Scientific Research: How APOE4 Increase The Risk Of Alzheimer's Disease, Dementia.
Apolipoprotein E: Definition, Function, Clinical Significant And How APOE4 Increase The Risk Of Alzheimer's And Dementia.
What is APOE?
Apolipoprotein E (APOE) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular disease.
APOE belongs to a family of fat-binding proteins called apolipoproteins. In the circulation, it is present as part of several classes of lipoprotein particles, including chylomicron remnants, VLDL, IDL, and some HDL. APOE interacts significantly with the low-density lipoprotein receptor (LDLR), which is essential for the normal processing (catabolism) of triglyceride-rich lipoproteins. In peripheral tissues, APOE is primarily produced by the liver and macrophages, and mediates cholesterol metabolism. In the central nervous system, APOE is mainly produced by astrocytes and transports cholesterol to neurons via APOE receptors, which are members of the low density lipoprotein receptor gene family. APOE is the principal cholesterol carrier in the brain. APOE qualifies as a checkpoint inhibitor of the classical complement pathway by complex formation with activated C1q.
Function of APOE
APOE transports lipids, fat-soluble vitamins, and cholesterol into the lymph system and then into the blood. It is synthesized principally in the liver, but has also been found in other tissues such as the brain, kidneys, and spleen. In the nervous system, non-neuronal cell types, most notably astroglia and microglia, are the primary producers of APOE, while neurons preferentially express the receptors for APOE. There are seven currently identified mammalian receptors for APOE which belong to the evolutionarily conserved LDLR family.
APOE was initially recognized for its importance in lipoprotein metabolism and cardiovascular disease. Defects in APOE result in familial dysbetalipoproteinemia aka type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron, VLDL and LDL. More recently, it has been studied for its role in several biological processes not directly related to lipoprotein transport, including Alzheimer's disease (AD), immunoregulation, and cognition. Though the exact mechanisms remain to be elucidated, isoform 4 of APOE, encoded by an APOE allele, has been associated with increased calcium ion levels and apoptosis following mechanical injury.
In the field of immune regulation, a growing number of studies point to APOE's interaction with many immunological processes, including suppressing T cell proliferation, macrophage functioning regulation, lipid antigen presentation facilitation (by CD1) to natural killer T cell as well as modulation of inflammation and oxidation. APOE is produced by macrophages and APOE secretion has been shown to be restricted to classical monocytes in PBMC, and the secretion of APOE by monocytes is down regulated by inflammatory cytokines and upregulated by TGF-beta.
Clinical Significants of APOE4
As of 2012, the E4 variant was the largest known genetic risk factor for late-onset sporadic Alzheimer's disease (AD) in a variety of ethnic groups. However, the E4 variant does not correlate with risk in every population. Nigerian people have the highest observed frequency of the APOE4 allele in world populations, but AD is rare among them. This may be due to their low cholesterol levels.
Caucasian and Japanese carriers of two E4 alleles have between 10 and 30 times the risk of developing AD by 75 years of age, as compared to those not carrying any E4 alleles. This may be caused by an interaction with amyloid. Alzheimer's disease is characterized by build-ups of aggregates of the peptide beta-amyloid. Apolipoprotein E enhances proteolytic break-down of this peptide, both within and between cells. The isoform APOE-ε4 is not as effective as the others at promoting these reactions, resulting in increased vulnerability to AD in individuals with that gene variation.
Although 40–65% of AD patients have at least one copy of the ε4 allele, APOE4 is not a determinant of the disease. At least one third of patients with AD are APOE4 negative and some APOE4 homozygotes never develop the disease. Yet those with two ε4 alleles have up to 20 times the risk of developing AD. There is also evidence that the APOE2 allele may serve a protective role in AD. Thus, the genotype most at risk for Alzheimer's disease and at an earlier age is APOE4,4. Using genotype APOE3,3 as a benchmark (with the persons who have this genotype regarded as having a risk level of 1.0), individuals with genotype APOE4,4 have an odds ratio of 14.9 of developing Alzheimer's disease. Individuals with the APOE3,4 genotype face an odds ratio of 3.2, and people with a copy of the 2 allele and the 4 allele (APOE2,4), have an odds ratio of 2.6. Persons with one copy each of the 2 allele and the 3 allele (APOE2,3) have an odds ratio of 0.6. Persons with two copies of the 2 allele (APOE2,2) also have an odds ratio of 0.6.
–Researchers found that the APOE4 gene may increase the risk of developing Alzheimer’s disease and other dementias by altering brain cells’ lipid metabolism.
–Choline supplements reversed these defects in cell studies, supporting further research in people carrying APOE4.
Neurons with amyloid plaquesThe study suggests that dementia may be caused by lipid imbalances in brain cells. This illustration shows neurons with amyloid plaques, a hallmark of Alzheimer’s disease, in yellow.
Certain genes can increase the risk of developing dementia, including Alzheimer’s disease. One of the most significant genetic risk factors is a form of the apolipoprotein E gene called APOE4. About 25% of people carry one copy of APOE4, and 2 to 3% carry two copies. ApoE4 is the strongest risk factor gene for Alzheimer’s disease, although inheriting ApoE4 does not mean a person will definitely develop the disease.
The APOE gene comes in several different forms, or alleles. APOE3 is the most common and not believed to affect Alzheimer’s risk. APOE2 is relatively rare and may provide some protection against Alzheimer’s disease.
The reason APOE4 increases Alzheimer’s risk isn’t not well understood. The APOE protein helps carry cholesterol and other types of fat in the bloodstream. Recent studies suggest that problems with brain cells’ ability to process fats, or lipids, may play a key role in Alzheimer’s and related diseases.
Lipid imbalances can impair many of a cell’s essential processes. This includes creating cell membranes, moving molecules within the cell, and generating energy.
Dr. Li-Huei Tsai and the late Dr. Susan Lindquist of MIT investigated how APOE4 affects lipid metabolism in brain cells. The study was funded by NIH’s National Institute on Aging (NIA), National Cancer Institute (NCI), and National Institute of Neurological Disorders and Stroke (NINDS). Dr. Priyanka Narayan of NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) was a co-first author. Findings were published in Science Translational Medicine on March 3, 2021.
The research team began by creating brain cells called astrocytes using stem cells. They used skin cells from people carrying APOE3 or APOE4 that were reprogrammed into a state where they could develop into any cell. Called induced pluripotent stem cells, these cells were then coaxed into becoming astrocytes, star-shaped cells that produce the most ApoE in the brain.
The researchers found changes in how APOE4 astrocytes were able to process lipids. The astrocytes accumulated droplets containing fats called triglycerides. These triglycerides had many more unsaturated fatty acid chains than normal. Lipid buildup in the APOE4 astrocytes was much greater than in APOE3 astrocytes. The researchers also found disruptions in lipid metabolism when they coaxed the cells into becoming other brain cells called microglia.
The team next tested whether yeast cells with the human version of APOE4 would have the same disruption in lipid metabolism. Lipid metabolism pathways are very similar between yeast and humans. Yeast with a copy of the APOE4 gene accumulated lipids much like the human cells did. Genetic screens in the yeast identified a molecular pathway that could be responsible for the defects. Boosting the activity of a pathway that normally produces phospholipids, an essential building block of the cell membrane, reversed some of the lipid accumulation.
Further research showed that supplementing the yeast cells’ culture with choline restored normal lipid metabolism. Choline is needed to synthesize phospholipids. Similar benefits were seen after treating the human APOE4 astrocyte cells with choline. These findings provide preliminary support for testing choline supplements in people who carry APOE4.
“What we would really like to see is whether in the human population, in those APOE4 carriers, if they take choline supplements to a sufficient amount, whether that would delay or give them some protection against developing dementia or Alzheimer's disease,” Tsai says.
However, it is important to keep in mind that results from isolated cells don’t often translate into successful approaches when tested in people.
Sources:
www.wikipedia.org
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