Amyloid Deposition Apolipoprotein E And Free Radicals

Apolipoprotein E is an important cholesterol-transporting protein and a major constituent of very low density lipoproteins (VLDL). There are three common alleles (e2, e3, and e4) and two less common alleles (sl and s5). The common alleles provide six possible genotypes. Apo s3/s3 is the most common genotype, occurring in about 65% of the world population. The apo s4/s4 genotype occurs in 2 to 3% of the population. It has been shown that there is a strong and apparently robust association of late-onset and sporadic AD with the e4 allele of apolipoprotein E.57 The frequency of the s4 allele is around 0.5 in affected individuals from families where several other members also have late-onset AD. It is around 0.40 in patients unselected for the presence of a family history, and around 0.12 in control populations. Corder et al.58 reported that the risk was increased as a function of the inherited dose of the gene (ApoE-4), and that the mean age of onset was lowered with each ApoE-4 (s4) allele. However, some 40% of people with AD do not possess an s4 allele, so it is neither necessary nor sufficient to cause the disease. Therefore, the ApoE gene probably modifies the risk and timing of expression of the disease. The presence of apo-lipoprotein E in both senile plaques and neurofibrillary tangles does, however, point to it playing a direct part in the pathogenesis of AD.59 Nicoll et al.60 have shown that the s4 allele is also associated with deposition of amyloid P-protein following head injury. This finding provides further evidence linking apolipoprotein E s4 allele with PAP deposition in vivo and suggests that environmental and genetic factors for AD may act additively.

ApoE-4 differs from ApoE-3 in having an arginine in position 112 instead of cysteine. As a result of this, glutamic acid 109 forms a salt bridge with arginine 112, and the arginine 61 side chain is displaced to a new position when compared to the structure of ApoE-3.61 Whether these minor structural differences will explain the role of Apo E in AD remains to be established.

Studies have demonstrated that ApoE-4 interacts with and precipitates PAP in vitro more readily than ApoE-3.62 Binding of PAP to ApoE-4 was observed in minutes, whereas binding to ApoE-3 required hours. Oxygen-mediated complex formation was implicated because binding was increased in oxygenated buffer and prevented by reduction with dithiothreitol or 2-mercaptoethanol. This finding again suggests that antioxidants may have therapeutic potential in AD (Figure 2.14).

A specific amino-acid sequence (244-272) in ApoE-4 appears to be critically required for the interaction with PAP and the precipitation of ApoE-3-pAP complexes. Drugs designed to bind to this specific site might inhibit the formation of SP and hence offer a new treatment approach in AD. Studies also suggest that there is a negative association, or protective effect, of the s2 allele of apolipoprotein E in AD.63

(soluble PAP)

Antioxidant therapy Radical Scavengers

(soluble PAP)

Antioxidant therapy Radical Scavengers

Radical Scavengers

complexes (sequence AA244-272 critical for binding)

complexes (sequence AA244-272 critical for binding)

Radical Scavengers aggregated PAP

figure 2.14 Fragmentation of pAP, interaction between pAP and ApoE-4 (244-271), and possible formation of senile plaques (SP).

Because AD is an important cause of morbidity in the elderly, this protective effect of apoE s2 on risk for AD may explain the reported positive association of apoE s2 with longevity.64

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