Apolipoprotein E APOE genes

Lentivirus vectors have also been used in the development of potential AD therapeutics. Dodart and colleagues recently delivered varying alleles of the apolipoprotein E (apoE) gene,... 

There are special genetic risk factors for Alzheimer s disease - such as, for instance, the e4 allele of the apolipoprotein E (APOE) gene, isotonic variation in CYP46, CYP46 C - that significantly increase the risk of Alzheimer s disease development (Bookheimer et al. 2000 Borroni et al. 2004). Accordingly, it seems reasonable to assume that the majority of those who precipitate the disease are carriers of risk factors. 

Among these susceptibility genes, the apolipoprotein E (APOE) gene (19ql3.2) (AD2) is the most prevalent as a risk factor for AD, especially in those subjects harboring the APOE-4 allele (see Fig. 4), whereas carriers of the APOE-2 allele might be protected against dementia. 

The genetic basis for the more common late-onset AD appears more complex. Genetic susceptibility is more sporadic and it may be more dependent on environmental factors.9 The apolipoprotein E (apo E) gene on chromosome 19 has been identified as a strong risk factor for late-onset AD. There are three variants of apo E however, carriers of two or more of the apo E4 allele have an earlier onset of AD (approximately 6 years earlier) compared with non-carriers.9 Only 50% of AD patients have the apo E4 allele, thus indicating it is only a susceptibility marker. 

In 1993/1994 a series of publications caused a stir in the AD research community, since for the first time they linked a specific neuropathological process in late-onset AD to a genetic marker. Researchers looking at the composition of plaques found that the protein apolipoprotein E (ApoE) was associated with p-amyloid in the cerebrospinal fluid (CSF) of AD patients (Strittmatter et al., 1993). The gene for ApoE is on the same human chromosome (number 19) which was a risk factor in some AD pedigrees. The gene for ApoE comes in three versions (alleles) Apo s2, Apo s3 and, most importantly, Apo s4 these result in three slightly different variants of the protein. Humans carry two versions of the allele and so can have none, one or two of any of the versions of the Apo... 

Fig. 10.15 Pharmacogenomic response to a multifactorial therapy in Alzheimer s disease (AD) according to a trigenic cluster integrated by the apolipoprotein E (APOE), presenUin 1 (PSl), and presenilin 2 (PS2) genes. (Adapted from refs. 13 0, and 291.)...

LRP is a member of the LDL receptor gene family (ref. 649) and, like the LDL receptor, performs an essential role in the removal of certain lipoprotein particles from the bloodstream. As Heeren et al. (ref. 650) explain, triglycerides are transported mainly by two distinct classes of lipoproteins, the chylomicrons and the very-low-density lipoproteins (VLDL). After assembly in the intestine, chylomicrons are carried via lymph into the bloodstream, where they are transformed at the endothelial surface to remnant lipoproteins through the catalytic action of lipoprotein lipase (for review, see ref. 651,652). After lipolysis, the lipoprotein lipase remains associated with the chylomicron remnants and, in conjunction with apolipoprotein E (apo E) (ref. 653-655), facilitates their clearance by the liver into hepatocytes (ref. 656) via LDL receptors and the LRP (ref. 657-660). (The essential role for both receptors in chylomicron remnant removal in vivo has been demonstrated in gene knockout and gene transfer experiments (ref. 661,662 for review, see ref. 663).)... 

Xu Q, Bernardo A, Walker D, Kanegawa T, Mahley RW, Huang Y (2006) Profile and regulation of apolipoprotein E (ApoE) expression in the CNS in mice with targeting of green fluorescent protein gene to the ApoE locus. J Neurosci 26 4985 994. 

Interaction of Dietary Fat and Hepatic Lipase Gene Polymorphism on HDL-C.. 12 Interactions of Apolipoprotein E (APOE) Genotype with Obesity and Alcohol... 14 Interaction of Polyunsaturated Fatty Adds (PUFA) and APOAl G-A... 

Three major alleles of the APOE gene (APOE2, APOE3, and APOE4), which codes for the plasma protein apolipoprotein E (apoE), have been studied for their associations with plasma lipoprotein concentrations. Polymorphisms in the APOE gene have been shown to influence plasma lipoprotein concentrations in carriers of certain alleles. Specifically, the E4 allele has been associated with increased LDL-C, whereas the E2 allele has been linked with lower LDL-C." Both E2 and E4 have been linked with increased plasma triglycerides."... 

Apolipoprotein E (APOE) is the major lipoprotein within the CNS it is synthesized by astrocytes (Pitas et al., 1987) and by neurons under physiological and pathological conditions (Harris et al., 2004). APOE is a polymorphic 299-amino acid protein. The gene is located on chromosome 19 and has three possible alleles, s2, s3, and s4. APOE-zi is the most common (frequency in population 60-70%), followed by APOE-zA with a frequency of 15-20%, mAAPOE-z2 with a frequency of 5-10%. The three isoforms differ by single amino acid substitutions (cysteine to arginine) at two positions. APOE-e4 lacks both cysteine residues (Cys" and Cys ), while APOE-e3 and APOE-e2 contain 1 and 2 cysteine residues, respectively (Mahley and Huang, 2006). 

Fig. 10.8 Absolute genetic variation (AGV) and relative genetic variation (RGV) between Alzheimer s disease and vascular dementia associated with bigenic, trigenic, and tetragenic clusters of Alzheimer s disease (AD)-related genes. APOE, apolipoprotein E PS, presenilin. (Adapted from refs. 12,19,20, and 59.)...

APOE, apolipoprotein E PS, presenilin A2M, a-enzyme AGT, Angiotensinogen cFOS FBI, homolog PRNP, Prior Protein gene Source. Adapted from ref. 42. 

Seitz, A., Gourevitch, D., Zhang, X.M., et al. (2005) Sense and antisense transcripts of the apolipoprotein E gene in normal and APOE knockout mice, their expression after spinal cord injury and corresponding human transcripts. Hum. Mol. Genet., 14, 2661-2670. 

Some people with elevated lipoprotein levels have VLDL that migrates on electrophoresis in the (3 band rather than the pre-(3 band (see Box 2-A). The presence of the (3-VLDL is associated with a high incidence of artery disease,218 which is most likely to develop in persons homozygous for a genetic variant of apolipoprotein E. The problem may arise because apo-E is required for receptor-mediated uptake of VLDL, which interacts both with tissue LDL receptors and with hepatic apo-E receptors. Genes for many of the... 

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