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What Is Alzheimer’S Disease? Alzheimer’S

What is Alzheimer’s disease? Alzheimer’s disease is known to be the main reasons for an individual to experience dementia, which is the loss of memory and judgment. According to the Alzheimer’s Association, most of the individuals that are diagnose with Alzheimer’s are 65 years old and older. However, younger individuals could be at risk of being diagnose with the disease as well. There has been multiple causes of Alzheimer’s disease and one has been due to stress exposure to the individuals, since it can cause an individual to start receiving the beginning states of the disease (Torres-Berrio and Nava Mesa, 2019).

Abrams mentions that Alzheimer’s disease is known to be caused by genetic and environmental factors. The researchers identified ApoE to be the most important genetic reasoning as to why humans can be affected by the disease. ApoE is identified to be in the brain and have three different types of isoforms. These forms are called ApoE2, ApoE3, and ApoE4. These isoforms are different in the amino acids located in the 112 and 158 of the protein, which differ from a having a cysteine or arginine substitution. Cysteine could play a major factor for those individuals that have Alzheimer’s since they are involve in the isomers that could be related to the disease. ApoE4 contains arginine in both 112 and 158 position. However, ApoE2 contains cysteine in 122 and 158 position, while ApoE3 contains arginine in the 158 position and cysteine in the 112 position. (Abrams Et. al., 2011).

The purpose of this study is to look into the way in which the mechanism of the apolipoprotein E (ApoE) can affect and influence an individual risk of having Alzheimer’s disease and the way in which isomers ApoE2 and ApoE3 could be involved. As mentioned, ApoE2 and ApoE3 both have cysteine. For these reasons, the researcher’s hypothesis, that S-Nitrosylation, which is related to the cysteine amino acid, contributes to an individual’s risk of having Alzheimer’s disease. The researchers tested the hypothesis by doing a series of methods such as looking at the interaction of ApoE and NOS1. (Abrams Et. al., 2011).

Results

In the cell base model, the researchers found that there was an interaction between ApoE and NOS1. The transiently transfection found that there was no different between the binding of all isoform types and the NOS1. This means that ApoE2,3, and 4 have similar bonding with the NOS1. When visualizing the ApoE3 and NOS1 in human hippocampus using immunofluorescences, the researchers found that there was a high overlap between ApoE3 and NOS1. Finally, the Co-IP found that on the ApoE4 allele, there is a low amount of NO production in central nervous system related cells. The researchers explained that this could be due to the fact that ApoE4 has the arginine production. Compared to ApoE2 and ApoE3, which have a high amount of NO production and contained the cysteine amino acid, instead of arginine. (Abrams Et. al., 2011).

For the Biotin-Switch Assay, when it came to the NO donor, the test showed that the bands contained ApoE2 and ApoE3, however, it was not shown for ApoE4. The test also showed that the band was stronger in ApoE2 then ApoE3.This means that ApoE2 and ApoE3 both have a connection to the NO. In the homozygous ApoE3 and ApoE4, the same results were observed, since the ApoE4 did not appear in the Biotin-Switch Assay band. Meaning that homozygous human ApoE3 from human hippocampus, is connected to the NO. This can be the reasons as to why the ApoE3 is related to Alzheimer’s disease.

The researchers found that the atomic model suggest that the position 112, where the cysteine is located, is close to R61 and E109 sidechains. R61 and E109 are not involved in the stabilization of receptor binding. This could be an issue since it can mean that the receptors are not being stabilize correctly. For these reasons, the researchers mentioned, that if R61 and E109 affects receptor binding, this could also take a risk of binding in LDL receptor. The LDL receptor has been identified as one of the reasons for Alzheimer’s disease (Waldron et al., 2006). However, the researchers should give an explanation as to why the LDL receptor is involved in Alzheimer since it was not mentioned.

Discussion

This paper had useful information that can help with the research of Alzheimer’s disease. ApoE2 and ApoE4 could lead to finding a cure and preventions of the disease. The paper, however, should have included more detailed explanation of the LDL receptor since It was not mentioned in the introduction. This caused confusion since I did not know how to incorporate the LDL receptor to the results that were found in the 3D model. The LDL receptor is usually mentioned in cholesterol related issues, that’s why I believe is important for the reader to know why it could affect patients with Alzheimer’s.

I do not believe that the paper was well written, since the information was not provided in the usual format of a primary source. The methods and results were all included in the same section of the paper, this created confusion since I was not able to quickly identify the methods in the paper. For the next step, I believe that the researchers should look into ApoE2 in humans. The paper mentioned that it was rare in homozygous human brain. For those reasons, I believe that knowing more information about it can be important. Conclusion

This research was able to identify factors that could help with findings about Alzheimer’s disease. The researchers found a connection between ApoE2 and ApoE3, and Alzheimer’s disease. This was due to the fact that ApoE2 and ApoE3 contained the amino acid cysteine. Furthermore, it was found that only ApoE2 and ApoE3 were able to interact with NSO1. Compared to ApoE4, which did not have any interactions. For these reasons, the researchers finalize that S-Nitrosylation can play a big part on Alzheimer’s disease. More researcher should focus on the role of LDL and the way in which it can affect patients that have Alzheimer’s. This paper was helpful to learn about possible reasons for Alzheimer’s. Hopefully, future researchers can allow the creation of a new drug by using ApoE2 and ApoE3.

Appendix

Methods

The researchers looked at the interactions between ApoE and NOS1, which is the nitric oxide, using a cell base model. To accomplish this, the researchers did transfection, which is used to look at the protein function. There are two types of transfection, which are, transiently and stable. The stable is done when the gene is delivered into the nucleus, incorporating the gene into the genome of the individual. (Kim and Eberwine 2010). In this researcher, they did a transiently transfection. Transiently transfection is done by a delivery of the gene into the nucleus without incorporating it into the genome of the individual, this is for a temporary research (Kim and Eberwine 2010). The researchers did this by incorporating the NOS1 into a cell culture called HEK-293, which are human embryonic kidney cells, with all of the ApoE isoforms. (Abrams Et. al., 2011).

Co-IP also known as Co-Immunoprecipitation was used to test if all of the isoforms were able to bind to the NOS1. Similarly, using Immunofluorescence, the researchers looked at the overlaps between the ApoE3 and NOS1, when it came to an increase of the arginine transport. Immunofluorescence is used to tag the cells that are being studied. This makes it easier for researchers to look at the interaction between NOS1 and the ApoE3 since the color allows the visualization of the different cells. (Abrams Et. al., 2011).

To test for ApoE protein and S-Nitrosylation, the researchers did a purification of a recombination of different human ApoE proteins, which then lead them to do a biotin-switch assay. A biotin-switch assay is used to test if the S-Nitrosylation is detected in the samples used for the experiment since it can allow the detection of proteins. The biotin switch will block all of the S-H groups and S-NO bonds are removed. The SH left will cause a fluorescence that will detect the S-Nitrosylation present in the sample. (Cayman Chemical). Following this method, the researchers did the same process, using human hippocampus lysates that were homozygous ApoE3 and ApoE4 alleles. This can be helpful to look at the effect of ApoE3 and ApoE4 in human brains. (Abrams Et. al., 2011).

To look at the psychological aspects of S-Nitrosylation of the ApoE proteins, the researchers made three dimensional atomic models of the receptors using crystal structure template. The three-dimensional atomic models can allow the researchers to look at the characteristics of the molecule which can be helpful for researchers to visualize what’s impacting the molecule. (Abrams Et. al., 2011).