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To Study the Precursor Protein of Alzheimer’s Disease – Beta Amyloid.

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Submitted By ash9530327
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Alzheimer’s disease is a wholesale loss of synapses, contact points via which nerve cells relay signals to one another and a parallel deterioration in brain function, notably in the ability to remember. Amyloid beta (Aβ) denotes peptides of 36–43 amino acids that are crucially involved in Alzheimer's disease as the main component of the amyloid plaques found in the brains of Alzheimer patients. The peptides result from the amyloid precursor protein (APP), which is being cut by certain enzymes to yield Aβ. Study has shown that Beta amyloid begins life as a solitary molecule but tends to bunch up , initially into small clusters that are still soluble and can travel freely in the brain, and finally into the plaques that are hallmarks of Alzheimer’s. The study showed for the first time that in this clustered form, beta-amyloid can bind strongly to a receptor on nerve cells, setting in motion an intercellular process that erodes their synapses with other nerve cells.
Further looking into this protein and the information regarding it in various databases, the following was sequence was found out for the Beta amyloid A4 protein in Homo sapien in SWISSPROT.
>sp|P05067|A4_HUMAN Amyloid beta A4 protein OS=Homo sapiens GN=APP PE=1 SV=3

This sequence was curated. And on BLASTing the sequence the following result was found.
E-value: 0.0 Score: 4058 Identity: 100.0%
The sequence for the same protein was retrieved- Amyloid beta A4 protein (Pan troglodytes), which is the common chimpanzee.

>sp|Q5IS80|A4_PANTR Amyloid beta A4 protein OS=Pan troglodytes GN=APP PE=2 SV=1
The blast result for this was-
E-value: 0.0 Score: 4,054 Identity: 99.9%
The alignment of both these sequence is-
CLUSTAL O(1.2.1) multiple sequence alignment

SP|Q5IS80|A4_PANTR MLPGLALLLLAAWTARALEVPTDGNAGLLAEPQIAMFCGRLNMHMNVQNGKWDSDPSGTK 60 ************************************************************
SP|Q5IS80|A4_PANTR TCIDTKEGILQYCQEVYPELQITNVVEANQPVTIQNWCKRGRKQCKTHPHFVIPYRCLVG 120 ************************************************************
SP|Q5IS80|A4_PANTR EFVSDALLVPDKCKFLHQERMDVCETHLHWHTVAKETCSEKSTNLHDYGMLLPCGIDKFR 180 ************************************************************
SP|Q5IS80|A4_PANTR GVEFVCCPLAEESDNVDSADAEEDDSDVWWGGADTDYADGSEDKVVEVAEEEEVAEVEEE 240 ************************************************************
SP|Q5IS80|A4_PANTR EADDDEDDEDGDEVEEEAEEPYEEATERTTSIATTTTTTTESVEEVVREVCSEQAETGPC 300 ************************************************************
SP|Q5IS80|A4_PANTR RAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVCGSVMSQSLLKTTQEPLARD 360 *******************************************.****************
SP|Q5IS80|A4_PANTR PVKLPTTAASTPDAVDKYLETPGDENEHAHFQKAKERLEAKHRERMSQVMREWEEAERQA 420 ************************************************************
SP|Q5IS80|A4_PANTR KNLPKADKKAVIQHFQEKVESLEQEAANERQQLVETHMARVEAMLNDRRRLALENYITAL 480 ************************************************************
SP|Q5IS80|A4_PANTR QAVPPRPRHVFNMLKKYVRAEQKDRQHTLKHFEHVRMVDPKKAAQIRSQVMTHLRVIYER 540 ************************************************************
SP|Q5IS80|A4_PANTR MNQSLSLLYNVPAVAEEIQDEVDELLQKEQNYSDDVLANMISEPRISYGNDALMPSLTET 600 ************************************************************
SP|Q5IS80|A4_PANTR KTTVELLPVNGEFSLDDLQPWHSFGADSVPANTENEVEPVDARPAADRGLTTRPGSGLTN 660 ************************************************************
SP|Q5IS80|A4_PANTR IKTEEISEVKMDAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVITL 720 ************************************************************
SP|Q5IS80|A4_PANTR VMLKKKQYTSIHHGVVEVDAAVTPEERHLSKMQQNGYENPTYKFFEQMQN 770 **************************************************
The protein sequence in both the organisms is found to be closely identical. This gives us an idea that it is the same protein with almost same protein sequence which gives rise to the plaque formation in the brain leading to the disease.

By SCOP I found out that it belongs to the class of Peptides. Its superfamily is Amyloid peptides. It is commonly known as Alzheimer's disease amyloid beta-peptide.

The following are the protein domains-
• Alzheimer's disease amyloid beta-peptide [58607] o Human (Homo sapiens) [TaxId: 9606] o Rat (Rattus norvegicus) [TaxId: 10116]
• Islet amyloid polypeptide [103742] o Human (Homo sapiens) [TaxId: 9606]
• Transthyretin amyloid peptide [103744] o Human (Homo sapiens) [TaxId: 9606]
• Fibril-forming peptide[118402]
THE PATHWAY (using KEGG) The pathway can help us in finding out the Apoptotic mechanisms in Alzheimer neurofibrillary degeneration, mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis in Alzheimer's disease, possible causes of Alzheimer's disease: amyloid fragments, free radicals, and calcium homeostasis, etc.
The structure of Beta amyloid (using PDB)
“Crystal Structure of the Complex Formed Between Phospholipase A2 and a Hexapeptide Fragment of Amyloid Beta Peptide, Lys-Leu-Val-Phe-Phe-Ala at 1.2 A Resolution.” Amyloid beta is commonly thought to be intrinsically unstructured, meaning that in solution it does not acquire a unique tertiary fold but rather populates a set of structures. As such, it cannot be crystallized and most structural knowledge on amyloid beta comes from NMR and molecular dynamics. Its structure enables it to form clusters. The mechanism by which amyloid beta may damage and kill neurons is by generating reactive oxygen species during the process of its self-aggregation.
There are two intervention strategies which can prevent Alzheimer’s-
On studying the strategy of immunotherapy, the following abstract was drawn. (using PDB) Immunotherapy targeting of amyloid beta (Abeta) peptide in transgenic mouse models of Alzheimer disease (AD) has been widely demonstrated to resolve amyloid deposition as well as associated neuronal, glial, and inflammatory pathologies. These successes have provided the basis for ongoing clinical trials of immunotherapy for treatment of AD in humans. Acute as well as chronic Abeta-targeted immunotherapy has also been demonstrated to reverse Abeta-related behavioral deficits assessing memory in AD transgenic mouse models. We observe that three antibodies targeting the same linear epitope of Abeta, Abeta(3-7), differ in their ability to reverse contextual fear deficits in Tg2576 mice in an acute testing paradigm. Reversal of contextual fear deficit by the antibodies does not correlate with in vitro recognition of Abeta in a consistent or correlative manner.

The normal function of βeta amyloid is not well understood. Though some animal studies have shown that the absence of Aβ does not lead to any loss of physiological function, several potential activities have been discovered for Aβ, including activation of kinase enzymes, protection against oxidative stress, regulation of cholesterol transport, functioning as a transcription factor, and anti-microbial activity. The glymphatic system clears metabolic waste from the mammalian brain, and in particular beta amyloids. The rate of removal is significantly increased during sleep.
This disease is genetic. And can be hereditary. Autosomal-dominant mutations in APP cause hereditary early-onset Alzheimer's disease. The gene for amyloid precursor protein is located on chromosome 21, and accordingly patients with trisomy 21 (Down's syndrome) have a very high incidence of Alzheimer's disease. -X-

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