The Relationship between Cholesterol and AD
As many know cholesterol is a risk factor for many disease and illness. Not surprisingly many studies nationwide have proved that it contributes to the development of Alzheimer’s Disease (AD). Many studies have been conducted to find the relationship between cholesterol and AD; in this review the studies focused on the apolipoprotein E (APOE), its different encodings: e4 allele, e3 allele, and e2 allele. It will also explain how APOE could neuronal cholesterol could help produce neurofibrillary tangles (NFTs) and amyloid plaques), and how oxidized cholesterol also attributes to the development of AD. Another topic covered will be how current findings of the relationship between cholesterol and AD can help find a cure or put a halt to AD.
Alzheimer’s disease (AD) is the most common form of dementia with 24 million nationwide suffering from it(Xue-shan et al., 2016). AD, which is characterized by accumulation of amyloid A? peptides and intracellular neurofibrillary tangles (NFTs) (Picard et al., 2018) This causes the patient to lose the ability to think and destroys their memory. Although AD is highly related to aging, there are many factors that take a part in the development of AD; studies have recently targeted the contribution of cholesterol. An important cholesterol transporter in the brain known as apolipoprotein E (APOE). APOE is most commonly encoded by the e2 allele, e3 allele, and the e4 allele, each allele affects the patient differently.
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Many studies have proven that the e2 allele has at least some protective properties and reduces the risk of developing AD, while the e3allele and e4 allele raise the risk of developing AD (Huynh, Davis, Ulrich, and Holtzman. 2018). Over the last few decades the e4 allele has been infamous and identified as the biggest risk factor of AD (Picard et al., 2018). Picard et al, studied about 20 cholesterol metabolism genes known to be suspects in helping the development of late-onset Alzheimer’s Disease; however, of those 20 only a few showed any significant correlation between AD, and of course APOE being the top suspect. (Picard et al., 2018). Although this suggest once again that APOE’s e4 allele does heighten the risk of developing it is yet to be fully understood.
Patients lacking APOE have been known to suffer from peripheral hypercholesterolemia, and recent studies have suggested that APOE encourages and helps the synaptic connections. The contradiction in these results that suggest the e4 allele only causes a higher risk for developing AD when either there is a loss of protection or gain of toxic a toxic function after injury. However, it must be noted that neither answer has been truly proven. (Huynh, Davis, Ulrich, and Holtzman. 2018). Another explanation of how APOE affect the brain is how APOE affects the accumulation of amyloid plaques. (Huynh, Davis, Ulrich, and Holtzman. 2018).
Studies suggest knowing how AD is characterized has helped scientists find a connection with neurol cholesterol (NC). It is believed that NC affects the enzymes that break down amyloids creating plaques, it could also play a part in creating intracellular neurofibrillary tangles by influencing the tau phosphorylation. (Picard et al., 2018) APOE, Amyloid plaques, and AD were first brought together in the 1900s when scientist noticed that e4 allele and amyloid plaques seemed to constantly overlap. Further studies later showed that the e4 allele does help the amyloid plaques to form and later lead to the development of AD. (Huynh, Davis, Ulrich, & Holtzman. 2018). In addition, NC is believed to cause the formation of neurofibrillary tangles (NFTs) by influencing the tau phosphorylation which has been supported by many studies including Picard et al.’s (Picard et al., 2018). The e4 allele has been proven to promote the endocytosis of app which therefore increases the production of tau proteins. This leaves more of them to phosphorylate which can be the reason it creates NFTs making it easier for AD to develop (Xue-shan et al., 2016).
As mentioned before as many as 20 cholesterol metabolizing genes were studies and up until recently only the e4 allele was shown to have a significant influence of AD. However, recently it has been proven through GWAS, that CLU and ABCA7 also affect the development of AD significantly. Much like e4 allele these trafficking genes are not optimal for transporting cholesterol and end up causing problems (Dong, Gim, Yeo, & Kim, 2017). With so many new studies out it is hard to truly pin point what agitates the development of amyloid plaques and NFTs. Studies have also found a correlation between oxysterols and the way they affect how spare cholesterol is dealt with in the brain (Picard et al., 2018).
Among the many studies conducted it was realized that the oxidation of cholesterol can cause AD to further develop. The brain uses about 25% of the inhaled oxygen, making it particularly defenseless to oxidative damage; mixing this with the high lipid content makes it easy for cholesterol to become oxidized (Gamba, Testa, Gargiulo, Staurenghi, Poli, and Leonarduzzi, 2015). 24s-OH and 25-OH are oxysterols that bind to NR1H3 and help regulate APOE among other cholesterol transporters. The oxidation of cholesterol allows it to cross the peripheral tissues and leave the brain; however, when there is an abundance of oxysterols they prevent the cholesterol synthesis preventing it from crossing the blood brain barrier (Picard et al., 2018). The dead cells can be toxic and the only way to get rid of them is by being converted into the oxidized form of cholesterol: 24(S)-hydroxycholesterol this happens to be in high numbers in patients developing dementia. (Picard et al., 2018). A study conducted on both humans and mice suffering from AD showed that there was a direct connection between oxidative stressed and amyloid plaques; it is not yet known if the oxidative stress is a result of the forming of the plaques or the cause (Gamba, Testa, Gargiulo, Staurenghi, Poli, and Leonarduzzi, 2015). The relation of oxidized cholesterol and AD seems to be activated once the brain cells have expired.
Cell death can be traced back to mitochondrial impairment which causes tau hyperphosphorylation compromising the synaptic connections (Gamba, Testa, Gargiulo, Staurenghi, Poli, and Leonarduzzi, 2015). This can circle back to the belief that tau phosphorylation can cause NFTs when cholesterol is present. Even though the dying cell drives the reactions that could cause the development of AD, the main culprit continues to appear, the e4 allele. Studies concluded that the oxysterols in patients with AD are in some way linked to the formation of amyloid plaques and even neuron death, knowing this can help clarify the relationship between how cholesterol metabolism affects the development of AD (Gamba, Testa, Gargiulo, Staurenghi, Poli, and Leonarduzzi, 2015).
Another study focusing on the relation of the LDL receptor- related protein 1(LRP1) and AD, resulted in knowing that LRP1 binds to agitated cholesterol metabolizing genes such as APOE. LRP1 engulfs the APOE and sends them into the lysosome where they are successfully recycled into the cell surface (Xue-shan et al., 2016).This Showed that is stopped the forming of excess cholesterol that can the reason AD is developing. LRP1 might be a huge step in finding a cure or slowing down the development of AD (Xue-shan et al., 2016). However, further studies will need to be conducted to confirm this.
Once scientist can finally pinpoint the relationship between oxidation of cholesterol and AD they can develop therapies and methods to prevent the disease from forming. Although most of the findings in many nationwide genome studies only proved that there is many contradicting results when dealing with the development of AD; it has helped better understand the disease and shown what studies to focus on. Knowing how AD is characterized and finding how it is connected to NC not only brought about more questions but a possible solution. In one study a cholesterol metabolizing gene, rs2269657-T allele brought about an exciting finding. This allele seemed to reduce the density of the plaque in the frontal cortices (Picard et al., 2018). Once the patient had passed there was a reduced level of SREBF2 mRNA in the rs2269657-T; this backed evidence that reducing the SREBF2 could slow down and reduce the development of AD (Picard et al. 2018).
Shown by extensive study there is no denying that the metabolism of cholesterol seems to be the common factor in facilitating the development of AD. The relationship between the two is still not fully understood, but thankfully all the recent studies done by scientist over the last few decades we have a starting point. Leading forward scientists will be able to get closer and closer to truly understanding AD and how to cure and prevent it.
Gamba, Paola, Testa, Gabriella, Gargiulo, Gariulo, Simona, Staurenghi, Erica, Poli, Giuseppe, and Leonarduzzi, Gabriella (2015). Oxidized cholesterol as the driving force behind the development of Alzheimer’s disease. Front. Aging Neurosci (2015) https://doi.org/10.3389/fnagi.2015.00119
Kim, D. H., Gim, J., Yeo, S. H., Kim, H. Integrated late onset Alzheimer’s disease (LOAD) susceptibility genes: Cholesterol metabolism and trafficking perspectives. Gene, 597(2017), 10-16. http://dx.doi.org/10.1016/j.gene.2016.10.022
Picard, C., Julien, C., Frapper, J. Miron, J., Theroux, L., Dea, D., …Poirier, J. (2018). Alterations in cholesterol metabolism – related genes in sporadic Alzheimer’s disease. Neurobiology of Aging, 66(2018), 180.e1 – 180.e9. https://doi.org/10.1016/j.neurobiolaging.2018.01.018
Huynh, Tien-Phat V., Davis, Albert A., Ulrich, Jason D., and Holtzman, David M. (2018). Apolipoprotein E and Alzheimer Disease: The influence of apoE on amyloid-? and other amyloidogenic protein. Erratum, 59(2018), 1546. http://www.jlr.org/content/early/2017/02/27/jlr.R075481.full.pdf+html
Xue-shan, Zahao, juan, Peng, Qi, Wu, Zhong Ren, Li-hong, Pan, Zhi-han, Tang, Zhi-Sheng, Jiang, Gui-xue, Wang, Lu-shan, Lui (2016). Imbalanced cholesterol metabolism in Alzheimer’s disease. Clinica Chimica Acta, 456(2016) 107-114 https://doi.org/10.1016/j.cca.2016.02.024