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APP, APOE, Complement receptor 1, Clusterin and PICALM and their involvement in the Herpes simplex life-cycle. Neuroscience Letters 483, 93-100 2010

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Enhanced links to genes are provided by Kegg pathway analyses of Alzheimer's disease genes and of the herpes simplex life cycle  

Abstract

The major Alzheimer’s disease susceptibility genes (APOE, Clusterin, Complement receptor 1 (CR1) and phosphatidylinositol binding clathrin assembly protein, PICALM) can be implicated directly (APOE, CR1) or indirectly (clusterin and PICALM) in the Herpes simplex life cycle. The virus binds to proteoliposomes containing APOE or APOA1 and also to CR1, and both clusterin and PICALM are related to a mannose 6-phosphate receptor used by the virus for cellular entry and intracellular transport. PICALM also binds to a nuclear exportin used by the virus for nuclear egress. Clusterin and complement receptor 1 are both related to the complement pathways and play a general role in pathogen defence. In addition, the amyloid precursor protein APP is involved in Herpes viral transport and gamma-secretase cleaves a number of receptors used by the virus for cellular entry. APOE , APOA1 and clusterin, or alpha 2-macroglobulin, insulysin and caspase 3, which also bind to the virus, are involved in beta-amyloid clearance or degradation, as are the viral binding complement components, C3 and CR1. There are multiple ways in which the products of key susceptibility genes might be able to modify the viral life cycle and in turn the virus interacts with key proteins involved in APP and beta-amyloid processing. These interactions support a role for the Herpes simplex virus in Alzheimer’s disease pathology and suggest that antiviral agents or vaccination might be considered as viable therapeutic strategies in Alzheimer’s disease.

Herpes simplex, Alzheimer’s disease susceptibility genes and pathological processes.

Alzheimer’s disease is a devastating condition characterised by beta-amyloid deposition in amyloid-containing plaques, an accumulation of the phosphorylated microtubule protein tau in neurofibrillary tangles and by massive cortical and hippocampal cell loss [1;2] . A number of susceptibility genes and environmental risk factors, the latter including infection with herpes simplex and other pathogens (C. Pneumoniae, H.Pylori, inter alia)  [3] have been implicated in the disease. Herpes simplex infection in mice also induces neuronal degeneration in the entorhinal cortex and hippocampus, as well as memory deficits, all features of Alzheimer’s disease [4] and C.Pneumoniae infection can also provoke cerebral beta-amyloid deposition in mice [5] .It is likely that both environmental and genetic influences play a role in the disease, and that genes and environment may act together to influence its incidence and  pathology.  For example, many cholesterol and lipoprotein-related genes are implicated in Alzheimer’s disease and dietary factors that influence Alzheimer’s disease risk and progression can clearly be related to cholesterol homoeostasis [6;7] . As discussed below, the herpes simplex virus can also be related to a number of Alzheimer’s disease susceptibility genes and pathological processes.

Two genome-wide association studies (GWAS) have identified apolipoprotein E, (APOE) clusterin (CLU), complement receptor 1 (CR1) and the phosphatidylinositol binding clathrin assembly protein, PICALM, as major susceptibility genes in Alzheimer’s disease. The authors pointed out areas of convergence between these genes; For example, both APOE and clusterin are involved in lipoprotein and cholesterol function and both CR1 and CLU are members of the complement pathways involved in pathogen defence [8;9] . There is a further common feature. These genes, and several others, can all be related to the Herpes Simplex virus, which, via this association, can be related to a number of APP and beta-amyloid processing pathways. These and other interactions are summarised in a database at http://www.polygenicpathways.co.uk/herpalz.htm

The Herpes simplex virus binds to artifical proteoliposomes containing APOE or APOA1, as well as to all classes of serum lipoprotein in Man (Very low density, Low density and High density lipoprotein) [10] . The herpes simplex and influenza virus also bind to complement receptor 1 on erythrocytes [11] HSV-1 infection has been implicated as a risk factor in Alzheimer’s disease, acting in synergy with APOE4 [12] . Viral DNA is found in Alzheimer’s disease amyloid plaques, and HSV-1 infection also results in beta-amyloid () deposition and tau phosphorylation, the key hallmarks of Alzheimer’s disease, in mice or neuroblastoma cells [13-15] . Possession of the human APOE4 allele in mice also favours cerebral infection by the herpes virus [16] .

The Herpes simplex viral glycoprotein C acts as a CR1 mimic and, like CR1, binds to complement C3 components, blocking complement pathways and preventing the formation of the membrane attack complex (MAC) [17] (Fig 1). This forms a channel that inserts into pathogen cell membranes, killing them by lysis. This complex is activated by the immune network in response to pathogen invasion and can also target the host cells which contain the pathogen [18] .  This complex is present in dystrophic neurites and in the neuronal cytoplasm in Alzheimer’s disease, suggesting a role in neuronal cell death [19;20]  Clusterin inhibits formation of this complex by binding to several of its components (C7, C8 C9) [21] . In addition a Herpes simplex virion component, CD59 [22] also prevents MAC complex formation via binding to C8 and C9 [23] (Fig 1). Clusterin, CR1 and Herpes simplex all prevent formation of this complex, which could pave the way for other infectious agents implicated as Alzheimer’s disease risk factors (e.g. C.Pneumoniae and  Helicobacter pylori) [3] . Interestingly H.Pylori eradication in infected Alzheimer’s disease patients has been shown to improve cognitive function [24] .

Although other receptors are the principal routes of entry, the Mannose-6-phosphate receptor (M6PR) is used by Herpes simplex in certain cells [25] . This receptor is also involved in the routing of the virus to endosomes [26] and the viral glycoprotein D blocks the entry of lysosomal enzymes to the endosomal compartment by binding to M6PR; one of several ways by which the virus blocks apoptosis [27] (Fig 1). The mannose-6-phosphate receptor binds to clusterin [28] and its traffic through the endosomal compartments is controlled by PICALM, whose overexpression reduces M6PR localisation in endosomes, suggesting blockade of its transport from the plasma membrane or the trans-golgi network [29] . The herpes simplex virus also uses exportin (Crm1) dependent pathways for nuclear egress [30] . PICALM and other endocytic-regulatory proteins bind to Crm1 [31] . Although there have been no studies specifically addressing the roles of PICALM or clusterin in viral traffic, both of these clearly influence endosomal routing pathways that are used by herpes simplex.

APOE, clusterin and complement receptor 1 play key roles in beta amyloid clearance as do two further viral binding proteins APOA1 [10] , and alpha -2 macroglobulin (A2M) [32] . This is primarily mediated via lipoprotein receptors. A2M, or APOE-bound are cleared by LRP1 (low density lipoprotein receptor-related protein 1 ) while LRP2 (megalin) clears clusterin-bound [33] [34] . Apoer2 (LRP8) is a receptor for both APOE and clusterin [35] APOA1 is also involved in beta-amyloid clearance via its transporter ABCA1 [36] . The Varicella Zoster and herpes simplex glycoprotein E binding protein , insulin-degrading enzyme [37] is also involved in beta-amyloid degradation [38] as is caspase-3 [39] which is activated by the viral US3 kinase [40] .The HSV-1 binding protein, complement C3 is also a ligand for LRP1 and LRP8, both of which play a role in C3 cellular uptake [41] . Beta amyloid in the bloodstream is processed by its binding to complement C3, which subsequently binds to complement receptor 1 on erythrocytes [42] .  As plasma levels of beta-amyloid may influence cerebral beta-amyloid efflux [43] this could impact on the cerebral load of beta-amyloid.

Interestingly, the lipoprotein and complement pathways may also be linked via clusterin, as the formation of the MAC attack complex is increased in kidney subepithelial cells by antibodies to the clusterin receptor megalin (LRP2). Impaired clusterin import via LRP2  reduces its inhibitory effects on MAC complex formation  [44] . It is not known whether this is relevant to cerebral clusterin/LRP2/MAC  interactions. However LRP2 and  clusterin are expressed in the brain and the MAC complex has been detected in Alzheimer’s disease dystrophic neurites and neuronal cytoplasm [19;20]  and links between the lipoprotein and complement compartments may be relevant to complement related lysis.

In addition to these effects, APP is involved in anterograde herpes simplex transport in squid axons [45] .A 15 amino acid APP C-terminus peptide is important for general anterograde transport in this system [46]   . The APP binding protein APPBP2 (amyloid beta precursor protein (cytoplasmic tail) binding protein 2 or pat-1) also plays a role in anterograde APP and viral transport in mammalian systems and bind to the herpes virus US11 protein   [47;48] . Furthermore, gamma-secretase , the beta-amyloid generating protease, also cleaves the viral receptors, nectin1 alpha (PVRL1) [49] and syndecans 1 and 2 [50] [51] . Both beta-amyloid [52] and herpes simplex [53] also bind to other heparan sulphate proteoglycans, suggesting further areas of beta-amyloid/viral interaction. The virus also binds to chondroitin sulphate proteoglycans [54] . Interestingly an astrocytic form of APP, appican, which contains the beta-amyloid sequence, belongs to this family [55] . It is bound to chondroitin-4,6 sulphate [56] , a receptor for HSV-1 [57] , raising the intriguing possibility that this form of APP  could be used as a viral receptor. Viral binding to all  classes of serum lipoprotein (VLDL, LDL, HDL)   [10] also raises the possibility, so far untested, that lipoprotein receptors, and APP, whose extracellular domain binds to APOE [58] ,  might be involved in viral entry. Finally, fibrillar beta-amyloid, the toxic form of the peptide, enhances the infectivity of several viruses including herpes simplex in various cell lines. This was thought to be due to enhanced fusion of the viral lipid envelope with the cell membrane as beta-amyloid and other artificial fibril producing peptides also promoted the association of lipid vesicles with cells [59] . Although fibrillar beta-amyloid facilitates viral entry, the normal peptide has been shown to have antimicrobial activity against a variety of pathogenic bacteria, hinting at a physiological role for beta amyloid in pathogen defence [60] .

As can be seen in Fig 1, which summarises these effects, the virus targets many of the processes related to APP and beta-amyloid processing as well as the complement pathways. In turn, major susceptibility gene products as well as APP, beta-amyloid and gamma-secretase are involved in the viral life cycle. Over 30 immune or pathogen defence related genes (including CR1 and clusterin) have also been implicated in Alzheimer’s disease and polymorphisms therein are likely to influence their efficacy in relation to pathogen defence [61] (see http://www.polygenicpathways.co.uk/herpalz.htm

Polymorphisms in the major susceptibility genes are likely to affect several pathological processes, including lipoprotein/complement networks involved in beta-amyloid clearance (APOE/CLU/CR1) or inflammatory and immune defence systems (CR1/CLU) [8;9] . The virus apparently targets the same pathways, via its interactions with susceptibility gene products (Fig 1), and may thus act in synergy with the gene products to aid in the promotion of Alzheimer’s disease pathology.   These susceptibility genes might also influence viral infectivity, as is the case for APOE4 [62] .

Anti-HSV-1 immunoglobulin M seropositivity, a marker of primary infection or viral reactivation, as opposed to lifelong infection, correlates well with the future development of Alzheimer’s disease [63] . Anti HSV-1/IgM screening in the early stages of Alzheimer’s disease, or in the ageing population, might help to clarify the role of HSV-1 in Alzheimer’s disease, perhaps identifying those who might benefit from antiviral trials. It may also be informative to stratify the results of GWAS studies in relation to HSV-1 and other infectious agent’s seropositivity, to define potential gene/infection interactions.

The multinational GWAS studies have unearthed potential pathways involved in Alzheimer’s disease, including cholesterol/lipoprotein, APP processing and inflammation/immune defence networks. The genes identified, and others, are also closely related to herpes simplex, suggesting that the virus may interfere with the same pathways. Herpes simplex viral infection increases beta-amyloid deposition and tau phosphorylation and provokes cortical and hippocampal neurodegeneration and memory deficits in mice (see introduction), all key elements related to Alzheimer’s disease. It is thus well worth considering that herpes viral infection plays a key role Alzheimer’s disease pathogenesis, in genetically susceptible individuals. The possible implication of HSV-1 and other pathogens in Alzheimer’s disease warrants well-designed clinical trials with antiviral and/or antibacterial agents, as already suggested [13] .


Table 1 A glossary of the abbreviations used in the text.

Amyloid precursor protein related

Complement related

APP

Amyloid precursor protein:  Beta and gamma secretase cleavage generate beta amyloid

CR1

Complement receptor 1; Complement inhibitor

Appican

Chondroitin sulphate proteoglycan form of APP

C3

C4

Complement components C3 and C4

CASP3

Caspase 3: Degrades Abeta

CD59

Complement inhibitor

IDE

Insulin degrading enzyme: Degrades Abeta

MAC

Complement membrane attack complex: Assembly inhibited by Clusterin and CD59

Cholesterol/lipoprotein related

Herpes simplex receptors

ABCA1

Cholesterol/lipoprotein  transporter

CSPG

Chondroitin sulphate proteoglycan

A2M

Alpha-2 macroglobulin: Binds to ABeta and lipoprotein receptors

HSPG

Heparan sulphate proteoglycan

APOA1, APOE

Apolipoproteins

M6PR

Mannose-6-phosphate receptor

CLU

Clusterin/  Apolipoprotein J

PVRL1

poliovirus receptor-related 1 (herpesvirus entry mediator C)

LRP1

Lipoprotein receptors

SDC1

SDC2

Syndecans 1 and 2

(Heparan sulphate proteoglycans)

LRP2 (Megalin)

Miscellaneous

LRP8 (Apoer2)

Crm1 XPO1

Nuclear exportin

   

PICALM

Phosphatidylinositol binding clathrin assembly protein

Fig 1.

The relationships between key Alzheimer’s disease susceptibility gene products and herpes simplex. Genes implicated in Alzheimer’s disease are in black boxes with white lettering (referenced at http://www.polygenicpathways.co.uk/alzpolys.html ) Binding between components is represented by linked diamonds. HSV-1 binding to various components is illustrated by the stalked asterisk: Boxes labelled ? indicate that the literature infers a link between the virus and the target, although not directly verified for the particular protein. For example PICALM is involved in M6PR traffic, which is relevant to HSV-1, but PICALM/herpes interactions have not been studied. Similarly Appican is a chondroitin sulphate proteoglycan, a family of receptors used by herpes simplex to gain cellular entry, but appican/herpes interactions have not been studied.

Left: Beta-amyloid (β-Amy) facilitates viral entry: The sorting of the mannose-6-phosphate viral receptor is modulated by PICALM, which also binds to crm1 that is used by herpes simplex for nuclear egress.

Top: The viral receptors PVRL1 and syndecans, as well as APP, are cleaved by gamma-secretase. The virus and beta-amyloid bind to heparan sulphate proteoglycans (HSPG) and the virus binds to chondroitin sulphate proteoglycans (CSPG), of which appican is a member. Viral binding to lipoproteins may also implicate lipoprotein receptors and APP in viral entry. APP is involved in anterograde viral transport, and the transport of both APP and the virus is mediated via APPBP2.

Right:  Beta-amyloid processing is mediated via caspase-3 and insulin degrading enzyme and by lipoprotein and complement receptors, as shown.

Bottom: Viral, or CR1 binding to complement component C3 blocks the complement cascade and prevents formation of the membrane attack complex (MAC). Clusterin and the viral binding CD59 also prevent formation of this complex by binding to its components. Complement cascade


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