INHIBITION OF AMYLOID PLAQUE FORMATION

Alzheimer's is the most common cause of dementia, a general term for memory loss and other cognitive abilities serious enough to interfere with daily life. Alzheimer's disease accounts for 60-80% of dementia cases.

The brain has 100 billion nerve cells (neurons). Each nerve cell connects with many others to form communication networks. Groups of nerve cells have special jobs. Some are involved in thinking, learning and remembering. Others help us see, hear and smell.

To do their work, brain cells operate like tiny factories. They receive supplies, generate energy, construct equipment and get rid of waste. Cells also process and store information and communicate with other cells. Keeping everything running requires coordination as well as large amounts of fuel and oxygen.

Scientists believe Alzheimer's disease prevents parts of a cell's factory from running well. They are not sure where the trouble starts. But just like a real factory, backups and breakdowns in one system cause problems in other areas. As damage spreads, cells lose their ability to do their jobs and, eventually die, causing irreversible changes in the brain.


Alzheimer's disease (AD) is the most common form of dementia that affects everyday life through memory loss and cognitive changes. The Alzheimer's Association reports that one in ten people over 65 and almost one third of people over 85 have Alzheimer's disease.
Symptoms of Alzheimer's disease usually develop slowly with a tendency to gradually worsen over time, moving from mild forgetfulness to widespread brain disorders. To date, none of the phase III clinical trials aimed at anti-AD therapy have demonstrated a statistically significant treatment effect in patients with AD. Therapeutic approaches included the use of monoclonal antibodies that recognize different Aβ epitopes and exhibit different binding selectivity [Clinical Development of Aducanumab, an Anti-Aβ Human Monoclonal Antibody Being Investigated for the Treatment of Early Alzheimer's Disease.]
neurodegenerative, alzheimer s, alzheimer s disease, alzheimer's dementi dementi, album dementia dementia, amyloid, amyloid protein, amyloid precursor protei, plaques
Symptoms of Alzheimer's disease usually develop slowly with a tendency to gradually worsen over time, moving from mild forgetfulness to widespread brain disorders.
neurodegenerative, alzheimer s, alzheimer s disease, alzheimer's dementi dementi, album dementia dementia, amyloid, amyloid protein, amyloid precursor protei, plaques
We concluded that the dimers of mutant amyloids form stable and unstable dimeric complexes.
We concluded that the dimers of mutant amyloids form stable and unstable dimeric complexes. If the dimeric complex is stable, then the formation of high molecular weight structures was much slower. This was due to the fact that the stable amyloid peptides were in no hurry to enter into chemical reactions with other amyloid peptides to achieve equilibrium.
It remained to solve the question: how will we determine the stability of the dimeric complex.
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Let me remind you that since 2015 our company has been dealing with the issues of the stability of protein compounds.
Let me remind you that since 2015 our company has been dealing with the issues of the stability of protein compounds. We introduced a numerical stability criterion for protein dimers; this value is the condition number of the matrix of potential energy of pairwise electrostatic interaction between two proteins. The higher this number, the more unstable the biological complex. We calculated the stability values for the known dimeric amyloid complexes taking into account mutations and obtained a numerical stability value for each dimer, which was presented in the form of a graph. Higher values indicate a lower stability value and vice versa. Our goal is the identification of dimeric amyloid complexes, which would be characterized as sufficiently stable dimeric complexes. One of the peptides in the dimer complex will be exactly the amyloid peptide, and the second companion we have to find. The second partner in the dimer complex will be an inhibitor based on the amino acid sequence.

Fig.1. Graph of values for stability indicator lg(cond(w)) that were obtained by considering the interaction of wild form wtABeta and interaction of mutant peptide forms mutABeta from Table 1.

The stability of biological complex is plotted in Fig. 1. The mutation names and the way the structures of a higher order are formed are indicated in the plots. A large arrow between the plots indicates the direction for values characteristic of the formation of structures with a higher molecular weight such as oligomers, protofibrils, and fibrils. A thick line at a level of 5.53 arbitrarily separates structures that tend to (the region below the line). The "FAB" designation on the plot corresponds to the stability value upo interaction of the solanezumab region with an amyloid peptide (a structure in the PDB:4XXD database) [12].

On the strength of experimental data on missense mutations and their biological effect, we draw a separation line at a level of 5.53 that separates mutations in peptides leading to enhanced formation of higherorder structures from mutations in ABeta peptides exhibiting a reduced capacity to form high-molecularweight structures. In choosing a value if 5.53, we considered two threshold values: interactions between the wild-type ABeta peptides for which lg(cond(w)) was 5.5372 and the interaction between two mutant forms of the ABeta K16N(LYS16ASN) peptide, the dimer form of which does not cause toxicity in the human body. In this case, lg(cond(w)) was 5.5264. Dashed lines in the plots indicate values obtained for interactions between [wtABeta]2 peptides. Two vertical arrows pointing away from the line drawn at 5.53 indicate directions in the regions characterized by the lower (arrow up) or higher
(arrow down) stability of dimer complexes. The present grading was obtained and tested for a three-dimensional complex from the PDB:2MXU database [12].

How can we get such an amino acid sequence?

First stage
neurodegenerative, alzheimer s, alzheimer s disease, alzheimer's dementi dementi, album dementia dementia, amyloid, amyloid protein, amyloid precursor protei, plaques
Second Stage
neurodegenerative, alzheimer s, alzheimer s disease, alzheimer's dementi dementi, album dementia dementia, amyloid, amyloid protein, amyloid precursor protei, plaques
Third Stage
neurodegenerative, alzheimer s, alzheimer s disease, alzheimer's dementi dementi, album dementia dementia, amyloid, amyloid protein, amyloid precursor protei, plaques
chemical structure, chemical structure of water, chemical bonding and molecular structure class, chemical formula of water
Fig.2. Amino acid sequence of the ABeta(11–42) peptide, with
its missense mutations being indicated. AAR numbering is
given in two variants: for the peptide itself and relative to its
predecessor protein APP.
Since the method proposed in this work concerns a new insight into the stability of peptide amyloids, we will provide a fragment of such an amyloid peptide ABeta (11–42) that corresponds to the length of amino acid sequence of a three-dimensional structure from the PDB:2MXU database [5]. Figure 2 shows the amino acid sequence of ABeta (11–42) peptide in which missens mutations (see Table 1) that lead to different biological and pathophysiological changes in the human body are indicated [23]. Figure 2. shows the amino acid sequence of AB (11–42) peptide indicating missense mutations (see table 1), which entail various biological and pathophysiological effects in the human body

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Ordering work with us, you save almost 90% on preliminary screening experiments to find the most suitable immunoglobulins
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Three-dimensional map of the energy interaction of the amino acid sequences of an antibody with an antigen
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Determination of the affinity range for various substitutions of amino acid residues, during the formation of an antibody-antigen complex before an in vitro experiment
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The results obtained will determine the key amino acid residues that make the greatest changes in the affinity of the dimeric complex.
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