Alzheimer's disease is neuropathologically defined by the presence in the brain of two features, amyloid deposits of the Ap peptide and neurofibrillary tangles (NFT) of the tau protein. The risk of AD is increased by inheritance of the e4 allele of apoE, and decreased by inheritance of the e2 allele of apoE.1 Apolipoprotein E e4 is associated with increased amy-loid,23,77,78 but not increased NFTs.78 Thus, it has been postulated that apoE4 is involved either in increased deposition of Ap, or decreased clearance of Ap.
The putative apoE-Ap interactions have been supported by several different studies. Apolipoprotein E binds Ap in vitro, whether apoE is delipidated79 or bound to lipopro-teins.80 Apolipoprotein E can also promote Ap aggregation in vitro;81-83 this model is supported in vivo in mouse models of amyloidogenesis showing that apoE knockout mice have considerably delayed Ap deposition.84 Ap clearance can be promoted by interactions with the lipoprotein receptors LRP,85,86 gp330,87,88 and scavenger receptor A-I.89,90 The apoE isoforms may differentially affect these various clearance mechanisms. Apolipoprotein E may also affect Ap levels by altering the interaction between the amyloid precursor protein and LRP.91,92
The studies of apoE as a genetic risk factor in AD promoted analysis of apoE receptor genes as candidate risk factors for AD. No consistent linkage was found between AD and polymorphisms in the LDL receptor gene,93 the VLDL receptor gene,28,93-95 and a polymorphism in the 3' untranslated region of LRP.93,96,97 However, a polymorphism in exon 3 of LRP has been linked to AD in several studies.98-101 While this polymorphism does not alter the amino acid sequence of LRP, it has sparked further interest in analysis of other regions of LRP and other ligands of LRP as potential genetic risk factors.
In summary, recent investigations have revealed a complex family of exchangeable apolipoproteins which can be synthesized by resident CNS cells and contribute to the classes of lipoproteins found in the brain. These lipoproteins form a unique class of particles, distinct from that seen in the periphery, which appears to be capable of mediating both lipid removal and delivery. The CNS lipoproteins have available a wide array of at least five potential receptors, each with a unique cellular and regional distribution and with multiple splice forms and soluble forms. This much diversity no doubt underlies a similar diversity in cellular function which we are only beginning to understand. Efforts in this direction are progressing rapidly, however, due in large part to the identification of members of this family of ligands and receptors as candidate genes in Alzheimer's disease.
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