ApoE gene and Alzheimer's disease (1)

Abstract: The E4 variation of ApoE gene is the most important risk variation of Alzheimer's disease The risk of Alzheimer's disease increases 3-4 times in the population with one E4 mutation, and 12-15 times in the population with two E4 mutations E4 variation is very common, about 20-30% of the population carries E4 variation Patients with E4 variant have younger symptoms, faster course of disease, and larger and stronger amyloid plaques in the brain By analyzing the known experimental evidence, this paper discusses the effect of E4 variation on the structure and function of apoE protein, and how these changes lead to the deposition of amyloid plaques, and finally induce the symptoms of Alzheimer's disease At the same time, it also tries to explain why the development of drugs based on the mechanism of eliminating amyloid protein failed in clinical trials Alzheimer's disease (AD), commonly known as Alzheimer's disease, may be the last major disease that has no medicine to cure, and it is also the biggest thought of pharmaceutical companies in the world In the past 30 years, the development of new drugs for Alzheimer's disease has failed, and a lot of money has been spent What's more, it's disappointing that the night is long and I don't know where the road is Many people began to abandon the amyloid beta hypothesis and replace it with a more fashionable but vague concept However, before entering any new target, it is necessary to carefully examine the biggest genetic risk factor of Alzheimer's disease, ApoE gene and its E4 variation through what molecular mechanism to promote the accumulation of amyloid protein and eventually induce Alzheimer's disease The gradual loss of memory and cognitive ability is a symptom of Alzheimer's disease, which results from the progressive death of brain nerve cells There is a large amount of amyloid protein deposition in the brain of Alzheimer's disease patients, and with the death of brain cells, the brain atrophy seriously The amyloid hypothesis was once the main accepted pathogenesis of Alzheimer's disease This hypothesis holds that the deposition of amyloid outside nerve cells is the prelude and inducement to the death of nerve cells Therefore, inhibiting the production of amyloid or clearing the deposition of amyloid may be able to treat or slow down Alzheimer's disease However, until now, the drug design based on this hypothesis has failed in clinical trials Figure 1: brain atrophy in Alzheimer's patients Alzheimer's disease can be divided into family early onset and sporadic late onset The former is small in number, accounting for about 5% of the total number of patients with Alzheimer's disease, generally before the age of 65 These early-onset Alzheimer's disease is a single gene disease, mainly involving three genes, app, PSEN1 and psen2 APP gene encodes the precursor protein that directly produces amyloid protein, while PSEN1 and psen2 genes encode the enzyme involved in cutting amyloid precursor Some mutations in these three genes can lead to over production of amyloid The pathogenic mechanism of the three genes provides a solid basis for the amyloid hypothesis However, most (more than 95%) Alzheimer's disease is sporadic late onset, which belongs to polygenic complex disease That is to say, a single gene mutation can not decide whether it will get sick or not, but multiple genetic factors add or reduce each other, and at the same time, it is affected by multiple environmental factors such as gender, age, diet structure and living habits The earlier the onset of Alzheimer's disease, the greater the genetic factors, and the later the onset of patients, the smaller the genetic factors, and more affected by environmental factors Although we all think that Alzheimer's is a terrible disease that has no cure, in fact, only those lucky people who don't die early of cancer, heart disease, stroke and other fatal diseases have the chance to experience it The longer you live, the more likely you are to develop Alzheimer's E4 variation of ApoE gene is the biggest risk factor of Alzheimer's disease Up to 67% of patients diagnosed with Alzheimer's before age 75 carry E4 variants But in the patients who were diagnosed after 80 years old, the carrying rate of E4 was only 13%, which was the same as that of the people whose brains were still healthy after 80 years old For Caucasians, carrying one E4 variant increases the risk of Alzheimer's by three to four times, while carrying two E4 variants increases the risk to 13 to 15 times The sensitivity of different races to E4 mutation is also different Black people living in Africa have the lowest sensitivity Carrying one E4 mutation does not increase the risk of Alzheimer's disease, but carrying two e4s only slightly increases the risk The Japanese were the most sensitive, with one E4 variant increasing the risk by 5-7 times, and two E4 variants increasing the risk by 33 times However, carrying E4 mutation is neither a sufficient condition nor a necessary condition for Alzheimer's disease; about half of the people who carry E4 mutation live to 80 years old and have not been diagnosed with Alzheimer's disease, on the contrary, about 40% of the patients who have been diagnosed before 80 years old do not carry E4 mutation 87% of the patients who were diagnosed after 80 years old did not carry E4 mutation Alzheimer's disease patients with E4 mutation not only had earlier onset, but also worsened more quickly Pathological observation also found that the amyloid plaques in the brain of patients with E4 mutation were more and larger than those without E4 mutation Figure 2: distribution of E4 variation of ApoE gene in different age groups of patients diagnosed with Alzheimer's disease More than 100 genes have been reported to be associated with sporadic late-onset Alzheimer's disease, and at least 20 of them have a strong molecular biological mechanism Some mutations will reduce the pathogenic risk of ApoE gene E4, such as the inactivation of CASP7 gene and the inactivation of ABCA1 gene, while others will increase the pathogenic risk of E4 ApoE gene encodes a lipoprotein called apoE, which is mainly expressed in liver and brain In general, lipoproteins and lipid molecules chime with each other to form lipoproteins, which assist in the transport of lipid molecules in the water phase, and transport the lipid molecules into the target tissue by combining with receptors on the cell surface There are five kinds of lipoproteins in blood, including chylomicron, VLDL, IDL, LDL and HDL Lipid molecules transported by lipoproteins include triglycerides, cholesterol, phospholipids and various fat soluble vitamins ApoE mainly exists in three kinds of lipoproteins, including chyle particles, VLDL and HDL Its main function is to participate in the absorption, synthesis and distribution of cholesterol Figure 3: five kinds of lipoproteins in blood, apoE in chyle, VLDL and HDL ApoE is closely related to the absorption and utilization of cholesterol in diet Besides the brain, apoE is mainly synthesized and secreted by hepatocytes into the blood High cholesterol diet can induce the synthesis of apoE Fat molecules in food are absorbed and synthesized into chyle particles through the intestine Chylomicrons are large lipoproteins, which mainly contain triglycerides from food, but also a small amount of cholesterol, phospholipids and oil-soluble vitamins (including vitamins A, D, K and carotene) Chylomicrons are secreted through the gut, enter the blood through the lymphatic vessels, and reach the highest concentration after meal Chylomicrons circulate in the body with the blood When they pass through muscle, liver, fat and other tissues, the lipoprotein lipase (LPL) embedded on the surface of these tissue cells will "harvest" the triglycerides on chylomicrons and absorb them into tissue cells As triglycerides are "harvested", the particles become smaller and smaller Finally, cholesterol molecules are mainly left, which are called chyle particle residues At this time, apoE chimeras with cholesterol rich residues, which is responsible for transporting the residues and their bile alcohol into the liver and other target tissues that need cholesterol It can be seen that apoE is a very related gene to diet There are two sources of cholesterol in the body, one is from food, the other is from the liver's autonomic synthesis Cholesterol rich foods include eggs, dairy products, fish, shrimp, seafood and animal offal When the cholesterol intake from food is insufficient, there will not be enough cholesterol transported into the liver cells, and the liver will start its own synthesis to supplement the body's needs Cholesterol synthesized by the liver is packaged in VLDL lipoproteins and enters the blood VLDL is the precursor of LDL, which we usually call "bad cholesterol" ApoE is involved in the synthesis and secretion of liver cholesterol by chimerism with VLDL In addition, apoE can be combined with a class of HDL lipoproteins to recover redundant and damaged cholesterol molecules from peripheral tissues and transport them back to hepatocytes for reuse or destruction E4 mutations in the ApoE gene also increase the risk of cardiovascular disease, but not as much as Alzheimer's A large number of apoE receptors are expressed in liver, gonad and adrenal gland ApoE relies on receptor mediated endocytosis to transport lipid molecules such as cholesterol into target tissues The tissues expressing apoE receptor are those that need to synthesize steroids with imported cholesterol as raw materials, such as gonadal cells, adrenal cells, thyroid cells and skin cells As the "warehouse" and "processing plant" of cholesterol in the body, liver has the most receptors, which are used to schedule and balance the "purchase" and "shipment" of cholesterol ApoE receptor mainly includes LDLR (LDL receptor) and LRP (LDL receptor related receptor family) receptor families The common feature of these receptors is that they all have one or more lipoproteins binding regions with negatively charged amino acids, which are just compatible with the receptor binding regions with positively charged amino acids on lipoproteins These receptors do not specifically receive apoE, and LDLR mainly receives apoB containing lipoproteins on hepatocytes LDL is what we usually call "bad cholesterol" There is also a positively charged amino acid region similar to apoE on apoB for binding to the receptor LDLR gene deficiency and apoB receptor binding region variation can lead to familial hypercholesterolemia The variation of apoE receptor binding region will lead to familial type III hyperlipidemia Figure 4: LDL receptor family members that can receive apoE The green region is the ligand receiving region with negative charge In the brain, apoE is mainly synthesized by astrocytes, and chimes with cholesterol and phospholipids to form HDL like lipoproteins Different from the peripheral blood system, there are five kinds of lipoproteins There are only two kinds of lipoproteins in the brain, which are synthesized by astrocytes One contains apoE and the other contains APOJ ApoE and APOJ are both lipoproteins Their functions are to chime with oil molecules to form lipoproteins and assist oil molecules in intercellular transport In the brain, apoE is the most important lipoproteins with high lipid content and mainly cholesterol APOJ has low lipid content and mainly contains phospholipids The main physiological function of apoE in the brain may be to transport cholesterol and phospholipid to nerve cells for maintenance, recovery and expansion of nerve cells Very interesting.