Higher avidity binding of apolipoprotein (E–AII) complex than of apolipoprotein E monomer to β‐amyloid

Apolipoprotein E (apoE) is believed to be closely involved in the pathogenesis of Alzheimer's disease (AD) because of its ability to bind to β‐amyloid (Aβ), the primary component of senile plaques. The presence of cystein residues in apoE2 and apoE3 allows these isoforms to form disulfide‐linked complexes, such as apo(E–AII) complex and apo(AII–E–AII) complex. A 50‐kDa complex [which corresponded to apo(E–AII)–Aβ, because it reacted with any of the three antibodies, anti‐apoE, anti‐apoAII, or anti‐Aβ] was detected by immunoblot analysis in native cerebrospinal fluid (CSF) obtained from nondementia patients with the apoE phenotype E3/E3. However, a band considered to represent apoE–Aβ was not observed. The dissociation constant (Kd) values obtained for the specific binding of recombinant apoE2, apoE3, and apoE4 to Aβ 1–42 were 48.1 ± 2.2 nM, 63.7 ± 2.1 nM, and 75.9 ± 1.8 nM, respectively. In contrast, the binding affinity of the partially purified apo(E3–AII) complex to Aβ 1–42 was very high, the Kd being 5.5 ± 0.5 nM. No basic difference was observed between lipidated and nonlipidated apoE in terms of the characteristics of the binding of apoE isoforms to Aβ 1–42 ; however, lipidation reduced the binding capacity of each isoform in a dose‐dependent manner. These findings seem consistent with the generally accepted idea that apoE4 is a risk factor for AD, insofar as only apoE4 is unable to form a complex with apoAII owing to its lack of a cystein residue. In addition, it is possible that apoE3 monomer (and possibly apoE2 monomer), like apoE4 but unlike apo(E–AII) complex, can act as a risk factor in the pathogenesis of AD. J. Neurosci. Res. 58:301–307, 1999. © 1999 Wiley‐Liss, Inc.