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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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 A2MLPL 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
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        
LHCGR luteinizing hormone/choriogonadotropin receptor GeneCards Haasl et al,2008        

MC2R melanocortin 2 receptor (adrenocorticotropic hormone receptor) Biogrid

GeneCards
deQuervain et al,2004        
NPFFR2 neuropeptide FF receptor 2 Abraham et al, 2008        
SST Somatostatin GeneCards Vepsalainen et al, 2007 None      

Channels and ionotropic

Gene Alzheimer's Atherosclerosis Modifications in AD Relationship with other gene products HSV-1
ANK3 ankyrin 3, node of Ranvier (ankyrin G) Morgan et al, 2007        
CACNB2 calcium channel, voltage-dependent, beta 2 subunit Liang et al, 2009        
GRIN2B glutamate receptor, ionotropic, N-methyl D-aspartate 2B Jiang et al, 2009        
GRIN3A glutamate receptor, ionotropic, N-methyl-D-aspartate 3A Liu et al, 2009        
KCNH7 potassium voltage-gated channel, subfamily H (eag-related), member 7 Abraham et al, 2008        
KCNJ6 potassium inwardly-rectifying channel, subfamily J, member 6 GeneCards Grupe et al, 2007     Involved in the control of insulin secretion by glucose  
KCNMA1 potassium large conductance calcium-activated channel, subfamily M, alpha member 1 Beecham et al, 2009        
KCTD12 potassium channel tetramerisation domain containing 12 Beecham et al, 2009        
KCNU1 potassium channel, subfamily U, member 1 GWAS study: Harold et al, 2009        
SCN2A sodium channel, voltage-gated, type II, alpha subunit Beecham et al, 2009        
           

Heat shock

Gene Alzheimer's Atherosclerosis Modifications in AD Relationship with other gene products HSV-1
DNAJC28 DnaJ (Hsp40) homolog, subfamily C, member 28 Kimura et al, 2007        
HSPA1B
heat shock 70kDa protein 1B (HSP70-2) GeneCards
(Clarimon et al. 2003a)
 

 

 
 
HSPA5 heat shock 70kDa protein 5 (glucose-regulated protein, 78kDa) Grupe et al, 2007      Binds to A2M and LDLR  

Blood and serum related

Gene Alzheimer's Atherosclerosis Modifications in AD Relationship with other gene products HSV-1
ALB albumin Biogrid GeneCards Kimura et al, 2006     Forms a complex with APOE Derguniv, 1994  
F13A1 coagulation factor XIII, A1 polypeptide GeneCards Gerardino et al, 2006  val34leu Protective vs myocardial infarction Franco et al, 2000      
HBG2 hemoglobin, gamma G Perry et al, 2006        
NGB Neuroglobin Szymanski et al, 2008  Lin et al, 2008      
TTR Transthyretin Cuenco et al, 2009     Transports thyroid hormones and retinol; Associates with APOA1: Ligand for LRP2 Binds to HSPG2  

DNA repair

Gene Alzheimer's Atherosclerosis Modifications in AD Relationship with other gene products HSV-1
MCM3AP MCM3 minichromosome maintenance deficient 3 (S. cerevisiae) associated protein Biogrid GeneCards (Taguchi et al. 2005)  
MRNA upregulated in hippocampus (Taguchi et al. 2005)  initiation of DNA replication  
OGG1 8-oxoguanine DNA glycosylase GeneCards Mao et al, 2007     DNA repair  
PARP1 poly (ADP-ribose) polymerase family, member 1 Biogrid GeneCards

Infante et al, 2007

  Interacts with POU2F1 Nie at al, 1998 Inhibited by RPS3A HSV-1 protein ICP8 binds to LMNA and PARP1 (mouse two-hybrid) Taylor and Knipe 2004
RFC1 replication factor C (activator 1) 1, 145kDa GeneCards Bi et al, 2008     DNA replication and repair.Binds to RFC3  
RFC3 replication factor C (activator 1) 3, 38kDa Heinzen et al, 2009     Binds to RFC1  
XRCC1 X-ray repair complementing defective repair in Chinese hamster cells 1 Dogru-Abbasoglu et al, 2007        
           
           

Spliceosome/Ribosome

Gene Alzheimer's Atherosclerosis Modifications in AD Relationship with other gene products HSV-1
BAT1 HLA-B associated transcript 1 Gnjec et al, 2008     splicing factor required for association of U2 small nuclear ribonucleoprotein with pre-mRNA, and plays an important role in mRNA export from the nucleus to the cytoplasm.  
CWC15 CWC15 spliceosome-associated protein homolog Beecham et al, 2009        
RPS3A ribosomal protein S3A GeneCards Grupe et al, 2006     Inhibits PARP1(see Entrez gene data)  

 

Orphans

Gene Alzheimer's Atherosclerosis Modifications in AD Relationship with other gene products HSV-1
C1orf49 Liu et al, 2007        
C6orf155 GWAS study: Harold et al, 2009        
c10orf112 Zubenko et al, 1998        
c11orf30 GWAS study: Harold et al, 2009        
C12ORF41, hCG2039140 Grupe et al, 2007        
C20orf132 Potkin et al, 2009        
C21orf63 Kimura et al, 2007        
LOC388458
Beecham et al, 2009        
LOC729993
         

Table 9 Miscellaneous genes associated with Alzheimer's disease. 

  Gene Alzheimer's disease Atherosclerosis/ hypercholesterolemia Modifications in AD Relationships with other gene products HSV-1
AGBL4 ATP/GTP binding protein-like 4 Beecham et al, 2009        
ABCC2 ATP-binding cassette, sub-family C (CFTR/MRP), member 2 Kuwano et al, 2006        
AHSG
alpha2-Heremans-Schmid glycoprotein Biogrid GeneCards
(Geroldi et al.
 2005)
Associated with sub-clinical atherosclerosis Lehtinen et al, 2007and carotid artery stiffness Mori et al, 2007
 
     
ALDH18A1 aldehyde dehydrogenase 18 family, member A1 pyrroline-5-carboxylate synthetase GeneCards Grupe at al, 2006        
ARSA arylsulfatase A
cerebroside sulfatase Biogrid GeneCards
(Philpot et al. 1997)

 
Sulfatide levels are decreased in the CSF of early Alzheimer's disease patients(Irizarry 2003) Generates sulfatides transported by lipoproteins (Han et al. 2003)  
ARSB arylsulfatase B Potkin et al, 2009     hydrolyzes sulfate groups of N-Acetyl-D-galactosamine, chondriotin sulfate, and dermatan sulfate  
ATP8A1 ATPase, aminophospholipid transporter (APLT), class I, type 8A, member 1 Beecham et al, 2009        

ATXN1 Ataxin 1

Beecham et al, 2009        
BCR breakpoint cluster region GeneCards Grupe et al, 2007        
ATF7 activating transcription factor 7 GeneCards Lin et al, 2006        
CAV1 Caveolin 1 caveolae protein, 22kDa Heshmati et al, 2009    mRNA upregulated in hippocampus and frontal cortex Gaudreault et al, 2004 scaffolding protein encoded by this gene linking integrin subunits to the tyrosine kinase FYN, Regulates APP processsing Kang et al, 2006  
CALHM1 calcium homeostasis modulator 1 Boada et al, 2010        
CECR2 cat eye syndrome chromosome region, candidate 2 Lee at al, 2008        
CHD4 chromodomain helicase DNA binding protein 4 Lee et al, 2008        
CSK c-src tyrosine kinase Giedraitis et al, 2009        
CUBN cubilin (intrinsic factor-cobalamin receptor) Abraham et al, 2008      Vitamin B12 receptor  
DFNB31 deafness, autosomal recessive 31 (WHRN; CIP98; USH2D) OMIM GeneCards Li et al, 2006        
DISC1 disrupted in schizophrenia 1 Beecham et al, 2009        
DKK1 dickkopf homolog 1 Morgan et al, 2007     Ligand for LRP6  
DOPEY2 dopey family member 2 GeneCards Kimura et al, 2006        
DPYS dihydropyrimidinaseBiogrid GeneCards (Taguchi et al. 2005)
 
MRNA downregulated in hippocampus (Taguchi et al. 2005) 
 
 
ELAVL4 ELAV (embryonic lethal, abnormal vision, Drosophila)-like 4 (Hu antigen D) Beecham et al, 2009        
EFNA5 Ephrin A5 Potkin et al, 2009        
ENTPD7 ectonucleoside triphosphate diphosphohydrolase 7 GeneCards Kuwano et al, 2006        
FAM63a Grupe et al, 2007        
FAM113B Beecham et al, 2009        
GNA11 guanine nucleotide binding protein (G protein), alpha 11 (Gq class)Biogrid GeneCards (Taguchi et al. 2005)
 

 

 
 
HHEX homeobox, hematopoietically expressed Biogrid GeneCards Bjork et al, 2006     Putative role in hematopoietic differentiation  
WWC1(KIBRA) WW and C2 domain containing 1 GeneCards

Rodriguez et al, 2007 (in older patients)

    Interacts with dynein light chain 1 and plays a role in estrogen receptor signaling (ESR1)  
KLF5 Kruppel-like factor 5 (intestinal) Giedraitis et al, 2009        
LMNA lamin A/C Biogrid GeneCards Grupe et al, 2007 (UK only)     Nuclear lamina protein: Binds to SREBF1 Lloyd et al, 2002 Phosphorylation by HSV-1 US3 kinase modifies nuclear distribution Mou et al, 2007. Binds to viral proteins UL31 and UL34 Reynolds et al, 2004. ICP8 binds to LMNA and PARP1 (mouse two-hybrid) Taylor and Knipe 2004
LPAR5 lysophosphatidic acid receptor 5 Lee et al, 2008        
LRAT lecithin retinol acyltransferase (phosphatidylcholine--retinol O-acyltransferase)
Abraham et al, 2008        
LRRK2 leucine-rich repeat kinase 2 Zhao et al, 2009        
LRRTM3 leucine rich repeat transmembrane neuronal 3 GeneCards Liang et al, 2007     Promotes APP processing by BACE1 Majercak et al, 2006  
LSM14A LSM14A, SCD6 homolog A (S. cerevisiae) Abraham et al, 2008        
NCAPD2 (CNAP1) non-SMC condensin I complex, subunit D2 Biogrid GeneCards Li et al, 2004 Lee at al, 2008        
NPAS2 neuronal PAS domain protein 2 Abraham et al, 2008        
MEF2A MADS box transcription enhancer factor 2, polypeptide A (myocyte enhancer factor 2A) Biogrid GeneCards Gonzalez et al, 2007  Wang 2005  

 MEF2 promoter site on BACE1 Lahiri et al, 2006

The ICP0 protein of HSV1 interacts with histone deacetylases (HDAC4,5 and 9) via an amino terminal domain responsible for suppressing the activity of myocyte enhance factor MEF2A by nuclear sequestration. ICP0 overcomes the HDAC mediated suppression of MEF2A Lomonte et al, 2004
MS4A6A membrane-spanning 4-domains, subfamily A, member 6A GWAS study: Harold et al, 2009        
NEDD9 neural precursor cell expressed, developmentally down-regulated 9 GeneCards Li et al, 2007        
NMNAT3 nicotinamide nucleotide adenylyltransferase 3 GeneCards Liu et al, 2007     enzyme involved in NAD biosynthesis  
ODZ3 odz, odd Oz/ten-m homolog 3 Beecham et al, 2009        
OTC ornithine carbamoyltransferase Hansmannel et al, 2009        
PAX2 paired box 2 Heinzen et al, 2009        
PGBD1 piggyBac transposable element derived 1 GeneCards Grupe et al, 2007        
PCGF5 polycomb group ring finger 5 Grupe et al, 2006        
PCMTD1 protein-L-isoaspartate (D-aspartate) O-methyltransferase domain containing 1 Abraham et al, 2008        
PDLIM5 PDZ and LIM domain 5 Beecham et al, 2009        
PDE9A phosphodiesterase 9A Abraham et al, 2008        
PIN1 peptidylprolyl cis/trans isomerase) NIMA-interacting 1 Biogrid GeneCards Segat et al, 2007     Regulates beta-catenin (CTNNB1) signalling Ryo et al, 2001 and TP73 function Mantovani et al, 2004. Restores function of phosphorylated tau (MAPT) Lu et al, 1999  
POMT1 protein-O-mannosyltransferase 1Biogrid GeneCards Li et al, 2006      
PKP2P1 plakophilin 2 pseudogene 1 GeneCards Li et al, 2004        
PRUNE2 prune homolog 2 Potkin et al, 2009        
PPM1H protein phosphatase 1H (PP2C domain containing) GeneCards Li et al, 2004     Phosphatase of unknown function  
PPP2R2B protein phosphatase 2 (formerly 2A), regulatory subunit B, beta isoform GeneCards Chen et al, 2008     Part of a regulatory protein phosphatase 2a complex regulating multiple pathways  
PPP1R11 protein phosphatase 1, regulatory (inhibitor) subunit 11 Beecham et al, 2009        
PRND prion protein 2 (dublet) Golanska et al, 2009        
PRNP
prion protein Biogrid GeneCards
(Dermaut et al. 2003)
 

 
Binds to APOE (Baumann et al. 2000) Herpes simplex infectivity is reduced in PRNP knockout mice Thackray and Bujdoso, 2006
PTPLA protein tyrosine phosphatase-like (proline instead of catalytic arginine), member A Liang et al, 2009        
RALGPS2 Ral GEF with PH domain and SH3 binding motif 2 GeneCards Liu et al, 2007        
RELN Reelin Seripa et al, 2008     Binds to LRP8 and VLDLR  
RGSL2 regulator of G-protein signaling like 2 GeneCards Liu et al, 2007        
RUNX1 runt-related transcription factor 1 (acute myeloid leukemia 1; aml1 oncogene) Biogrid GeneCards Grupe et al, 2007     Involved in haematopoesis  
S100B S100 calcium binding protein B Lambert et al, 2007     Interacts with AGER, MAPT, and TP53  
SASH1 SAM and SH3 domain containing 1 Heinzen et al, 2009        
SEL1L sel-1 suppressor of lin-12-like Saltini et al, 2006        
SGPL1 sphingosine-1-phosphate lyase 1GeneCards Morgan et al, 2007      Metabolises sphingosine-1-phosphate to phosphoethanolamine  
SHISA9 shisa homolog 9 Beecham et al, 2009        
TARDBP TAR DNA binding protein
(TDP-43)
Shibata et al, 2009      
TET1 tet oncogene 1 Morgan et al, 2007        
THEM5 thioesterase superfamily member 5 GeneCards Grupe et al, 2007        
TMEM63C transmembrane protein 63C Szymanski et al, 2008        
TNK1 tyrosine kinase, non-receptor, 1 GeneCards Grupe et al, 2007        
TRIM15 tripartite motif-containing 15 Beecham et al, 2009        
TP73 tumor protein p73 Biogrid GeneCards

Li et al, 2004

  Activity controlled by PIN1 Mantovani et al, 2004  
WBSCR17 Williams-Beuren syndrome chromosome region 17 : UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase-like 3; Abraham et al, 2008        
YWHAZ tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta polypeptide GeneCards Mateo et al, 2008        
ZBP1 Z-DNA binding protein 1 Potkin et al, 2009        
ZNF155 Zinc finger protein 155 Abraham et al, 2008        
ZNF224 Zinc finger protein 224 Beecham et al, 2009        
ZNF225 Zinc finger protein 225 Abraham et al, 2008        

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