C.J.Carter:
Flat 4, 20 Upper Maze Hill, St Leonard’s on Sea East Sussex
Autoantibodies to beta-amyloid are common in the ageing population and in Alzheimer’s disease and may derive from aberrant forms of beta-amyloid (Abeta) or from antigens with homology to it. The latter seems likely, as glycoprotein B of the Herpes simplex virus (HSV-1) and 69 other viruses and phages, including HHV-6, Hepatitis C, polyoma viruses and HIV-1 show exact homology with a VGGVV C-terminal fibrillogenic sequence, an epitope that labels beta-amyloid in the Alzheimer’s disease brain. Other viruses, including those causing the common cold and influenza also show significant homology with known and predicted beta amyloid epitopes, as do a number of allergens (food, pollen and insect venoms and most notably house dust mites). Bacteria implicated as risk factors in Alzheimer’s disease (C.Pneumoniae, B.Burgdorferri , H.Pylori, P.Gingivalis) also contain matching Abeta proteins as does the meningitis causing fungus, C.Neoformans, which has been associated with a rare but curable misdiagnosed form of Alzheimer’s disease. Immune activation occurs in the Alzheimer’s disease brain, as evidenced by many immune-related proteins in plaques and by the presence of the complement membrane attack complex in neurones. These observations suggest that Alzheimer’s disease is an autoimmune disorder triggered by pathogens with homology to beta-amyloid, whose antibodies target and kill the neurones within which the peptide resides, via immune and inflammatory activation and complement-related lysis. Viruses matching the Abeta target regions of beneficial catalytic autoantibodies include those from components of the Mediterranean diet (plant viruses) and from the papillomavirus and other cancer-inducing viruses, both of which (cancer and diet) are inversely associated with Alzheimer’s disease risk. As a vaccine against the human papillomavirus already exists, it may have a role to play in the prevention of Alzheimer’s disease. This scenario explains most of the epidemiological observations in Alzheimer’s disease which is more common in women and Afro-Americans, as is HSV-2 seroprevalence; related to the number of pregnancies and thus greater exposure to childhood infections, and less severe in nuns, who are shielded from sexually transmitted diseases. Atopy and autoimmune disorders are common in Alzheimer’s disease in accord with allergen homology to Abeta, and the use of anti-inflammatory agents has been reported to reduce the risk of developing Alzheimer’s disease. HIV-1 infection can cause dementia with Alzheimer’s disease pathology, again in accord with Abeta homology. The four major risk genes in Alzheimer’s disease, APOE, clusterin, complement receptor 1 and PICALM can all be related to viral life cycles and clusterin and complement receptor 1 are both complement inhibitors. This scenario is also relevant to familial Alzheimer’s disease, as the four mutant forms of APP717 and the Swedish mutant (APP670/671) convert the surrounding peptide to matches with commensal bacterial flora (E.Coli, E. Faecalis, P.Gingivalis) and to viruses with high seroprevalence (HHV-6, norovirus and polyoma viruses) and to those causing influenza and the common cold. Multiple lines of evidence thus suggest that late-onset and Familial Alzheimer’s disease are autoimmune disorders caused by diverse common pathogens and allergens that are homologous to beta-amyloid or mutant APP fragments. Antibodies to these multiple agents are a likely source of the autoantibodies to beta-amyloid in the ageing population and would accumulate with repeated antigen exposure and age, the greatest risk factor in Alzheimer’s disease. Vaccination, which has already been shown to reduce the incidence of Alzheimer’s disease (diphtheria, influenza, tetanus, and polio), pathogen screening and elimination, and immunosuppressant therapy may be of therapeutic benefit in this disorder. This scenario is also relevant to several other autoimmune disorders including multiple sclerosis, myasthenia gravis, pemphigus vulgaris, systemic lupus erythematosus, and Chronic obstructive pulmonary disease where the known autoantigens also line up with the reported viral risk factors. Mutant proteins from other genetic diseases (Huntington’s disease and other PolyGlutamine repeat disorders) and cystic fibrosis also align with very common viruses. This may well be a near universal phenomenon, reflecting the idea that all life evolved from viruses, which have however left behind a deadly legacy of human viral derived proteins with homology to antigenic regions of the current virome. This could well be responsible for most of our ills. This also suggests that vaccination using epitopes to the non-homologous regions of the viral culprits may be of benefit in autoimmune and even in human genetic disorders.
Introduction
Autoantibodies to beta-amyloid are common in the ageing population and in Alzheimer’s disease and may exert a beneficial role in adsorbing the toxic peptide or catalysing its destruction. They may also mount an immune attack against beta-amyloid, activating inflammatory pathways and complement cascades that kill the neurones in which the peptide resides (1-3) . The membrane attack complex of the complement pathway is present in Alzheimer’s disease neurones (4;5) , supporting a role for aberrant immune/complement activation within the brain. The source of these autoantibodies is not clear. They could be derived as a response to abnormal forms of beta-amyloid or from antibodies to other antigens that cross-react with the peptide.
It has already been noted that glycoprotein B of the Herpes simplex virus shows marked homology with beta-amyloid, particularly matching a VGGVV C-terminus pentapeptide (6) (Fig 1). The VGGVG epitope has been used to label beta-amyloid1-40 in extracellular neurofibrillary tangles (7) . This pentapeptide, per se, forms aggregates characterised by twisted ropes and banded fibrils (8) . This is a characteristic of both beta-amyloid and of HSV-1 glycoprotein B peptide fragments containing this sequence. The viral glycoprotein B fragments form thioflavine T positive fibrils which accelerate beta-amyloid fibril formation, and are neurotoxic in cell culture (9) .Herpes simplex infection (HSV-1) has been shown to be a risk factor in Alzheimer’s disease, acting in synergy with possession of the APOE4 allele (10) . HSV-1 infection in mice or neuroblastoma cells increases beta-amyloid deposition and phosphorylation of the microtubule protein tau (11;12) .Viral infection in mice also results in hippocampal and entorhinal cortex neuronal degeneration and memory loss, all as found in Alzheimer’s disease (13) . A recent study has also shown that anti-HSV-1 immunoglobulin M seropositivity, a marker of primary viral infection or reactivation, in a cohort of healthy patients, was significantly associated with the subsequent development of Alzheimer’s disease. Anti-HSV-1 IgG, a marker of lifelong infection showed no association with subsequent Alzheimer’s disease development (14) . All of these factors support a viral influence on the development of Alzheimer’s disease. Antibodies to the Potato virus Y, which is highly homologous to beta-amyloid (Fig 1), are also able to label beta-amyloid containing plaques in the Alzheimer’s disease brain (15) . It is therefore possible that beta-amyloid autoantibodies are derived from such homologous antigens. Homology searches within viral and microbial proteomes and allergenic proteins showed that many are highly homologous to immunogenic regions of the beta-amyloid peptide and also that APP mutations in Familial Alzheimer’s disease convert the surrounding peptides to matches to very common viruses and bacteria.
Methods
Homology searches against viral, bacterial or fungal proteomes were performed via the NCBI or Uniprot BLAST servers and sequence alignments via the CLUSTAL server at UniProt (16) . Homology with allergen sequences was determined by interrogation of the Structural database of Allergenic Proteins (17) http://fermi.utmb.edu/SDAP/index.html and from homology searches at the AllergenOnLine database http://www.allergenonline.org/ (18) . Epitopes containing viral/beta amyloid matching sequences were found using the Human Immune epitope database. www.immuneepitope.org (19) . B-Cell epitopes were identified using the BepiPred server http://www.cbs.dtu.dk/services/BepiPred/ (20) .
Results
The homology between HSV-1 glycoprotein B and beta-amyloid1-42 is shown in Fig 1. A homology search against viral proteomes showed that a number of other viruses contain this VGGVV sequence (Table 1). These include adenovirus 8, Dengue virus, Herpes Simplex (HSV-1, 2 and 6) hepatitis C, Lactate dehydrogenase-elevating virus, the polyoma virus and HIV-1, viruses infecting family pets (cats, guinea pigs and goldfish) and farmyard animals (cattle, horses, pigs and poultry) and viruses infecting certain foodstuffs (cherries, radish, strawberries and raspberries, tomatoes, potatoes, watermelon, oysters, salmon and shrimp). The VVGGV sequence is also present in a number of phages infecting bacteria that cause common childhood and adult diseases (Gastroenteritis, food poisoning, hospital infections (nococosmial), and wound infections). It should be noted that the VGGVV sequence was restricted to 69 viruses and phages (Table 1) out of 2463 viral genomes in the NCBI database.
A further homology search against the viral proteome database revealed that many other common viruses express proteins with marked homology (pentapeptides or more) to other sequences within the beta-amyloid peptide (Table 2). These viruses include Adenovirus D, Coxsackie virus B2, influenza, hepatitis C and Yellow fever, numerous HIV-1 or HIV-2 proteins, and the human papillomavirus. Bovine and poultry viruses were also well represented. Phages infecting campylobacter, enterobacteria, lactococcus, mycobacterium, streptococci and vibrio (Pentapeptide or more) as well as Listeria and pseudomonas (Tetrapeptide matches) were also represented . These infect very common benign or infection-related bacteria. Although less homologous, viruses causing the common cold, mumps, rubella and polio nevertheless contained exactly matching tetrapeptide beta-amyloid sequences.
Numerous plant viruses contain both the VGGVV and other matching beta-amyloid sequences. Plant viruses are generally considered as benign or unable to infect humans. However, they are obviously ingested and exist in human faeces (21) . The Pepper mottle virus has recently been associated with fever in Man (22) suggesting that phytonosis might be more common than thought. A capsid protein of this virus contains the YEVHHQ sequence of beta-amyloid as do a number of other plant viruses, including the potato virus. This sequence is immunogenic (in beta-amyloid) and antibodies to the potato virus label amyloid plaques in the Alzheimer’s disease brain (15) . Sequences within the potato virus polyprotein show 54% identity with beta-amyloid1-28 (Fig 1).
Many of the viruses containing beta-amyloid sequences are very common (eg influenza and Herpes viruses and even the common cold virus) and the beta-amyloid matching phages are associated with a number of bacteria causing common gastrointestinal problems (e.g. clostridum, salmonella and vibrio) or associated with hospital infections (Pseudomonas, Serratia). Exposure to these agents, which possess myriad strains, is ineluctable and each exposure is likely to increase the risk of generating antibodies that might also target the beta-amyloid peptide.
Bacteria and Fungi implicated in Alzheimer’s disease
The VGGVV sequence, and others, are also present in proteins from C.Pneumoniae, Borrelia Burgdorferri and Helicobacter pylori (Table 3) all of which have been implicated as risk factors in Alzheimer’s disease (23;24) . Indeed, in infected Alzheimer’s disease patients, H.Pylori eradication can have beneficial effects on cognition (25) . C.Pneomoniae (penta- and hexapeptides) B.Burgdorferri (pentapeptides) and H.Pylori (Penta- and hexapeptides) proteins all contain matching beta-amyloid fragments. Tooth loss and periodontitis have also been cited as risk factors in Alzheimer’s disease (26;27) . Porphyromonas gingivalis and Streptococcus mutans are major cause of periodontitis, and proteins from these bacteria also contain the VGGVV and other internal beta-amyloid sequences (Table 3).
There are two case reports in the literature recording subjects diagnosed with Alzheimer’s disease, both with a three year history of dementia. Cryptococcal meningitis was subsequently diagnosed, and in both cases, antifungal treatment resulted in an almost complete recovery (28;29) C.Neoformans is the agent responsible for Cryptococcal meningitis and contains a number of proteins showing a striking similarity with beta-amyloid internal sequences, including exact homology with an N-terminus octapeptide and a c-terminus heptapeptide as well as the VGGVV sequence (Table 3).
Allergenic proteins
A search of the allergen databases showed that stretches within the beta-amyloid peptide, exactly match those in several common allergens, particularly in European (hexapeptide) and American (pentapeptide) house dust mites (Table 2, Fig 3 ) and in a rice fungus Aspergillus Oryzae. Rather less pentapeptide or more matches were found in this class but very many common pollen, fungal , insect venom, domestic animal (cat, cattle and horse) and food allergens (beans, rice, potato, tomato and nuts ) contain tetrapeptide sequences matching those of beta amyloid . House dust mites, as well as containing relatively large consensual sequences, display a large number of smaller peptide matches along the length of the beta-amyloid peptide (Table 2) suggesting that these ubiquitous and unavoidable creatures could play a rather unexpected role in Alzheimer’s disease.
Immune activation in the Alzheimer’s disease brain
A number of immune-system related proteins are found in amyloid
plaques or neurofibrillary tangles. Interleukin 1 alpha, interleukin 6, and
tumor necrosis factor are all been localised within plaques (30) and acute
phase proteins involved in inflammation, such as amyloid P, alpha-1 antichymotrypsin
and C-reactive protein are also plaque components (31) while Immunoglobulin
G is located in the plaque corona (32) . Large increases in IgG levels have
been recorded in the brain parenchyma, in apoptotic dying neurones and in
cerebral blood vessels in the Alzheimer’s disease brain (33) . Complement
component C3 is found in Alzheimer’s disease amyloid plaques along with complement
C4 (34) . Complement components Clq, C3d, and C4d are present in plaques,
dystrophic neurites and neurofibrillary tangles (5) .
The membrane attack complex (MAC), composed of complement
proteins C5 to C9, forms a channel that is inserted into the membranes of
pathogens, destroying them by lysis. These components cannot be detected in
temporal cortex amyloid plaques in Alzheimer’s disease (34;35) . However the MAC complex is present in dystrophic neurites
and neurofibrillary tangles (5) and others have detected this complex in neuritic plaques
and tangles, along with deposition of C1q, C3 and clusterin
(36) . The membrane attack complex
has also been detected in the neuronal cytoplasm in AD brains and associated
with neurofibrillary tangles and lysosomes (4) .The presence of the MAC complex in neurones might suggest
that neuronal lysis by the MAC complex could contribute to neuronal cell death
(5) .
Pathogen seropositivity in Alzheimer’s disease
Increased seropositivity to IgM anti HSV-1 antibodies has been reported to predict the risk of subsequently developing Alzheimer’s disease (14) . Increased seropositivity in Alzheimer’s disease has also been reported for Helicobacter pylori (37) and increased HHV-6 immunoreactivity has been observed in Alzheimer’s disease CSF samples (38) . No differences in the seropositivity of Adenovirus, Chlamydia Group B, Coxiella burnettii, Cytomegalovirus, Herpes simplex virus, Influenza A, Influenza B, Measles and Mycoplasma pneumoniae were found in a study of 33 Alzheimer’s disease patients and 28 controls (39) . However, there are a large number of diverse pathogenic antigens with homology to beta-amyloid, any of which may have been present, potentially provoking immune response-related neuronal loss, many years prior to seropositivity testing.
Antibodies and antigenicity
The tenet of the autoimmune hypothesis is that viral and other pathogens and environmental allergens with homology to beta-amyloid will trigger the production of antibodies that also target the beta-amyloid peptide. Those provoking a robust immune, inflammatory and complement response risk killing beta-amyloid containing neurones. Antibodies to the Potato virus (15) and to Borrelia antigens (24) ) have already been shown to label amyloid plaques in the Alzheimer’s disease brain and antibodies to a phage epitope (AEFRH) also label beta-amyloid (40) .
Potential cross-reactivity can partly be tested in silico but ultimately requires the characterisation of the autoimmune beta-amyloid epitopes present in Alzheimer’s disease and cross-reactivity testing between pathogenic and environmental antigens and beta-amyloid. Thus far, the precise epitopes labelled by beta-amyloid autoantibodies have not been fully characterised.
The initial rendezvous of antigens with the immune system is with B-cells which bind to, engulf and digest the antigen. The B-cell epitope antigenicity prediction (20) for beta-amyloid is illustrated in Figs 2 and 3, over which are laid the pathogens and allergens that match particular sequences within the beta-amyloid peptide. As can be seen, Coxsackie, HIV-1, HSV-1, Hepatitis C, influenza, mumps, the respiratory syncitial virus, rhinoviruses (common cold) and clostridia, enterobacteria and vibrio phages match sequences that lie within predicted antigenic regions of beta-amyloid (Fig 2). An increase in immunogenicity is also observed within the VGGVV sequence, which has been used as an epitope to label beta-amyloid (7) . Allergenic proteins whose sequences match those of antigenic portions of beta-amyloid include those from fungal, nut, pollen, insect venom and house dust mites (Table 2, Fig 2).
As a further theoretical test, all consecutive tetrapeptide sequences within beta-amyloid were screened against the human epitope and the HIV-1 molecular Immunology databases to determine which antigens contain these epitopes. As shown in Tables 2 to 7 many viral, fungal, bacterial, parasite and allergen antibodies contain tetrapeptide sequences from the beta-amyloid peptide. In addition, apart from beta-amyloid isoforms and a small number of mammalian proteins, the major matching epitopes were concentrated in viral, bacterial, fungal and allergen classes (i.e. not other species or other mammalian proteins). These databases contain over 73,000 epitopes, so again the results returned are highly specific to these classes. This at least shows that antibodies that have been used to label these viruses, pathogens and allergens, contain beta-amyloid sequences, and that potential cross-reacting antibodies are concentrated in these classes.
The ability of autoantibodies to adsorb beta-amyloid can be considered as useful, and certain of these appear to be associated with reduced plaque volume (1) . Other autoantibodies, present in normal and Alzheimer’s disease sera, also possess catalytic properties and are capable of destroying the toxic peptide. Such antibodies do not form stable immune complexes and are less likely to activate immune inflammatory and complement related cell lysis (2) . This is where the danger lies, as antibodies capable of mounting a full-blown immune response against beta-amyloid are likely to kill the cells in which the peptide resides. It is relatively common to find Alzheimer’s disease pathology at autopsy (plaques and tangles) in patients who were cognitively normal shortly before death (41) . In such patients, it is tempting to suggest that immune-activating antibodies are rare.
Catalytic beta-amyloid auto-antibodies cleave the beta-amyloid peptide primarily between the two histidines (H/Q) at Abeta13-14 , and to a lesser extent at other positions as shown in Figs 2 and 3 {Taguchi, Planque, et al. 2008 1720 /id} . The major cleavage site is within a non-immunogenic region of the peptide. Interestingly, several plant viruses (Amaranthus, Pepper, Pistachio, Potato, Rice, Soybean, Sunflower and Zucchini (courgette) and allergens (Rice, Pistaccio, Soybean as well as the cat allergen and insect venoms) express proteins homologous to this particular region. Rather intriguingly, several of these plants/vegetables are constituents of the Mediterranean diet which has been reported to reduce the risk of developing Alzheimer’s disease (42) . Such diets impact on cholesterol/lipoprotein function and on atherosclerosis, a major contributory factor in Alzheimer’s disease (43;44) but could also conceivably be related to beneficial antibodies generated by the ingestion of common plant viruses, a possibility that also suggests potential immunisation strategies.
Certain proteins from three cancer-causing viruses, Epstein-Barr (HSV-4), Hepatitis B and the human Papillomavirus virus are also homologous to this catalytic antibody target region, suggesting a plausible explanation for the inverse association between cancer and Alzheimer’s disease (45)
Vaccinations and Alzheimer’s disease
It has been noted that the risk of developing Alzheimer’s disease was reduced following vaccination against diphtheria, influenza, polio or tetanus (46) . Again, sequences within proteins of these pathogens are homologous to beta-amyloid as shown in Fig 2, (which represents the viral proteins rather than the epitopes used for vaccination). This is rather encouraging as it suggests that, if the effect of vaccination is due to beta-amyloid homology, other vaccines might similarly reduce the incidence of Alzheimer’s disease. The papillomavirus vaccine, already used to prevent cervical cancer (47) , is a prime candidate as a viral protein matches the beta-amyloid region targeted by catalytic autoantibodies. However, as there is an evident danger of creating potentially toxic beta-amyloid autoantibodies, characterisation of the epitopes targeted by such vaccines must be of prime concern.
Epidemiological studies
These observations suggest that Alzheimer’s disease may have an autoimmune component, triggered by antigenic proteins with homology to beta-amyloid. Such a scenario helps to explain several, indeed most, epidemiological features of Alzheimer’s disease. For example, Atopy and autoimmune diseases are common in Alzheimer’s disease (48;49) , and could relate to allergen homology with beta-amyloid. Alzheimer’s disease prevalence is higher in women and in Afro-Americans (50) , as is HSV-2 prevalence (51) .
. Herpes simplex infection is a risk factor in Alzheimer’s disease acting in synergy with the APOE4 allele (52) and dementia, with Alzheimer’s disease pathology is common in HIV-1 infected patients (53) , a situation perhaps explained by viral protein homology with beta-amyloid. Such homology with pathogen proteins could also explain the association of Borrelia Burgdorferri, Helicobacter pylori, C.Pneumoniae (23;24) and by inference P.Gingivalis and Streptococcus mutans (oral pathogens causing periodontitis and tooth loss (26;27) ) with Alzheimer’s disease. The incidence of Alzheimer’s disease is also related to the number of pregnancies (54) , which might be explained by greater exposure to common childhood illnesses (cf phage/bacterial homology with beta-amyloid). It has also been noted that nuns, who are less exposed to sexually transmitted pathogens, show some resistance to the ravages of Alzheimer’s disease (41) . An autoimmune scenario may also explain why the use of non-steroidal anti-inflammatories reduces the risk of developing Alzheimer’s disease (55) as do fish consumption and the Mediterranean diet (42;56) .Such diets are rich in N-3 polyunsaturated fatty acids, which also possess anti-inflammatory properties (57) . The beneficial effects of these diets and also of statins (58) are likely to be related to multiple problems in cholesterol and lipoprotein homoeostasis in Alzheimer’s disease (59) but may also be related to pathogens and the immune system. For example viral entry is often lipid dependent a a factor related to fusion of the viral lipid envelope with cell membranes, and the cellular entry of HIV-1 and herpes simplex is cholesterol and lipid raft -dependent and blocked by nystatin (60;61) . Statins also habe immunosuppressant properties (62) . The potential role of viruses as constituents of the Mediterranean diet has been discussed above in relation to their homology with beta-amyloid regions targeted by beneficial catalytic autoantibodies. The inverse association between cancer and Alzheimer’s disease might also be explained in these terms (see above) and the beneficial effects of vaccination can also be related to pathogen homology with beta-amyloid (diphtheria, influenza, tetanus and polio). The risk promoting effects of aluminium in Alzheimer’s disease (63) might also be explained by its common self-prescribed use as an antacid in gastrointestinal disturbances (64) often caused by phage/bacterial pathogens with homology to beta-amyloid.
In short almost all epidemiological observations related to Alzheimer’s disease can be explained in terms of pathogens and/or autoimmunity.
Late-onset Alzheimer’s disease susceptibility genes
Four genes, Apolipoprotein E, clusterin, complement receptor 1 and PICALM,
are the main suspects in Alzheimer’s disease (65-67) each of which can be
implicated in viral life cycles. For example, APOE binds to HSV-1 (68) and
Hepatitis C viruses (69) and the Alzheimer’s disease risk allele, APOE4, is
also related to HSV-1 and HIV-1 infection, although, curiously, it protects
against Hepatitis C infection (70) . Complement receptor 1 and clusterin
are both involved in the complement cascades that play a crucial role in pathogen
defence (71) . In addition the influenza virus and HSV-1 both bind to complement
receptor 1 on erythrocytes (72) . One of the receptors used by
Herpes simplex for cellular entry is the Mannose-6-phosphate receptor, M6PR
(73) . This receptor binds to clusterin (74) 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
(75) . The Herpes simplex and Influenza viruses also uses exportin
(Crm1) dependent pathways for nuclear egress (76;77) . PICALM and other endocytic-regulatory proteins bind to Crm1
(78) .
Many minor genes (see www.polygenicpathways.co.uk/alzpolys for references) are also implicated in viral life cycles. For example lipoprotein receptors implicated in Alzheimer’s disease (LRP1, LDLR, VLDLR) are used by human rhinoviruses to gain cellular entry (79) . The nectin receptor PVRL2 is a Herpes viral receptor (80) , as is insulin degrading enzyme (81) . In addition over 30 immune related genes (chemokines, cytokines, complement related, toll receptors HLA-antigens) have been implicated as risk factors. All of these might be expected to modulate immune defence.
Given the plethora of viral and environmental beta-amyloid homologues, and the presence of autoantibodies to beta-amyloid in healthy aged subjects, it seems likely that the functional gene variants in the control group, rather than the Alzheimer’s disease risk promoting genes, may be more important. These are presumably those that prevent the ravages of autoimmunity.
Familial Alzheimer’s disease
Familial early-onset Alzheimer’s disease is caused by a number of different mutations in presenilins and the APP gene, including several mutations as APP717 (V/I, V/M, V/G, V/L) (London mutation and others) and at KM670/671NL (Swedish mutation) (inter alia :see http://www.molgen.ua.ac.be/ADMutations/) (82) . These are not within the beta-amyloid sequence. Both mutations modify APP processing and increase the generation of Abeta 1-42 (83;84) . In so doing, they may thus be able to increase the probability of Abeta encountering autoantibodies, both in the brain and in the periphery resulting in a feed forward further generation of autoantibodies by the immune system.
The APP717 mutant is within two gamma-secretase cleavage sites generating an undecapeptide as shown in Fig 1. The Swedish mutation is immediately prior to the beta-secretase cleavage site that, with gamma-secretase, generates beta-amyloid and frees the native or mutant APP670/671 terminus (85) . Homology searches against viral and bacterial proteomes were performed using the native and mutant forms of the APP717 undecapeptide and the nonapaptide upstream of the Swedish mutation sites (Fig 1). The APP717G mutant increased the predicted B-type immunogenicity of the peptide, but other mutants were without effect (not shown).
Native APP717 is homologous to several phages, viruses and bacteria, many of which are common; for example Enterobacteria, lactococcus and staphylococcus phages, adenovirus, cytomegalovirus, the parainfluenza virus and rotavirus and the less common rabies and coronaviruses (Table 4). This native form also shows homology with several bacterial species, which for the most part, with the exception of Lactobacilli, are pathological rather than commensal (Table 5).
The various APP717 mutations alter this matching profile in a number of ways. For example the V/F mutation creates matching peptides to Herpes viruses HSV-2, 3 and 8 and markedly increases the number of hits in relation to homology, particularly within bacterial flora (mainly due do many strains of the commensal E.Faecalis) (Tables 4 and 5).
The APP717 V/G mutant creates a peptide region homologous to proteins from human herpes virus 6, a pathogen with seroprevalence approaching 100% (86) and to the JC and BK polyomaviruses which also display high seroprevalence in the normal population ( 39% and 82% respectively (87) ) . This mutant also creates regions homologous to the endemic soil bacterium B.Cereus, to a bacterium causing verrucas, and to P.Gingivalis a constituent of the oral flora that plays a role in periodontitis and tooth loss (tables 4 and 5).
The V/I mutant creates homologues to proteins from over 30 Rhinococcal strains causing the common cold, to the mumps virus and to the common Norovirus responsible for vomiting sickness, as well as to the endemic soil bacteria B.Cereus and S.Aureus, and the commensal E.Coli and P.Gingivalis (Table 4,5).
The V/L mutant creates regions homologous to proteins from Influenza A and B viruses and to Hepatitis C and Herpes viruses 4 and 5, as well as to the commensal E.Coli and Streptococcus Hominis (Tabke 4,5).
The native APP670/671 peptide is homologous to a number of influenza viruses, which are almost exclusively avine. The Swedish mutant increase the number of viral matches to the upstream peptide, particularly to enterobacterial phages, and creates homologous regions to several species of human adenoviruses, which also show high seroprevalence (88) , and to the respiratory syncitial virus as well as to human rhinoviruses and again to E.Coli. Several of these mutant peptides are homologous to mycobacterial phages (see Tables 6,7 ), perhaps explaining why tuberculosis (as well as possession of the HLA-DR3 allele) have been reported as risk factors in familial Alzheimer’s disease (49) . The epitopes generated by these mutants are again concentrated within viral and pathogen proteins, particularly the Vaccinia Virus (Tables 4-7). There do not appear to have been any studies on autoantibodies in familial Alzheimer’s disease but the large number of viral and bacterial peptides perfectly matching the mutant surrounds suggests that autoimmunity may also play a major role in this disorder. Although clearly genetic, its pathology may be autoimmune related, as well as to, or perhaps rather than aberrant beta-amyloid processing.
In short, these mutants, in different ways, all increase the number and variety of viral and bacterial matches, to commensal (Particularly E.Coli, E.Faecalis and P.Gingivalis ) as well as to pathological species (Clostridia, Mycobacteria, Vibrio, inter alia) and create homologous regions to very common pathogens causing the common cold, influenza, herpes infections and periodontitis.
APP transgenic mice
If autoimmunity rather than problems in APP processing is relevant, this could explain why APP transgenic models do not faithfully mimic Alzheimer’s disease (i.e. extensive cholinergic neuronal loss, loss of hippocampal afferents and efferents and massive cortical degeneration) (89) . There have been two studies assessing the effects of infection in APP transgenic mice. Repeated Streptococcus Pneumoniae infection had no effect on pathology or behaviour in APP Tg2576 transgenic mice (Swedish mutant) (90) . S.Pneumoniae displays homology to both the native and mutant forms of the relevant peptide (Table). Borna virus infection resulted in a reduction in beta-amyloid immunoreactivity in the brains of infected Tg2576 transgenic mice (91) . This virus also displays homology to both the native and mutant forms of the peptide (Table). S.Pneumoniae also expresses proteins containing the VGGVV sequence, as do a large number of other bacteria (not shown), while a homology search for Borna virus proteins containing VGGVV yielded no hits. However, in relation to autoimmunity, it is not the infection itself, but the antibodies generated in response to the infection that could cause the problem. A more suitable test might be repeated challenge with specific antigens in APP transgenic models.
Other models capable of producing cerebral beta-amyloid deposition in mice include C.Pneumoniae (92) or HSV-1 infection (11) , the latter also producing hippocampal and entorhinal cortex neuronal loss and memory deficits, perhaps more faithfully reproducing the pathology of Alzheimer’s disease (13) . Such models may be useful in APP transgenic mice.
Beta-amyloid and other Vaccines and therapies.
.
The F,G and I APP717 mutants all generate peptides homologous to the related Vaccinia and Variola (Smallpox) viruses (Table 4,6) . While vaccination against diphtheria, flu, tetanus and polio have been reported to reduce the risk of late-onset Alzheimer’s disease (see above) there is also a possibility of vaccine cross-reactivity with endogenous peptides such as beta-amyloid. Many of the epitopes formed by these mutant peptides are contained within Vaccinia viral proteins. There is thus a possibility that smallpox vaccination may be a contributory factor in familial Alzheimer’s disease, although this requires characterisation of the epitopes present in the vaccine, which was generated from the virus rather than from peptide components. The vaccinia virus has also been used as a primary vaccination against smallpox (93) following on from Edward Jenner’s pioneering experiments with cowpox over 200 years ago (94) . This is a contentious area, but the possibility that vaccination might trigger nefarious autoantibody generation does need to be addressed, particularly in future studies.
The potential use of beta-amyloid antibodies is based on their ability to reduce plaque burden and neurite dystrophy in APP transgenic mice (95)
Several studies have demonstrated that beta-amyloid antibodies reduce plaque
burden in APP transgenic models and that they can also improve cognitive performance
(96) . However amyloid antibodies extracted from the serum of old APP transgenic
mice potentiate the toxicity of beta-amyloid and Alzheimer’s disease patients
display an enhanced immune response to the peptide (97) . Again in transgenic
mice, different immune backgrounds can influence the type of immune responses
elicited by beta-amyloid. For example B-and T-cell responses to beta-amyloid
can be modified in HLA-DR3,
-DR4,
-DQ6 or -DQ8 transgenic mice (98) . HLA-antigen diversity in Man is also likely to determine the outcome of beta-amyloid/antibody interactions.
The results of this survey suggest that beta-amyloid autoantibodies might cause as well as mitigate against Alzheimer’s disease pathology. Beta-amyloid vaccination in Alzheimer’s disease (against Abeta1-42) has so far not been successful and sadly resulted in meningoencephalitis and the death of a patient (99) . While certain beta-amyloid antibodies may reduce plaque burden, there is an evident risk that they may also trigger an auto-immune response, potentially killing beta-amyloid containing neurones. Catalytic autoantibodies are less able to form stable immune complexes and likely represent the safest way forward in this area (2) . It is intriguing that the beta-amyloid region targeted by catalytic autoantibodies matches peptide sequences of viruses that are constituents of the Mediterranean diet and of cancer-inducing viruses (Epstein-Barr, Hepatitis B, and the papillomavirus) as both cancer and the Mediterranean diet are inversely associated with Alzheimer’s disease risk (see above). Vaccines to the human papillomavirus already exist (47) and could perhaps be considered as a therapeutic or preventive option in Alzheimer’s disease, after due consideration of the epitope matches.
If beta-amyloid autoantibodies are the culprits, techniques such as immunoadsorption, which has proved to be of benefit in Myasthenia gravis (autoimmunity to acetylcholine receptors (100) or immunosuppressant use might be considered as potential therapeutic options. There is indirect evidence in support of such treatment. Natural immunoadsorbants include silica, which is however toxic, (101) , tryptophan and phenylalanine (102) . Levels of silica in drinking water are inversely related to Alzheimer’s disease risk (103) and serum tryptophan levels are markedly depleted in Alzheimer’s disease patients, a marker of immune activation (104) .Phenylalanine plasma levels are in contrast increased in Alzheimer’s disease (105) . Fish oil (see above) also suppresses T-Lymphocyte activation (106) and statins, which have also been reported to reduce Alzheimer’s disease risk (58) are also immunosuppressant (62) .
Heterogeneity in genetic and epidemiological studies
If there is one factor common to polygenic disorder research it is the discordance of genetic and environmental association data in this and other diseases. However, if, as suggested by this survey, there are dozens of potential Alzheimer’s disease triggers, all funnelling towards a common cause, this heterogeneity becomes part of the answer and not part of the problem. Different gene products are related not only to human physiology, but also to pathogen life cycles (e.g. rhinoviruses and lipoprotein receptors, APOE and Herpes Simplex or influenza and complement receptor 1) , a situation that has been discussed in relation to Alzheimer’s disease and Schizophrenia susceptibility genes and pathogens implicated in these disorders (107;108) . Viruses and bacteria are not uniformly distributed worldwide, nor is antibody seroprevalence, and different environmental risk factors may similarly vary from region to region. The heterogeneity observed in these studies thus has a rational basis, reflecting the heterogeneity of cause, and need not necessarily be considered as a statistical artefact
Relevance to other autoimmune and genetic diseases and evolutionary aspects
.
A homology search against viral proteomes with known autoantigens
from multiple sclerosis, myaesthenia gravis, pemphigus vulgaris, systemic
lupus erythematosus, and Chronic obstructive pulmonary disease retuned viral
matches, which in all cases were relevant to the viruses implicated as risk
factors in each disease (Table 8) , also identifying other suspects. Furthermore,
in other genetic disorders,
Phages and viruses are the simplest form of “life”, as defined by the possession of DNA/RNA and a proteinaceous structure, and were long ago proposed as the origin of higher cellular organisms (111;112) . There are currently 2463 viral genomes in the NCBI database, probably representing but a small proportion of those existing on the planet. While perhaps responsible for our origin these predecessors may have donated a legacy of human viral-derived proteins that closely match antigenic proteins in the currently existing virome that could be responsible for many human diseases including genetic disorders, autoimmune disorders, polygenic diseases, and those that have so far baffled research, such as ME (Myalgic encephalomyelitis/chronic fatigue syndrome) and fibromyalgia. This evidently has enormous implications for therapy and prevention, not only of autoimmune disorders, but also of polygenic and human genetic disorders, until now generally regarded as unassailable. Vaccination, using epitopes against the non homologous human protein regions of the phages and viruses could perhaps destroy the pathogen and prevent the associated problems related to autoimmunity.
Summary and conclusions
Many common viruses, phages, bacteria, fungi, parasites and allergens express proteins with marked homology to antigenic and other regions of the beta-amyloid peptide. Epitope similarity with beta-amyloid is concentrated within these classes and it seems likely that these antigens provide a source of the beta-amyloid autoantibodies found in the ageing population and in Alzheimer’s disease. While some of these antibodies may be benevolent, others may stimulate immune, inflammatory and other defensive measures, including complement mediated cell lysis that could kill the neurones in which the peptide resides. Activation of the immune system is supported by the presence of many immune-related proteins in Alzheimer’s disease amyloid plaques, and by the presence of the complement membrane attack complex in Alzheimer’s disease neurones. Reduced serum tryptophan levels, and an increased immune response to beta-amyloid also suggest immune activation. Familial Alzheimer’s disease may also have a strong autoimmune component, as the various APP mutants convert the surrounding peptides to matches to commensal bacteria (E.Coli, E.Faecalis and P.Gingivalis) and to viruses with a high seroprevalence (HHV-6, polyoma viruses, influenza and the common cold rhinoviruses). The categorisation of Alzheimer’s disease as an autoimmune disorder explains most of the epidemiological observations in Alzheimer’s disease and the major genes implicated in Alzheimer’s disease are all related to viral life cycles and/or to the complement arm of the immune defence network.
Diseases caused by these viruses, fungi or the bacteria infected with the phage/beta-amyloid homologues are very common and often recurrent (e.g. colds, influenza gastroenteritis or food poisoning) as is exposure to certain allergens (e.g. dust mites , cat, cow, horse allergens, pollen and food allergens, insect stings, marine algae etc) Over time, and with increasing age, the major risk factor in Alzheimer’s disease (113) , antibodies that may also target beta-amyloid are more likely to be produced, gradually increasing the probability of a self-immune attack on neurones containing the beta-amyloid peptide. There may thus be dozens, if not hundreds of triggers promoting Alzheimer’s disease risk, all funnelling towards an autoimmune scenario. If this is the case, then Alzheimer’s disease might be considered as an autoimmune disorder and immunosuppressants or antibody adsorption might have a role to play in its therapy, once diagnosed. C.Neoformans eradication can result in a complete recovery, in very rare cases of diagnosed dementia (28;29) , and Helicobacter elimination has been reported to ameliorate cognitive function in infected Alzheimer’s disease patients (25) . Aggressive targeting of opportunistic pathogens capable of mimicking the beta-amyloid peptide might thus be considered as a therapeutic option. Because so many are homologous to beta-amyloid, such therapy might well have to be tailored to individual pathogens, depending on the species identified by serum assay.
Vaccination against common diseases has already been shown to reduce the risk of developing Alzheimer’s disease (46) and, in the long term, vaccination against other common viruses and bacteria might also be of benefit, although it is evident that potential vaccine antibody cross-reactivity with beta-amyloid must be a prime concern. One such vaccine may already exist in the form of that for the human papillomavirus.
. In summary, the close homology of diverse viral, fungal bacterial and allergenic antigens with beta-amyloid and to peptides generated by APP mutations suggests an autoimmune component to familial and late-onset Alzheimer’s disease, triggered by these antigenic homologues. The autoimmune scenario explains many epidemiological observations and genetic studies also implicate the immune system and viral life-cycles. If autoimmunity is important, vaccination, viral and pathogen elimination and immunosuppressant therapy might be expected to play a role in the prevention and therapy of Alzheimer’s disease and perhaps provide new rationales for developing a cure. This type of viral matching is also relevant to other autoimmune and genetic disorders and may be a near universal phenomenon reflecting our viral ancestral roots. This generality could open new therapeutic avenues in many human diseases.
Acknowledgements: Thanks to the numerous authors for reprints, to Oliver Chao and Nasire Mahmudi for finding others, and to Maria Jesus Martin at Uniprot and Tao Tao at NCBI for help with the mysteries of BLAST and Clustal alignment settings.
Table 1: Virus and phage proteins containing the VGGVV sequence, and the
diseases they cause. Accession numbers are provided and seroprevalence is
recorded for human viruses where available.
| Virus |
Protein VVGGV |
Disease |
Seroprevalencs |
| Human Viruses |
|||
| Dengue virus 1 |
ACQ44424 Polyprotein |
Febrile tropical disease |
Endemic in some countries (eg
100% seroprevalence in |
| Hepatitis C |
ACY65348
envelope protein 2 : ADG28960 NS4A ABC58527 NS4B: ADC54771 Polyprotein |
Hepatitis |
An estimated 270-300 million people worldwide are infected with hepatitis C 1.8% (USA) (115) |
| Human adenovirus 8 |
BAH18864 17.7kDa protein |
Keratoconjunctivitis |
? |
| Human herpesvirus 1 |
P08665 Envelope glycoprotein B: ABI63489 UL27 |
Cold sores, mouth, throat, face, eye and CNS infection |
68% (USA)
(116) |
| Human herpesvirus 2 |
NP_044471 uracil-DNA glycosylase: BAG49514 Glycoprotein B |
Anogenital infections |
16% in |
| Human herpesvirus 6 |
AAA43846 Envelope glycoprotein B |
|
Approaching 100%
(86) |
| Human herpesvirus 6B |
BAA78260 Envelope glycoprotein B |
Causes Roseola, a near-universal childhood disease |
Approaching 100%
(86) |
| Human immunodeficiency virus |
ACQ42512 vif Protein |
Acquired immune deficiency syndrome |
Rare 0.02% (USA)
(117) |
| Lactate dehydrogenase-elevating virus |
YP_001008394 Polyprotein 1ab |
Not well characterised |
? |
| Polyomavirus HPyv6 and 7 |
ADE45477 VP2 |
Human infection |
No data on these strains but for other polyoma viruses can range from 9 to 69% (87) |
| Yellow fever virus |
NP_776003 Polyprotein : NS2A |
Yellow Fever |
75% |
| Phages infecting human bacteria and diseases associated with the bacteria |
|||
| Aeromonas phage |
YP_238875 WAC |
Gastroenteritis and wound infections |
|
Enterobacteria phage |
NP_037676 tail length tape measure protein
|
Normal gut flora, many of which can cause gastrointestinal problems |
|
| Escherichia
phage |
Chain
A, Ibv: YP_002003548 hypothetical protein |
Many are harmless but can cause diarrhoea to dysentery |
|
| Mycobacterium Phage |
ACU41726 GP233 YP_002014682 GP71 YP_655916 YP_655355 GP51 GP78 NP_818073 GP108 |
Pulmonary disease, Tuberculosis and leprosy |
|
Prochlorococcus phage
|
ACY76180 Hypothetical protein |
Marine cyanobacteria |
|
| Pseudomonas phage |
Tail fiber assembly protein |
Nosocomial hospital infections |
|
| Serratia
phage KSP20 |
TAILC_BPSK2 |
Nosocomial hospital infections |
|
| Streptomyces phage |
NP_958289 ORF9 |
Antibiotic producing bacteria |
|
| Vibrio phage |
AAQ96489 Hypothetical protein |
Gastroenteritis, septicaemia |
|
| Other phages |
|||
| Azospirillum
phage |
YP_001686888 Hypothetical protein |
Nitrogen fixing plant bacterium |
|
| Halomonas phage |
YP_001686782 hypothetical protein HAPgp46 |
Salt water |
|
| Microcystis
aeruginosa phage |
YP_851126 hypothetical protein MaLMM01_gp112 |
Harmful blue-green algae |
|
| Prochlorococcus
phage |
ACY76180 hypothetical protein PSSM2_305 |
Common marine cyanobacteria |
|
| Synechococcus
phage |
YP_003097380 tailfiber like protein hypothetical protein SRSM4_083 |
Marine cyanobacteria |
|
| Agricultural Viruses |
|||
| Bovine
herpesvirus 5 |
YP_003662471
Envelope glycoprotein K |
Cattle |
|
| Bovine
herpesvirus type 2 |
P12641
Envelope glycoprotein B |
Cattle |
|
| Bovine
viral diarrhea virus |
CAD67689
hypothetical protein |
Cattle |
|
| Avian
infectious bronchitis virus |
ACJ12832
polyprotein 1ab |
Poultry |
|
| Infectious bronchitis virus |
Replicase
polyprotein 1ab: , Ibv Nsp3 Adrp Domain |
Poultry |
|
| Equid herpesvirus 1, 4 and 9 |
YP_002333504 NP_045240 YP_053068 tegument protein UL37 |
Horse |
|
| Suid herpesvirus 1 |
YP_068340.Tegument protein UL37 |
Pigs |
|
| Swinepox virus |
NP_570175 kelch-like protein |
Pigs |
|
| Plant,
food and environmental viruses |
|||
| Anguillid herpesvirus 1 |
YP_003358210 ORF71 |
Eel |
|
| Viral hemorrhagic septicemia virus |
ADB93794 Polymerase: Large protein |
Fish |
|
| Cherry necrotic rusty mottle mosaic virus |
ABZ89196Replication protein |
Cherry |
|
| Radish mosaic virus |
BAG84603 Polyprotein |
Radish |
|
| Watermelon mosaic virus |
ACF60797 Polyprotein |
Watermelon |
|
| Ostreid herpesvirus 1 |
YP_024568ORF23 |
Oyster |
|
| Arabis mosaic virus |
BAF35852 Polyprotein: NTB binding domain |
Strawberries and raspberries |
|
| Viral hemorrhagic septicemia virus |
ADB93794Polymerase; Large protein |
Fish |
|
| Shrimp white spot syndrome virus |
NP_477731 wsv209 |
Shrimp |
|
| Antheraea pernyi nucleopolyhedrovirus |
ABQ12330 ETM |
Environment Insect Chinese Tuss Moth |
|
| Murid herpesvirus 2 |
NP_064139 pR34 |
Environment Rodents |
|
| Allpahuayo virus |
NP_064139 Nucleocapsid protein |
Environment Rodents |
|
| Helicobasidium
mompa endornavirus 1 |
YP_003280846
Polyprotein |
Environment Root rot fungus |
|
| Paramecium
bursaria Chlorella virus |
YP_001498106 and others Hypothetical proteins |
Environmental Algae |
|
| Archaeal
BJ1 virus |
YP_919057 hypothetical protein BJ1_gp30 |
Environmental |
|
| West
Caucasian bat virus |
YP_919057. Glycoprotein G |
Environmental Bat |
|
| Cyprinid herpesvirus 3 |
BAF48875 ORF62 |
Family pet Goldfish |
|
| Caviid herpesvirus 2 |
BAF48875 GP144 |
Family pet Guinea Pig |
|
| Macropodid herpesvirus 1 |
AAD11961 Glycoprotein B |
Zoo Marsupial |
|
| Macropodid herpesvirus 2 |
AAD11960. Glycoprotein B |
Zoo Marsupial |
|
| Macacine
herpesvirus 1 |
NP_851887 Glycoprotein B |
Zoo Monkey |
|
| Cercopithecine herpesvirus 1, 2 and 16 |
BAC58067 eg Envelope glycoprotein B |
Zoo Monkey |
|
| Papiine herpesvirus 2 |
AAA85650 Envelope glycoprotein B |
Zoo Monkey |
|
| Chimpanzee
alpha-1 herpesvirus |
BAE47051 Glycoprotein B |
Zoo Monkey |
|
| Allergens |
|||
| Lichwort
:Parietaria officinalis |
AAB36010
major allergen {N-terminal, band 2} |
Non-stinging nettle family growing on rubbish and walls |
|
Viral and allergen proteins matching tetrapeptide sequences, or more, within the beta-amyloid peptide (1-42). Shaded dark grey blocks represent viral matches to pentapeptides, or more, as shown by the numbers in each block. Allergens are boxed in light grey and protein accession numbers are provided. Species with protein epitopes containing these sequences are also illustrated. Short beta-amyloid epitopes (antibodies raised to peptides of 4-6 amino acids) are illustrated by the grey boxes with dashed surrounds. Matches to these short immunogenic peptides are perhaps more likely to cross-react with beta-amyloid.
| Tetrapeptide |
Viral
and allergen proteins |
Species with epitopes containing this
sequence |
Human /Mouse Epitopes |
|
|||||||
| DAEF |
Acc:158998780 Pecan Acc:18479082Hazelnut 4 |
|
|
|
Beta
amyloid |
|
Corylus
avellana (Hazel antigen,) Entamoeba histolytica (dysentery), Trypanosoma
cruzi |
Beta-amyloid |
|
||
| AEFR |
Acc:157418806
Herring worm 4 |
|
|
|
|
Junin,
Machupo and Vaccinia virus |
|
||||
| Beta-amyloid |
|||||||||||
| Beta-amyloid |
|||||||||||
| EFRH |
Coxsackie Virus B2 Capsid protein VP1; AAD17716 5 |
Polyprotein Rhinovirus
C ABK29455 4 |
Acc: 7117013 Bumble bee venom 4 |
AC:A23876 Bahia grass pollen 4 |
Beta
amyloid |
|
|||||
| Beta-amyloid |
|||||||||||
| FRHD |
gp35
Vibrio phage KVP40 NP_899628 5 |
gp037 Rhodococcus
phage ReqiPepy6 ADD80928 4 |
Polyprotein
Hepatitis C virus subtype 1b ACJ37243 5 |
|
Streptomyces
griseoflavus and pristinaespiralis, Deinococcus
radiodurans |
Beta-amyloid
: Glutamate receptor-interacting protein 1 Homo sapiens |
|||||
| RHDS |
Human respiratory syncytial
virus CAA24906 4 |
|
Beta
amyloid |
Corynebacterium
genitalium |
Beta-amyloid |
|
|||||
| HDSG |
Polymerase European bat lyssavirus 1 ACF37166 Polymerase Duvenhage virus ACF37214 polymerase Lyssavirus Ozernoe ACS70797 Large protein Rabies virus
ADD84791 5 |
38.7KD
protein Choristoneura occidentalis (Western Spruce Budworm) granulovirus
YP_654475 6 |
|
|
|
Human herpesvirus
4 |
Beta-amyloid |
|
|||
| DSGY |
hypothetical
protein P27p15 Enterobacteria phage phiP27 putative helicase NP_543067 Enterococcus
phage phiEF24C YP_001504154. 5 |
Acc: 119633262: American house dust mite 4 |
|
Haemophilus
influenzae Subtype 1H Monkeypox virus Tityus serrulatus (Scorpion venom) |
Beta-amyloid |
|
|||||
| SGYE |
HIV-1 reverse transcriptase ABO63585 4 |
large
protein Rabies virus ADD8479 5 |
Acc:
8118428 : Rice pollen Acc: 295812 Tomato 4 |
|
|
Beta-amyloid |
|
||||
| GYEV |
putative
DNA polymerase Pseudomonas phage LKA1 YP_001522870 4 |
|
HIV-1 reverse transcriptase AAZ49919 5 |
|
|
Vaccinia
Virus |
Beta-amyloid |
|
|||
| YEVH |
|
Polyprotein Potato virus Y: AAG44632 Pepper mottle virus PEMV capsid protein AAA46902 : Nib-CP polyprotein Amaranthus viridis leaf mottle virus CAE30467 polyprotein Sunflower chlorotic mottle virus ACA00155 6 |
|
|
|
- |
Beta-amyloid:
Integrin Alpha M Mus Musculus |
|
|||
| EVHH |
Polyprotein
bovine viral diarrhea virus AAC06278 5 |
|
AAG4447
Penicillium oxalicum 4 |
|
|
- |
Beta-amyloid |
|
|||
| VHHQ |
|
|
|
|
- |
Beta-amyloid |
|
||||
| HHQK |
Human
papilloma virus Oncoprotein E6 AAK95780 5 |
|
Acc:
5777414: Rubber plant Acc:62530262 Mugwort 4 |
Acc:
149786149 Pistaccio 4 |
|
|
- |
Beta-amyloid |
|
||
| HQKL |
|
|
|
|
|
Streptococcus
pyogenes; SARS coronavirus Guanarito virus |
Beta-amyloid |
|
|||
| QKLV |
ORF1
Hepatitis E 5 |
Acc: 119633262 American House dust mite allergen: Acc: 20385544European House dust mite allergen4 |
Acc:
8118439 Rice allergen: Acc: P40918 Davidiella tassiana fungal
plant pathogen: Acc: Q92260Heat shock 70 kDa proteinPenicillium citrinum
Fungus |
Acc:
P51528 Eastern yellowjacket venom Acc: P49369 Common wasp venom 4 |
Acc:
Q6R4B4 Alternaria alternata fungus
(causes asthma 4 |
|
Plasmodium
falciparum; Hepatitis E virus, HIV-1 |
Beta-amyloid |
|
||
| Clostridium
botulinum Hepatitis E virus, |
|
||||||||||
| KLVF |
AAB23464
Soybean allergen Acc: 170899 Candida boidinii |
|
|
|
|
Beta-amyloid
: Sus Scrofa: zona pellucida sperm-binding protein 3 |
|
||||
| SARS coronavirus,
Plasmodium falciparum, Clostridium botulinum, SARS coronavirus, Canine
parvovirus |
|
||||||||||
| LVFF |
|
polyprotein Zucchini yellow mosaic virus 6 |
P27762 common ragweed pollen: ACA23876 Bahia grass pollen 4 |
P30440 Major cat allergen 4 |
|
|
Chlamydophila
pneumoniae,Vaccinia virus |
Beta-amyloid |
|
||
| VFFA |
HSV-3 tegument protein CAI44881 4 |
Polyprotein Dasheen mosaic virus 4 |
|
gp24
Mycobacterium phage ACF05027 5 |
|
Major allergen
Felis catus |
Beta-amyloid |
|
|||
| FFAE |
ORF037
Staphylococcus phage 37 4 |
|
Fowl Adenovirus D ORF19 AAC71680 unknown fowl
adenovirus 8 AAC71680 6 |
|
Bacillus
anthracis |
|
|||||
| Mouse
Annexin A7 |
|
||||||||||
| FAED |
|
Gallid HerpesVirus 2 UL37-like protein ABF72276 6 |
Acc: 467660 Davidiella tassiana fungus Acc: Q9HDT3 Alternaria alternata: Acc: 14585753 Cochliobolus lunatus Acc: Q870B9E Rhodotorula mucilaginosa: AC:1392587 Aspergillus fumigatus Acc: 13991101 Penicillium citrinum. (All Fungi) 4
|
polyprotein Kelp fly virus polyprotein Kelp fly virus 5 |
Acc: P02769 Cow Allergen Acc: 399672 Horse allergen 4 |
Vibrio
vulnificus |
Beta-amyloid |
|
|||
| AEDV |
HSV-1 gB: Adenovirus 52 hexon HIV-1 : nonstructural protein 1 Influenza A virus 4 |
Acc:P43213PolCommon Timothy pollen Acc:P27760 Short ragweed: Acc:4090265 C37396 reed fescue: Acc:P43216 Velvet grass Acc:375486372 Candida albicans 4 |
Acc:1545803 American house dust mite Acc:6492307 Maynes House dust mite Acc:20385544 European house dust mite |
HSV-1,
Hepatitis C; Mycobacterium tuberculosis, Pollen antigen Phleum pratense,
Plasmodium vivax, Schistosoma mansoni |
Beta-amyloid
:H.Sapiens 60 kDa heat shock protein, mitochondrial precursor |
|
|||||
| EDVG |
Polyprotein precursor Rubella virus Envelope; glycoprotein G Human herpesvirus 2 4
|
putative
receptor binding protein Lactococcus phage HD3 AAT81524 6 |
Acc:4826572 Common timothy 4 |
ADH04370
envelope glycoprotein Human immunodeficiencyvirus 2 6 |
|
HSV-2,
Rubella virus |
Beta-amyloid |
|
|||
| DVGS |
Polyprotein Human rhinovirus
C 4. |
|
|
|
Mycobacterium
tuberculosis |
Beta-amyloid |
|
||||
| VGSN |
HIV-1 env ACB36783 5 |
BAH09387Arthroderma vanbreuseghemii (Rabbit dermatophyte) |
Gb:121584258 Penicillium citrinum 4 |
|
Hepatitis
B virus, Yellow fever virus, Candida albicans, Tacaribe virus |
Homo
sapiens amylin; Beta-amyloid islet amyloid polypeptide precursor
Mus musculus |
|
||||
| GSNK |
Hypothetical
phage protein Campylobacter phage CP220 6 |
fiber
protein Human adenovirus D 5 |
Acc: P00785 Actinidain Chinese fruit: Acc: 166317 Delicious macaque peach 4 |
Acc: 51093373 Fire ant venom 4 |
Plasmodium
berghei |
Beta-amyloid:
Homo sapiens, Immunoglobulin M |
|
||||
| SNKG
|
Hemagglutinin
Influenza A virus A/mallard/Ohio ABJ16576 6 |
polyprotein Large-leaved lupine mosaic virus 5 |
Acc: P25780 Europeaun house dust mite; Acc: P25780 Maynes house dust mite: 6 |
Acc: 167782086 Common Wasp venom Acc: 2038554 European House dust mite 4 |
Bovine
respiratory syncytial virus; Spirosoma linguale |
Beta-amyloid |
|
||||
| Acc: 166531 Aspergillus oryzae fungus 5 |
|||||||||||
| NKGA |
Acc: 11963326 American House dust mite 5 |
Human
respiratory syncytial virus, Clostridium botulinum |
Beta-amyloid
: Homo Spiens Collagen: C.Elegans protein |
|
|||||||
| Acc:
47606004 Japanese Acc:O64943 Juniper 4 |
|||||||||||
| KGAI |
HIV-1 envelope glycoprotein ACX43323 6 |
Acc:
2342526 IgE autoantigen Homo sapiens Acc:2723284 SART-1 autoantigen Homo sapiens
4 |
Acc:
169973 Soybean allergen 4 |
Plasmodium
falciparum,Bacillus anthracis |
Beta-amyloid |
|
|||||
| GAII |
Mumps Virus Fusion protein
AAK83222 HSV-6 H86 AAC40335 Tail length tape measure-related protein Salmonella phage SETP3 YP_001110853 :4 |
nonstructural
protein 1 Influenza A virus (swine) ACV93293 5 |
HIV-1 env HM001426 6 |
Acc: Q9SQI9 Peanut
allergen 4 |
crispr-associated
protein Cas5, hmari subtype Clostridium phage ZP_04863779 6 |
Chlamydia
trachomatis |
Beta-amyloid
, H.Sapiens. dihydrolipoamide S-acetyltransferase |
|
|||
| AIIG |
ACC:O04725 Couch grass pollen ACC:Q9M7M8 Rubber plant pollen ACC:Q9XG85 Stickyweed pollen Q9XF37 Celery Pollen |
ACC:
16555785 Pepper plant ACC: 16555787 Tomato ACC: 27528312 Peach ACC: 57021110 Cantaloupe melon ACC:
12659206 hazelnut ACC:O65810Soybean ACC: Q9XF41 Common
Apple ACC: 15809696 Lychee ACC: 18652049 Wild carrot ACC: 2317674 Buckwheat 4 |
Human
herpesvirus 5, Vaccinia virus, Dengue virus 2, Bovine viral diarrhoea
virus 1, Pseudomonas aeruginosa Sabia virus, Vaccinia virus, Coxiella
burnetii, Brucella melitensis biovar Abortus |
Beta-amyloid
: |
|
||||||
| IIGL |
Conserved
hypothetical protein Pseudomonas phage D3 AAF80834 putative protein Lactobacillus prophage
Lj965 AAR27468 4 4 |
Acc: P51528 Eastern yellow jacket venom Acc: P53357 Bald-faced hornet venomAcc: P49369Common Wasp venom Acc: 45510887 Paper wasp venom Acc:2231297 Cockroach allergen 4 |
Polyprotein St Louis encephalitis
polymerase ABN11819 ADF59230 4 |
RNA
polymerase Oropouche virus NP_982304 structural polyprotein precursor
Kyzylagach virus AAO33327 polyprotein Porcine teschovirus AAK12398 neuraminidase Influenza virus CAZ64818 Polyprotein Sindbis virus BAH70330 5 |
Beta-amyloid |
|
|||||
| IGLM |
polyprotein
Hepatitis C virus BAH70330 HIV-1 env 5 |
ACX45222 4 |
Capsid proteinAndean potato mottle virus AAA42421 6 |
Acc: 5815436 American House dust mite 4 |
|
Escherichia
coli, Human adenovirus 5 |
Beta-amyloid |
|
|||
| GLMV |
putative
DNA polymerase Burkholderia phage BcepC6B AAT38391 5 |
|
|
Potato
virus Y, Brucella abortus, Mycobacterium tuberculosis, Yersinia pseudotuberculosis
|
Beta-amyloid |
|
|||||
| LMVG |
Hypothetical
protein Streptococcus phage PH10 CAY56537 5 |
Polyprotein
Yellow fever virus AAB01971 6 |
hypothetical
protein Bovine viral diarrhea virus strain 3887 CAD67689 7 |
|
|
Beta-amyloid |
|
||||
| MVGG |
Hepatitis C
Ns4b ABC58497 HIV-1 gag GQ371529 replicase Cherry necrotic rusty mottle virus ABZ89196 6 |
AF177380_1 Couch grass BAA07773| Rice allergen Acc:3749962 Peanut allergen 4 |
|
Salmonella
enterica |
Beta-amyloid |
Beta
amyloid |
|
||||
| VGGV |
69
Viruses and phages See Table 1 5 |
Acc:
10944737 Hazel pollen: AAB36010: Stickyweed pollen Acc: P25985 Kidney bean: Acc: Q2VU97 Mung Bean Acc: 21044 Common Bean: Acc: 1398916 Acc: 963013 Aspergillus fumigatus 4 |
Acc: P49275Mite allergen Der f 3 American house dust mite 4 |
|
Beta
amyloid |
||||||
| GGVV |
Polyprotein
Bovine viral diarrhea virus 2 AAA82981 6 |
Poliovirus 1 Polyprotein AAQ03174 4 |
AAB36010
Stickyweed Acc: P85894 Black mulberry Acc:7803879 Malassezia sympodialis Yeast:
Acc: 3754863729 Candida albicans Acc: 6492307 precursor Maynes House dust mite Acc:20385544 European House dust mite 4 |
Corynebacterium
diphtheriae, Guanarito virus, Hepatitis C, Whitewater Arroyo virus |
|
||||||
| Beta-amyloid
:Bos Taurus: retinol binding protein 3, interstitial precursor |
Beta
amyloid |
||||||||||
| GVVI |
Acc:14161637 Pineapple Acc: Q9XF41 Apple Acc: P16348 Potato 4 |
Acc: Q5EF31 Crocus pollen Acc: 20736624 Common wheat Acc: 2317674 Buckwheat Acc: O22655 Maize Acc: P52184 Barley 4 |
|
HSV-1
UL45 NP_044647 4 |
|
Schistosoma
mansoni, Mycobacterium tuberculosis, Streptococcus mutans |
Human
ACAN protein |
||||
| Beta-amyloid
; Beta-amyloid |
|||||||||||
| VVIA |
Acc:
51316214 London Plane pollen Acc: O04403 Stickyweed pollen Acc: 21751 Wheat Acc:A0AT29Lentil 4 |
Acc:
88657350 German cockroach Acc: Q8T5G9 Archaeopotamobius sibiriensis
(Crustacean) Acc:413817 Malassezia sympodialis (Yast) 4 |
|
|
|
Francisella
tularensis, Mycobacterium avium Yellow fever virus, Vaccinia virus,
Streptococcus sobrinus, Human parainfluenza virus 2 |
|||||
Table 3: Beta-amyloid homologous regions for proteins from Borrelia Burgdorferri, Chlamydia Pneumoniae, Helicobacter pylori, Porphyromonas Gingivalis and Streptococcus Mutans. Protein accession numbers are provided and proteins with matches to pentapeptides or more are boxed in grey. The number of matching amino acids is shown in each box.
| Tetrapeptide |
Bacterial and Fungal proteins |
||||
| DAEF |
|
|
|
|
|
| AEFR |
C.Neoformans XP_568788 nucleoporin nup189 8 |
|
|
|
|
| EFRH |
|
|
|
||
| FRHD |
|
|
|
||
| RHDS |
Porphyromonas gingivalis YP_001930121 nicotinate phosphoribosyltransferase
5 |
|
|
||
| HDSG |
|
|
|
||
| DSGY |
|
|
|
|
|
| SGYE |
|
|
|
|
|
| GYEV |
P. Gingivalis
AAQ66366 GDP-mannose 4,6-dehydratase 5 |
|
|
|
|
| YEVH |
|
|
|
||
| EVHH |
|
|
|
|
|
| VHHQ |
|
|
|
|
|
| HHQK |
C.Neoformans EAL22689 CNBB1380 CNBB1380 5 |
Streptococcus mutans NP_720522 UA159 5 |
|
|
|
| HQKL |
Borrelia Burgdorferri YP_002474437
4 |
|
|
||
| QKLV |
Streptococcus mutans YP_003485284 putative deacetylase
NN2025 5 |
P. Gingivalis NP_905110 4 |
Helicobacter
pylori YP_003058029 5 |
|
|
| KLVF |
|
C.Pneumoniae NP_225149 4 |
Helicobacter pylori ABF84522 5 |
||
| LVFF |
|
P. Gingivalis BAA35086 4 |
|
|
|
| VFFA |
|
|
|
|
|
| |
|
|
|
|
|
| FFAE |
P. Gingivalis YP_001929160 alpha-amylase 5 |
|
Borrelia Burgdorferri
YP_002375334 |
|
|
| FAED |
C.Pneumoniae ACZ32801 ACZ32801 5 |
Borrelia Burgdorferri ZP_03087390 4 |
|
|
|
| AEDV |
|
|
|
|
|
| EDVG |
|
|
Borrelia Burgdorferri
YP_002775754 4 |
|
|
| DVGS |
Borrelia
Burgdorferri ZP_03796379
5 |
|
|
|
|
| VGSN |
|
|
|
|
|
| GSNK |
|
|
Borrelia Burgdorferri
AAC69850 4 |
|
|
| SNKG |
|
C.Neoformans AAW43455 5 |
Borrelia Burgdorferri
YP_002640982 4 |
|
|
| NKGA |
C.Neoformans AAW46377 5 |
|
|
ZP_03796084DNA
Borrelia burgdorferi 2 5 |
|
| KGAI |
NP_223696
Helicobacter pylori 6 |
ZP_03796006
Borrelia burgdorferi 5 |
Helicobacter
pylori Q9ZKF8 6 |
||
| GAII |
|
|
|||
| AIIG |
Streptococcus mutans BAH87814 hypothetical protein
NN2025 5 |
|
|
||
| IIGL |
|
NP_722409 Streptococcus mutans UA159 5 |
|
|
|
| IGLM |
C.Neoformans AAW43628 7 |
|
|
|
|
| GLMV |
|
|
|
|
|
| LMVG |
|
|
Helicobacter pylori ZP_03243748 5 Borrelia Burgdorferri EEG98688 5 |
|
|
| MVGG |
|
C.Pneumoniae ACZ32927 6 |
P. Gingivalis BAG34216 5 |
||
| VGGV |
C.Neoformans EAL22148 CNBC2860 AAW47124 CNN01610 AAW42376 5 |
Streptococcus mutans 5 YP_003484924 |
P. Gingivalis AAQ66697 5 |
||
| GGVV |
Helicobacter
pylori NP_222802 5 |
||||
| GVVI |
|
|
|
|
|
| VVIA |
|
|
|
|
|
Table 4: The
effects of the APP717 mutations (in Red) on homology to viral proteins.
Protein accession numbers are provided and amino acid matches are indicated
by the asterisks or by the red letter of the mutant amino acid. Species with
proteins containing epitopes matching those of the peptide amino acids are
also shown (Marked by E). Phages infecting commensal bacteria and common viruses
(eg Rhinoviruses and influenza) are highlighted in bold.
