression in neural and endothelial cells (Forloni et al. 1992): Oxysterols release IL1A (Sjogren et al. 2002) IL1A increases the expression of astrocytic and microglial HSPG2 (perlecan) in the hippocampus (Garcia et al. 1999).
IL1B: Interleukin 1Belta Biogrid GeneCards 2q14	(Kornman et al. 1999)	Increased protein in brain microvessels (Grammas and Ovase 2001)	Binds to A2M (Webb and Gonias 1998). Decreases APP expression in human glioma cells (Yang et al. 1993)and affects APP processing(Dash and Moore 1995)Insoluble amyloid beta peptides induce IL1B (Chong 1997). Inflammatory cytokines (IL1B, TNFA) play an important role in atherosclerosis by reducing cholesterol efflux and reverse cholesterol transport (Ohashi et al. 2005)
ILIRN interleukin 1 receptor antagonist Biogrid GeneCards2q14.2	Worrall et al, 2003		Inhibits effects of IL1A and IL1B
IL6 Interleukin 6 Biogrid GeneCards 7p21	(Chapman et al. 2003),	Increased protein in brain microvessels (Grammas and Ovase 2001). Increased plama levels (Licastro et al. 2000). Increased hippocampal mRNA(Blalock et al. 2004)	Increases APP expresion in neural cells (Ohyagi and Tabira 1993): b-amyloid peptides induce IL6 (Chong 1997).The APOE promoter region contains an IL6 responsive site (Lahiri 2004)
IL8 Interleukin 84q13-q21
IL10 Interleukin 101q31-q32
IL18 interleukin 18 (interferon-gamma-inducing factor) GeneCards11q22.2-q22.3	Tiret at al, 2005
IL33 interleukin 33 9p24.1
MICA MHC class I polypeptide-related sequence A	Quiroga et al, 2009
NP purine nucleoside phosphorylase OMIM Biogrid GeneCards	Tumini et al, 2007			Involved, with adenosine deaminase (ADA), in purine catabolism. Mutations in either enzyme result in a severe combined immunodeficiency (SCID)
PTGS2 prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) COX-2 Biogrid GeneCards	Abdullah et al, 2006 (protective promoter -765 polymorphism)	Orbe et al, 2006 (protective promoter G-765C polymorphism)		Transcription regulated by cholesterol and SREBF1 Smith et al, 2005	Non-steroidal anti-inflammatory drugs that inhibit cyclooxygenase also attenuate herpes viral reactivation. Many studies have shown that herpes infection is accompanied by an increase in the expresion and activity of PTGS2) and of prostaglandin E2 Reynolds and Enquist, 2006
SAMSN1 SAM domain, SH3 domain and nuclear localization signals 1 Biogrid GeneCards	Kimura et al, 2006			Involved in B-cell activation and differentiation
SSB Sjogren syndrome antigen B (autoantigen La)	GWAS study: Harold et al, 2009
TAP2 transporter 2, ATP-binding cassette, sub-family B (MDR/TAP) antigen peptide transporter 2 GeneCards	Bullido et al, 2006			Involved in antigen processing	Inhibited by the viral protein ICP47 (HSV1 and 2) Galocha et al, 1997
TAPBPL TAP binding protein-like	Lee at al, 2008
TLR4 Toll-like receptor 4 Biogrid GeneCards	Minoretti et al, 2006	Bjorkbacka, 2006		Lipopolysaccharide receptor involved in bacterial and viral defense. Oxidised lipoproteins Bjorkbacka, 2006 and saturated fats Lee et al, 2001 are also ligands Involved in beta-amyloid clearance Tahara et al, 2006	Upregulated by HSV-1 infection (encephalitis) in mice Bottcher et al, 2003
TNFA Tumor necrosis factor alpha Biogrid GeneCards 6p21.3 6p21	(Wang and Oosterhof 2000)	Increased protein in brain microvessels (Grammas and Ovase 2001)	Infusion stimulates expression of most liver enzymes of cholesterol synthesis (Ruan et al. 2002). Regulates SREBP1(Lawler, Jr. et al. 1998). Inflammatory cytokines (IL1B, TNFA) play an important role in atherosclerosis by reducing cholesterol efflux and reverse cholesterol transport (Ohashi et al. 2005)

Cytoskeleton, microtubules transport and structural

Gene	Alzheimer's disease	Atherosclerosis/ hypercholesterolemia	Modifications in AD	Relationships with other gene products	HSV-1
BIN1 bridging integrator 1	GWAS study: Harold et al, 2009 and Seshadri et al, 2010		Present in tangle proteomics study Wang et al, 2005	Binds to DNM2
COL11A1 Collagen Biogrid GeneCards	(Taguchi et al. 2005)		MRNA downregulated in hippocampus (Taguchi et al. 2005)
COL25A1 Collagen Type XXV alpha GeneCards	Forsell et al, 2008			Brain specific mambrane bound collagen cleaved by furin covertase. Product binds beta-amyloid peptides Hashimoto et al, 2002
DNM2 Dynamin 2 GeneCards	Aidaralieva et al, 2008			Posseses a CDC2 phosphorylation site Diatloff-zito et al, 2005: Dynamins are associated with microtubules: Involved in endocytosis and cell motility, including endocytosis of low density lipoprotein via OLR1Kashiwakura et al, 2004
DNMBP Dynamin Binding proteinBiogrid GeneCards	Kuwano et al, 2006			Dynamin plays a role in the endolysosomal delivery of cholesterol to the endoplasmic reticulum (Robinet et al. 2006). Links dynamin to actin regulatory proteins Cestra et al, 2005
GOLM1 (GOLPH2, GP73) golgi membrane protein 1 GeneCards	Genome-wide association study Li et al, 2007			Processes protein synthesized in the rough endoplasmic reticulum and assists in the transport of protein cargo through the Golgi apparatus.
KIF18B kinesin family member 18B	Li et al, 2008
KNS2 kinesin 2 Biogrid GeneCards	Dhaenens et al, 2004	None found		Microtubule motor protein transporting cargos, including APP Kamal et al, 2001	Kinesins play an important role in HSV-1 transport along microtubules Lee et al, 2006. The role of this particular kinesin has not been examined. KNS2 does however bind to APP Kamal et al, 2001which is involved in viral transport Salpute-Krishnan et al, 2003
MAL2 mal, T-cell differentiation protein 2	Potkin et al, 2009
MPHOSPH1 M-phase phosphoprotein 1 GeneCards	Liu et al, 2007			Kinesin related protein involved in cytokinesis Abaza et al, 2003. Binds to and regulates PIN1 Kamimoto et al, 2001
TRAK2 trafficking protein, kinesin binding 2 Biogrid GeneCards	Grupe et al, 2007			Binds to KIF5C and the tetrameric kinesin light-chain/kinesin heavy-chain complex Brickley et al, 2005.
MAPT microtubule-associated protein tau GeneCards Biogrid	(Lilius et al. 1999)		Component of tangles Hyperphosporylated tau (cf GSK3B) s a feauture of AD pathology (Lee 1996)	Cholesterol depletion increases MAPT phosphorylation (Sawamura et al. 2003). MAPT phosphorylation is increased in APOE deficient mice (Genis et al. 1995)in APOER2/VLDR2 double knockouts(Ohkubo et al. 2003)and in mice overexpressing human APOE4 in neurones(Tesseur et al. 2000;Meske et al. 2003;Fan et al. 2002;Fan et al. 2001)	A viral tegument protein, VP22, results in the hyperacetylation of microtubules Elliot and O'Hare,1998, a property shared by unphosphorylated tau (MAPT) Cho and Johnson, 2004and both tau and VP22 are able to stabilise microtubules via this mechanism. (MAPT is involved in the traffic of other viruses (JHM) but its role in herpes traffic has not been specifically examined Kallicharran and Dales, 1995.
MYH8 Myosin heavy polypeptide 8 GeneCards	(Taguchi et al. 2005)		MRNA downregulated in hippocampus (Taguchi et al. 2005)		Herpes viral capsids use myosins for active transport within the nucleus Forest et al, 2005 Feierbach et al, 2005: This particular myosin has not been examined
MYH13 myosin, heavy chain 13, skeletal muscle Biogrid GeneCards	Grupe et al, 2007				see above
PICALM phosphatidylinositol binding clathrin assembly protein	GWAS study: Harold et al, 2009
SEPT3 Septin 3	Takehashi et al, 2004
SORCS1 sortilin-related VPS10 domain containing receptor 1 OMIM GeneCards	Grupe at al, 2006			Gamma-secretase substrate Nyborg et al, 2006
SORCS2 sortilin-related VPS10 domain containing receptor 2	Beecham et al, 2009
SORCS3 sortilin-related VPS10 domain containing receptor 3	Beecham et al, 2009
SYN3 Synapsin 3	Lee at al, 2008
TTLL7 tubulin tyrosine ligase-like family, member 7	Heinzen et al, 2009
VCP valosin-containing protein	Kaleem et al, 2007			involved in vesicle transport and fusion, 26S proteasome function, and assembly of peroxisomes

Adhesion molecules

Gene	Alzheimer's disease	Atherosclerosis/ hypercholesterolemia	Modifications in AD	Relationships with other gene products	HSV-1
BCAM basal cell adhesion molecule (Lutheran blood group)	Yu et al, 2007
CNTN5 Contactin 5	GWAS study: Harold et al, 2009
CTNNA3 catenin (cadherin-associated protein), alpha 3 (VR22)Biogrid GeneCards	Martin et al, 2005				The Herpes simplex virus enters host cells via a number of different receptors including the herpes virus entry mediator (HVEM: Gene symbol TNFRSF14), and members of the nectin receptor family (PVRL1-4). Nectins are adhesion molecules connected to the actin cystoskeleton and recruited to cadherin-based adherens cell-cell junctions via afadin (MLLT4) Takahashi et al, 1999.The cadherin and nectin adhesion systems are interconnected via alpha-catenin (CTNNA3) Tachibana et al, 2000which binds to afadin Pokutta et al, 2002.
CTNND2 catenin (cadherin-associated protein), delta 2 (neural plakophilin-related arm-repeat protein)	Abraham et al, 2008			Binds to PSEN1 and PSEN2 Levesque et al, 1999
DSC1 Desmocollin 1 Biogrid GeneCards	Ramos et al, 2006			Required for cell adhesion and desmosome formation
HNT Neurotrimin GeneCards	Liu et al, 2007			Immunoglobulin domain-containing glycosylphosphatidylinositol (GPI)-anchored cell adhesion molecule
ICAM1 intercellular adhesion molecule 1 (CD54), human rhinovirus receptor Biogrid GeneCards	(Pola et al. 2003)	(Gaetani et al. 2002)	Increased expression in senile plaques astrocytes and vasculature (Verbeek et al. 1994;Akiyama et al. 1993;Frohman et al. 1991;Rozemuller et al. 1989)Increased hippocampal mRNA(Blalock et al. 2004)	Expression stimulated by beta amyloid in microglia (Apelt et al. 2002;Walker et al. 2001). Induced by hypercholesterolaemia (Sampietro et al. 1997)and by cholesterol treatment of human endothelial cells (Yuan et al. 2001)Induction of hepatic SREBF1 in ICAM1 knockout mice (Gregoire et al. 2002).	HSV-1 infectivity is increased in ICAM-1 knockout mice Noisakran et al, 2005
NCAM2 neural cell adhesion molecule 2 GeneCards	Grupe et al, 2007			ESR1 (see Entrez gene)
OPCML opioid binding protein/cell adhesion molecule-like GeneCards	Liu et al, 2007
PCDH11X protocadherin 11 X-linked	Carasquillo et al, 2009

Proteoglycans and viral receptors

Gene	Alzheimer's disease	Atherosclerosis/ hypercholesterolemia	Modifications in AD	Relationships with other gene products	HSV-1
ACAN Aggrecan GeneCards Chondroitin sulphate prorteoglycan	Grupe et al, 2007
HSPG2 heparan sulfate proteoglycan 2 (perlecan) Biogrid GeneCards 1p36	(Iivonen et al. 2003)		No change in hippocampal mRNA expression (Maresh et al. 1996)	Bind to beta amyloid and promotes fibrilogenesis (Castillo et al. 1997),. Binds and internalises low density lipoproteins enriched in LPL (Fuki et al. 2000) Binds to GRN Gonzalez et al, 2003) .	Glycoproteins B and C of Herpes simplex bind to Heparan sulfate proteoglycans Bender et al, 2005
PVRL2 poliovirus receptor-related 2 (herpesvirus entry mediator B)	Takei et al, 2009 Harold et al, 2009				Herpes virus receptor.Warner et al, 1998

Kinases and cell cycle

Gene	Alzheimer's disease	Atherosclerosis/ hypercholesterolemia	Modifications in AD	Relationships with other gene products	HSV-1
ARID1B AT rich interactive domain 1B (SWI1-like)	GWAS study: Harold et al, 2009
CCNT1 Cyclin T1 CDK9-associated C-type protein; cyclin C-related protein; subunit of positive elongation transcription factor b Biogrid GeneCards	Lin et al, 2006			Together with CDK9 forms a translation elongation factor p tefb whose efficacy is enhanced by binding to the androgen receptor AR Lee at el, 2001
CDC2 cell division cycle 2 protein, p34 protein kinase; cyclin-dependent kinase 1 (CDK1) Biogrid GeneCards	(Johansson et al. 2003)		Increased cortical protein expression in neurones with tangle inclusions.	Phosphorylates SREBP1 (SREBF1) Bengeochea-Alonso et al, 2006 and MAPT (Pei et al. 2002) Binds to PIN1 (see Biogrid)	Phosphorylates many Herpes viral proteins and is activated by viral infection Advani et al, 2000
CDK5 cyclin-dependent kinase 5 Biogrid GeneCards	Rademakers et al, 2005			Phosphorylates tau (MAPT) and APP Liu et al, 2003
CDKN2BAS CDKN2B antisense RNA (non-protein coding)	Emanuele et al, 2009
CDK5R1 cyclin-dependent kinase 5, regulatory subunit 1 (p35)	Mateo et al, 2008
DAPK1 Death associated protein kinase 1Biogrid GeneCards	Li et al, 2006		In progress	Involved in FAS and TNF-related apoptosis Cohen et al, 1999
DYRK1A dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A Biogrid GeneCards	Kimura et al, 2007			Phosphorylates SNCA Kim et al, 2006, MAPT Woods et al, 2001
RBL1 Retinoblastoma-like 1(p107)	Potkin et al, 2009

Mitochondrial

Gene	Chromosome	Alzheimer's	Atherosclerosis	Modifications in AD	Relationship with other gene products	HSV-1
ATP6 mitochondrially encoded ATP synthase 6	Mt	MtDNA deletion Corral-Debrinski et al, 1994				A truncated form of the herpes simplex protein, UL12 (UL12.5), localises to mitochondria and deletes host mitochondrial DNA Saffran et al, 2007.
ATP8 mitochondrially encoded ATP synthase 8	Mt	MtDNA deletion Corral-Debrinski et al, 1994				" "
COX1 mitochondrially encoded cytochrome c oxidase I	Mt	Mutation Davis et al, 1997
COX2 mitochondrially encoded c ytochrome c oxidase II	Mt	Mutation Davis et al, 1997
COX10 COX10 homolog, cytochrome c oxidase assembly protein, heme A: farnesyltransferase	17p12-p11.2	Vitali et al, 2009
COX15 COX15 homolog, cytochrome c oxidase assembly protein	10q24	Vitali et al, 2009
CYTB mitochondrially encoded cytochrome b	Mt	Polymorphism Chagnon et al, 1999
MT-CO3 mitochondrially encoded cytochrome c oxidase III	Mt	MtDNA deletion Corral-Debrinski et al, 1994
MT-L2 mitochondrially encoded tRNA leucine 2 (CUN)	Mt	MtDNA deletion Corral-Debrinski et al, 1994
ND1 mitochondrially encoded NADH dehydrogenase 1	Mt	Coon et al, 2006
ND2 mitochondrially encoded NADH dehydrogenase 2	Mt	Edland et al, 2002
ND3 mitochondrially encoded NADH dehydrogenase 3	Mt	MtDNA deletion Corral-Debrinski et al, 1994
ND4 mitochondrially encoded NADH dehydrogenase 4	Mt	MtDNA deletion Corral-Debrinski et al, 1994
ND4L mitochondrially encoded NADH 4L	Mt	MtDNA deletion Corral-Debrinski et al, 1994
ND5 mitochondrially encoded NADH dehydrogenase 5	Mt	MtDNA deletion Corral-Debrinski et al, 1994
ND6 mitochondrially encoded NADH dehydrogenase 6	Mt	Coon et al, 2006
RNR1 mitochondrially encoded 12S RNA	Mt	Polymorphism Tanaka et al, 2009
TFAM Mitochondrial transcription factor Biogrid GeneCards	10q21	(Gunther et al. 2004)			Key activator of mitochondrial transcription
TOMM40 translocase of outer mitochondrial membrane 40 homolog GeneCards	19q13	Grupe et al, 2007			Mitochondrial protein import
TRNG mitochondrially encoded tRNA glycine	Mt	MtDNA deletion Corral-Debrinski et al, 1994
TRNH mitochondrially encoded tRNA histidine	Mt	MtDNA deletion Corral-Debrinski et al, 1994
TRNQ mitochondrially encoded tRNA glutamine	Mt	Mt mutation Egensperger et al, 1997
TRNR mitochondrially encoded tRNA arginine	Mt	MtDNA deletion Corral-Debrinski et al, 1994
TRNS2 mitochondrially encoded tRNA serine 2 (AGU/C)	Mt	MtDNA deletion Corral-Debrinski et al, 1994
TRNT mitochondrially encoded tRNA threonine	Mt	Polymorphism Chagnon et al, 1999
Mitochondrial DNA deletions	Mt	Reviewed by Chen et al, 2006				A truncated form of the herpes simplex protein, UL12 (UL12.5), localises to mitochondria and deletes host mitochondrial DNA Saffran et al, 2007.

Ubiquitin related Ubiquitin and Alzheimer's disease

Gene	Alzheimer's	Atherosclerosis	Modifications in AD	Relationship with other gene products	HSV-1
CAND1 cullin-associated and neddylation-dissociated 1	Potkin et al, 2009
MAGI2 membrane associated guanylate kinase, WW and PDZ domain containing 2	Potkin et al, 2009
UBE2I ubiquitin-conjugating enzyme E2I (UBC9 homolog, yeast)	Ahn et al, 2009			Binds to AR, BLMH,ESR1, UCHL1, SREBF1, TP53
UBD Ubiquitin D (FAT10) Biogrid GeneCards	Grupe et al, 2007
UBQLN1 Ubiquilin 1 9q21.2-q21.3Biogrid GeneCards	Bertram et al, 2005			Interacts with PSEN1 and PSEN2 Mah et al, 2000 . Regulates PEN2 and NCSTN protein levels, controlling the degradation of the gamma-secretase complex Massey et al, 2005. Binds to CHRNA3, CHRNA4, controlling their surface expression by drawing the unassembled subunits to the proteasome Ficklin et al, 2005
UCHL1 Ubiquitin carboxyl-terminal esterase L1 (ubiquitin thiolesterase) OMIM Biogrid GeneCards	Xue and Jia,2006			SNCA (see Biogrid)

Peptides and their receptors

Gene	Alzheimer's	Atherosclerosis	Modifications in AD	Relationship with other gene products	HSV-1

GALP Galanin-like peptide precursor GeneCards	Grupe et al, 2007