Role of Apolipoprotein E in Alzheimer’s Disease: Clues from its Structure
A major advance toward understanding the etiology of Alzheimer’s disease (AD) was the discovery by Duke University investigators that one of the common alleles of the plasma lipid-transporting protein, apolipoprotein (apo) E, was a major susceptibility gene (Strittmatter et al. 1993a; Corder et al. 1993; Saunders et al. 1993; Roses et al. 1995). It was also demonstrated that allelic variation at the apoE gene locus affects the progression of the disease in an isoform-specific and dose-dependent manner: apoE4 > apoE3 > apoE2 (Roses et al. 1995; Corder et al. 1994). This breakthrough focused attention on and brought into clearer perspective a series of observations suggesting that apoE was linked to neurobiology in addition to its long-known role as a transporter of plasma lipids and modulator of plasma lipoprotein triglyceride and cholesterol metabolism (for reviews, see Mahley 1988 and Weisgraber 1994). Early studies had connected apoE to nerve regeneration following injury, where apoE participated in local capture and reutilization of neuronal membrane lipids at the injury site during the degeneration and regeneration processes (Boyles et al. 1989; Pitas et al. 1987; Skene and Shooter 1983; Müller et al. 1986; Ignatius et al. 1986). These studies led to the observation that the presence of apoE influences neurite outgrowth in primary neuronal cultures (Handelmann et al. 1992). More recently, apoE was shown to influence this outgrowth in an isoform-specifìc manner, with apoE3, the most common isoform, promoting neurite outgrowth and apoE4, the product of the AD susceptibility gene, retarding outgrowth (Nathan et al. 1994).
KeywordsHigh Density Lipopro Human apoE Lipoprotein Binding Major Susceptibility Gene Neuronal Membrane Lipid
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