Journal of Proteomics & Bioinformatics - Open Access

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Bioinformatic Analysis of Alzheimer’s Disease Using Functional Protein Sequences

Allam Appa Rao1 , Kiran Kumar Reddi2, Hanuman Thota2
1
International Center for Bioinformatics, Department of Computer Science and Systems
Engineering, Andhra University, Visakhapatnam-530003, India
2
Department of Computer Sciences and Engineering, Acharya Nagarjuna University, Guntur-522510, India

Corresponding Author: Prof. A. A. Rao, Principal, Andhra University College of Engineering, Visakhapatnam-530003,
India, Tel:+91-891-2844204; Fax: +91-891-2747969; E-mail: [email protected]

Received January 03, 2008; Accepted April 15, 2008; Published April 22, 2008

Citation: Allam AR , Kiran KR, Hanuman T (2008) Bioinformatic Analysis of Alzheimer’s Disease Using Functional Protein
Sequences. J Proteomics Bioinform 1: 036-042. doi:10.4172/jpb.1000007
Copyright: © 2008 Allam AR, etal. This is an open-access article distributed under the terms of the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author
and source are credited.

Abstract
Alzheimer’s disease is a progressive neurodegenerative disorder characterized by deposition of amyloid plaques composed of aggre-
gated amyloid beta plaques, and neurofibrillary tangles composed of hyperphosphorylated tau that leads to synaptic defects resulting in
neuritic dystrophy and neuronal death. Missense mutations in amyloid precursor protein (APP), PS-1 (presenilin-1 situated on
chromosome 14), PS-2 (presenilin-2 situated on chromosome 1) genes alter the proteolysis of APP and increase the generation of Aâ42
(amyloid â-42). The accumulation of Aâ42 as diffuse plaques triggers the inflammatory responses in the form of microglial activation
and release of cytokines. In addition, perturbation of equilibrium between kinases and phosphatases results in hyperphosporylation of
tau protein. These events culminate in neuronal degeneration and neuronal loss.
In the present study, we extracted huge amounts of data from various biological databases available online. It is found that there are 74
genes that may cause Alzheimer’s disease .We evaluated the role of 74 proteins that are likely to be involved in Alzheimer’s disease by
employing multiple sequence alignment using ClustalW tool and constructed a Phylogenetic tree using functional protein sequences
extracted from NCBI. Phylogenetic tree was constructed using Neighbour – Joining Algorithm in Bioinformatics approach. The
results of this study suggest that PS-1, PS-2, and APP have a dominant role in the pathogenesis of Alzheimer’s disease. The present
study raises the possibility that genetic components are more important in Alzheimer’s disease compared to environmental, metabolic,
and age related factors.

Keywords: Alzheimer's disease; Free radicals; Presenilin; Acetylcholine; Phylogenetic trees; Amyloid precursor protein

Introduction
Over the past 25 years, it has become clear that the proteins forming amyloidogenic processing of amyloid precursor protein (APP).
the deposits are central to the disease process. Amyloid-ß and tau Chemg et al., (2007) reviewed the recent findings regarding
make up the plaques and tangles of Alzheimer’s disease(AD), where the association of BACE1, γã-secretase and APP in lipid rafts,
these normally soluble proteins assemble into amyloid-like and discuss potential therapeutic strategies for AD that are
filaments(Michel and Maria, 2006). Recently Ballatore based on knowledge gleaned from the membrane environ-
et al. (2007) summarized the most recent advances in the ment that fosters APP processing.
mechanisms of tau-mediated neurodegeneration to forge an
integrated concept of those tau-linked disease processes that drive Missense mutations in amyloid precursor protein (APP),
the onset and progression of AD and related tauopathies. New presenillin-1 (PS-1) (chromosome 14), presenillin-2 (PS-2) (chro-
evidence indicates that tau may mediate neurotoxicity by al- mosome 1) genes alter the proteolysis of APP and increase the
tering the organization and dynamics of the actin cytoskel- generation of Aß42 (amyloid ß 42) .Genetic studies have led to the
eton (Gallo, 2007). Amyloid formation is a nucleation-de- identification of three genes in which mutations can cause AD:
pendent process that is accelerated dramatically in vivo and in the ß-amyloid precursor protein gene located on chromosome 21,
vitro upon addition of appropriate fibril seeds (Alexander presenilin 1 (PS1) located on chromosome 14 and presenilin 2
et al., 2006) AD is a progressive neurodegenerative disorder (PS2) located on chromosome 1(Hanuman et al., 2007). The accu-
characterized by amyloid plaques composed of aggregated mulation of Aß42 as diffuse plaques triggers the inflammatory
amyloid beta plaques, neurofibrillary tangles (NFT) composed responses due to microglial activation and release of pro-inflam-
of hyperphosphorylated tau and synaptic defects resulting in matory cytokines. In addition, perturbations in the equilibrium
neuritic dystrophy and neuronal death (Hutton and between kinases and phosphatases resulting in
McGowan, 2004). A growing body of evidence implicates hyperphosphorylation of tau protein that results in neuronal de-
cholesterol and cholesterol-rich membrane microdomains in generation and neuronal loss (Selkoe, 2001). The microtubule-

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www.omicsonline.com Research Article JPB/Vol.1/April 2008
associated protein tau is also involved in
the disease, but it is unclear whether treat-
ments aimed at tau could block Aß-induced
cognitive impairments(Erik et al.,
2007).
Several other genes that are considered to
increase susceptibility for AD include:
apolipoprotein E (ApoE 4) variant (Poierier
et al., 1995), 2-macroglobulin (Blacker et
al., 1998), the K-variant of butyryl-cho-
linesterase (Sridhar et al., 2006), and
several mitochondrial genes (Law et al.,
2001). Other factors that are believed to
play a role in the aetiopathogenesis of AD
include: brain metabolic abnormalities, en-
vironmental factors, and age related de-
crease in neuronal membrane fluidity that
could also produce neuronal death, in all
probability, by increasing the formation of
amyloid beta plaques and
hyperphosphorylation of tau protein (Iqbal
and Grundke-Iqbal, 2005).
Mutations in presenilins leads to dominant
inheritance of Familial Alzheimer’s disease
(FAD). These mutations are known to alter
the cleavage of γã-secretase of the amyloid
precursor protein, resulting in the in-
creased ratio of Aß42/ Aß40 and acceler-
ated amyloid plaque pathology in
transgenic mouse models (Wang et al.,
2006). Proteolytic processing of APP by ß-
secretase, γã-secretase, and caspases gen-
erates A-beta peptide and carboxyl-termi-
nal fragments (CTF) of APP, which have
been implicated in the pathogenesis of
Alzheimer’s disease (Selkoe, 1999). Mis-
sense mutations in the gene encoding APP,
as well as those in the genes encoding PS-
1 and PS-2, share the common feature of
altering the γã-secretase cleavage of APP
to increase the production of the
amyloidogenic Aß42, a primary component
of amyloid plaques in both familial and
sporadic AD.
In the present study, we focused on the
genes or proteins that are believed to have
a major role in the pathogenesis of
Alzheimer’s disease using bioinformatics
tools.

Materials and Methods

We collected 74 known proteins that are
believed to be involved in the pathogen-
esis of Alzheimer’s disease (Table 1). The
functional protein sequences in FASTA for-
mat for these proteins are collected from
NCBI (National Center for Biotechnology
Information, (http\\www.ncbi.nih.nlm.gov).
These sequences are given to ClustalW
(http\www.ebi.ac.uk\clustalw) for the Mul-
tiple Sequence Alignment, which calculates
the best match for the selected sequences,
and lines them up so that the identities,
Figure 1: The phylogenetic tree that was constructed based on the alignment score
of all the protein sequences involved in Alzheimer’s disease. A high degree of homol-
ogy was noted between presenilin1, presenilin 2, Amyloid beta (A4) precursor protein.
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www.omicsonline.com Research Article JPB/Vol.1/April 2008

S.No. Gene Name Ac. No. Length Tissue Type

(Amino acids)
1 A2M AAH26246 353 LIVER
2 ABCB1 AA130425 1280 CERABELLUM
3 ACHE AAH36813 546 BRAIN
4 AD7C-NTP AAC08737 375 NEURONAL
5 APLP1 AAH12889 650 OVARY
6 APOB AAH51278 825 LIVER
7 APOD AAH07402 189 MELANOTIC MELANOMA
8 APOE BBA96080 63 BLOOD
9 APP AAH65529 751 RETIOBLASTOMA
10 BACE1 AAH36084 501 BRAIN
11 ABCA2 AAH08755 867 EYE
12 ABAD AAH08708 252 BRAIN
13 BCHE AAH08396 64 BRAIN
14 BDNF AAH29795 247 BRAIN
15 CASP6 AAH00305 293 LUNG
16 CCK AAHO8283 115 PANCRESS
17 CCR5 AABO9551 215 NOT SPECIFIED
18 CD36 CCA83662 472 NOT SPECIFIED
19 CD40LG CAI42902 240 NOT SPECIFIED
20 CDH1 AAY68225 882 NOT SPECIFIED
21 CDK5 CAG33322 292 NOT SPECIFIED
22 CETP AAB59388 425 LIVER
23 CFTR NP_000483 1480 NOT SPECIFIED
24 CHAT AAI30618 630 CERABELLUM
25 CHRNA7 AAH37571 321 BRAIN
26 CLU AAH19588 449 BRAIN
27 CSF1 AAH21117 554 KIDNEY
28 CSNK1D AAH15775 409 SPLEEN
29 CTNNA3 AAH65819 516 PERIPHERAL NERVOUS SYSTEM
30 CTSD CAG33228 412 NOT SPECIFIED
31 CYCS AAH67222 105 CARCINONA
32 CYP19A1 AAH56258 359 PLACENTA
33 DBN1 AAH07567 649 RHABDOMYOSARCOMA
34 DCN AAH05322 359 LIVER

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35 DSCR1 AAH02864 197 LUNG
36 ESR1 CAI42285 595 NOT SPECIFIED
37 ESR2 AAH24181 323 TESTIS
38 FGF2 NP_001997 288 NOT SPECIFIED
39 FN1 AAH16875 268 CARCINOMA
40 GAL AAH30241 123 CARCINOMA
41 GLUL AAH51726 373 BRAIN
42 GSK3B AAM88578 74 FETAL BRAIN SYSTEM
43 HTR6 AAH74996 440 FETAL BRAIN SYSTEM
44 IGF1R AAH10607 55 BRAIN
45 FE65 AAH10854 708 LEIMYOSARCOMA
46 IL18 CAG46798 193 NOT SPECIFIED
47 LRP1 AAH21204 439 RHABDMOMYOOSAREOMA
48 MAPK1 AAH99905 360 BRAIN
49 MAPT AAH0558 352 BRAIN
50 NCSTN AAH47621 689 TESTIS
51 PIN1 AAH31971 45 TESTIS
52 PLAU AAH13575 431 CARCINOMA
53 PNMT NP_002677 282 NOT SPECIFIED
54 MCP1 AAO75526 25 NOT SPECIFIED
55 NP1 AAK61283 473 NOT SPECIFIED
56 NgR ABC69293 600 BRAIN
57 PAT1 AAC83973 585 NOT SPECIFIED
58 IVIg CAC29069 110 B-CELL
59 LPL CAG3335 475 NOT SPECIFIED
60 PSEN1 AAH11729 463 MELANOTIC MELONOMA
61 PSEN2 CAH73110 448 NOT SPECIFIED
62 S100B AAH01766 92 MELANOTIC MELONOMA
63 SNCA AAI08276 140 MELANOTIC MELONOMA
65 STH AI30322 128 CEREBELLUM
66 UBB AAH3899 229 BRAIN
67 VEGF AAA35789 191 NOT SPECIFIED
68 PRND AAH43644 176 TESTIS
69 PARP1 AAH14206 250 MELANOTIC MELONOMA
70 MAPK10 AAH35057 461 BRAIN
71 MAPK14 AAH31574 360 BRAIN
72 IL1RAPL2 AA10478 686 BRAIN
73 IL2RA CAI41071 200 NOT SPECIFIED
74 IDE CAI132670 1019 NOT SPECIFIED
Table 1: Tableshowinggenes/proteinsthathavebeenstudied in the presentstudy, which are believed to be involved in Alzheimer’s disease.
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similarities and differences can be seen. Based on these results,
the scores table and phylogenetic tree that shows the distance Several studies showed that Aß is toxic to cultured neuronal cells
between the protein sequences was constructed. The proteins and induces tau phosphorylation (Takashima et al., 1993). Tau is
with minimum distance are presenillin-1 (PS-1), presenillin-2 (PS- a microtubule-associated protein that stabilizes neuronal micro-
2) and amyloid precursor protein (APP). tubules under normal physiological conditions, however in cer-
tain pathological conditions like Alzheimer’s disease, tau protein
Results and Discussion undergoes modifications, mainly through phosphorylation that
can result in the generation of aberrant aggregates that are toxic
The bioinformatics analysis revealed three important proteins out to neurons (Avila et al., 2004). Amyloid vaccine (both passive
of 74 proteins that are key pathological proteins in the evolution and active immunization against amyloid) arrests and even re-
of Alzheimer’s disease. The present bioinformatics study revealed verses both plaque pathology and behavioral phenotypes in the
that the proteins: presenilin-1 (PS-1), presenilin-2 (PS-2), and amy- transgenic animals (Morgan et al., 2000). Aß42 fibrils can signifi-
loid precursor protein (APP) play a significant role in the patho- cantly accelerate neurofibrillary tangles formation in P301L mice
genesis of Alzheimer’s disease(Figure 1). providing further support to the hypothesis that amyloid beta
could be a causative pathogenic factor. Mutations in tau give rise
Factors that seem to influence the initiation and progression and to nerofibrillary tangles but not plaques and mutations in APP or
thus, have a role in the pathophysiology of AD are: i) Aß42/ Aß40 in the probable APP proteases give rise to both plaques and
ratio and oligomers of these peptides; ii) oxidative stress; iii) tangles indicates that amyloid pathology occurs upstream of tau
proinflammatory cytokines produced by activated glial cells, iv) pathology. Although the exact mechanism(s) by which amyloid
alterations in cholesterol homeostasis, and v) alterations in cho- beta causes neuronal death is not clear, there is evidence to sug-
linergic nervous system (Rojo et al., 2006). gest that it could enhance free radical generation and induce in-
Amyloid beta peptide and alzheimer’s disease flammation that could result in profound loss in the cholinergic
system of brain, including dramatic loss of choline
Familial Alzheimer’s disease (FAD) is associated with acetyltransferase level, choline uptake, and decrease in acetyl-
choline (ACh) level which are responsible for cognitive deficits in
mutations in APP, PS-1, and PS-2. AD.
These substances, along with their normal counterparts, undergo Oxidative stress and neuronal death
proteolytic processing in the endoplasmic reticulum (ER). The
mutated compounds, apart from increasing the ratio of Aß42 to One of the major age-related damaging agents are reactive oxy-
Aß40, may down-regulate the calcium buffering activity of the gen species (ROS). Increased levels of ROS (also termed “oxida-
ER. Decrease in the ER calcium pool would cause compensatory tive stress”), produced by normal mitochondrial activity, inflam-
increases in other calcium pools, particularly in mitochondria. In- mation and excess glutamate levels, are proposed to accelerate
crease in mitochondrial calcium levels are associated with en- neurodegenerative processes characteristic of Alzheimer’s
hanced formation of superoxide radical formation, and hence dam- disease (Huber et al., 2006).
age to the neurons and their senility (Harman, 2002). Amyloyd beta causes hydrogen peroxide (H2O2) accumulation in
Presenilins act as catalytic subunit of gamma secretase. cultured hippocampal neurons (Mattson et al., 1995) that re-
Presenilins, the causative molecules of FAD, are transmembrane sults in oxidative damage to cellular phospholipid membranes
proteins localized predominantly in the ER and Golgi apparatus. suggesting a role for lipid peroxidation in the pathogenesis of AD
Presenillins are thought to be involved in intramembrane pro- (Koppaka and Axelsen, 2000). The loss of membrane integrity due to
teolysis mediated by their gamma secretase activities. In addition, Abeta-induced free-radical damage leads to cellular disfunction,
presenilins interact with FKBP38 (human FK506-binding protein such as inhibition of ion-motive ATPase, loss of calcium homeo-
38) and form macromolecular complexes together with anti- stasis, inhibition of glial cell Na+-dependent glutamate uptake
apoptotic Bcl-2, thus it may regulate the apoptotic cell death (Wang system that results in NMDA receptors mediated delayed
et al., 2005). neurodegeneration, loss of protein transporter function, disrup-
tion of signaling pathways, and activation of nuclear transcrip-
Presenilins and their interacting proteins play a major role in the tion factors and apoptotic pathways.
generation of A-beta from the amyloid precursor protein (APP).
Three proteins nicastrin, aph-1 and pen-2 interact with presenillins Inflammation and neuronal death
to form a large enzymatic complex known as gamma secretase that Free radicals including H2O2 not only have direct neurotoxic ac-
cleaves APP to generate Aâα (Verdile et al., 2007). tions but also participate in inflammation. The fact that inflamma-
There are numerous proteases in the brain that could potentially tion plays a significant role in the pathobiology of Alzheimer’s
participate in Aß turnover. Aß (amyloid-beta) degrader candi- disease is supported by the observation that in the early stages
dates include: cathepsin D and E, gelatinase A and B, trypsin- or of the disease there is activation of microglial cells and reactive
chymotrypsin-like endopeptidase, aminopeptidase, neprilysin astrocytes in neuritic plaques and the appearance of inflamma-
(enkephalinase), serine protease complexed with 2-macroglobu- tory markers (Chong et al., 2001). Immune activation and/or
lin, and insulin-degrading enzyme (Saido, 1998). inflammatory activity have been shown to be significantly elevated
in the brains of AD patients compared with age-matched control
Genetic linkage studies have linked Alzheimer’s disease and plasma patients (Dumery et al., 2001). Continuous neuroinflammatory
Aß42 levels to chromosome 10q, which harbors the IDE (insulin- processes including glial activation is seen in AD (Calingasan
degrading enzyme) gene. IDE has been observed in human cere- et al., 2002). Microglia and astrocytes would be activated, perceiv-
brospinal fluid; and its activity levels and m-RNA are decreased ing Abeta oligomers and fibrils as foreign material, since Abeta
in AD brain tissue and is associated with increased amyloid beta assemblies are apparently never observed during the develop-
levels (Saido, 1998). ment of brain and in the immature nervous system (Selkoe,
2001).
Amyloid beta is the major component of amyloid plaques charac-
terizing Alzheimer’s disease. Amyloid beta accumulation can be Beta-Amyloid fibrils have been shown to activate parallel mito-
affected by numerous factors including increased rates of its pro- gen-activated protein kinase pathways in microglia and THP1
duction and/or impaired clearance. Insulin degrading enzyme is monocytes (McDonald et al., 1998). Recently, it was reported
responsible for the degradation and clearance of amyloid beta in
the brain (Edland, 2004).
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that microglia from human AD brain exposed to Abeta produced here strongly suggest that PS-1, PS-2 and APP play a dominant
and secreted a wide range of inflammatory mediators, including role in the pathogenesis of AD by inducing a pro-inflammatory
cytokines, chemokines, growth factors, complements, and reac- state.
tive oxygen intermediates (Lue et al., 2001). Significant dose-
dependent increase in the production of prointerleukin-1, Acknowledgment
interleukin-6, tumor necrosis factor-á,
α monocyte chemoattractant Authors Thankful to partial financial support from IIT up gradation
protein-1, macrophage inflammatory peptide-1, interleukin-8, and grants of AUC E(A).
macrophage colony-stimulating factor were observed after expo-
sure to preaggregated Amyloid beta-42. These evidences empha- References
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J Proteomics Bioinform Volume 1(1): 036-042 (2008) -042

ISSN:0974-276X JPB, an open access journal