Similar promotion of Aβ_1-42fibrillogenesis by native apolipoprotein E ε3 and ε4 isoforms

• Main Authors: Smith Jonathan D, LeVine Harry, Martins Ralph, Sweeney David, Gandy Sam
• Format: Article
• Language: English
• Published: BMC 2004-08-01
• Series: Journal of Neuroinflammation
• Online Access: http://www.jneuroinflammation.com/content/1/1/15

<p>Abstract</p> <p>The apolipoprotein E ε4 allele contributes to the genetic susceptibility underlying a large proportion (~40–60%) of typical, sporadic Alzheimer disease. Apolipoprotein E deficient mice made transgenic for human apolipoprotein E ε4 accumulate excess cerebral amyloid when compared to similarly prepared mice expressing human apolipoprotein E ε3. Therefore, it is important to search for relevant interactions(s) between apolipoprotein E ε4 and Aβ in order to clarify the biological role for apolipoprotein E ε4 in Alzheimer disease. Using a thioflavine T (ThT)-based assay, we have investigated the effects of native human apolipoprotein E isoforms on the kinetics of Aβ fibrillogenesis. No obvious profibrillogenic activity was detected in Aβ_1-40-based assays of any native apolipoprotein E isoform. However, when ThT assays were repeated using Aβ_1-42, modest, but statistically significant, profibrillogenic activity was detected in both apolipoprotein E ε3- and apolipoprotein E ε4-containing media and was similar in magnitude for the two isoforms. These data demonstrate that native apolipoprotein E possesses "pathological chaperone"-type activity for Aβ: in other words, the data indicate that a chaperone-like misfolding reaction can occur between native apolipoprotein E and Aβ. However, the equipotent activities of the apolipoprotein E ε3 and ε4 isoforms suggests the possibility that either extended co-incubation of apolipoprotein E and Aβ, or, perhaps, the inclusion in the reaction of other fibrillogenesis-modulation co-factors (such as metal ions, or inflammatory mediators such as reactive oxygen species, α₂-macroglobulin, apolipoprotein J, etc.) may be required for modeling <it>in vitro </it>the apolipoprotein E-isoform-specific-regulation of extracellular Aβ accumulation that occurs <it>in vivo</it>. Alternatively, other events, such as differential apolipoprotein E-isoform-mediated clearance of Aβ or of apolipoprotein E/Aβ complexes may underlie apolipoprotein E-isoform-dependent Aβ accumulation.</p>