ISOFORM-SPECIFIC BINDING OF HUMAN APOLIPOPROTEIN-E TO THE NONAMYLOID BETA-COMPONENT OF ALZHEIMERS-DISEASE AMYLOID

The non-A beta component (NAC) of Alzheimer's disease amyloid is a new ly discovered 35 amino acid peptide found to be closely linked to the beta-amyloid fibrils in senile plaques. Apolipoprotein E (apoE) is ano ther prominent constituent of senile plaques. In vitro studies have sh own that apoE binds beta-amyloid(A beta) with high avidity, but it is unknown to what extent apoE interacts with NAC. We examined the intera ctions between apoE and NAC and found that apoE bound synthetic NAC, f orming a complex that resisted reducing agents and separation on SDS-P AGE. The complex could be formed using apoE from either purified human very low density lipoprotein (VLDL) particles, unfractionated human c erebrospinal fluid (CSF), or recombinant protein. The binding was esta blished within 15 min upon mixing, and the interaction between NAC and apoE was dose-dependent and specific as revealed by competition exper iments. The NAC-apoE complex was affected by non-physiological pH, but not by reducing agents such as DTT or beta-mercaptoethanol. ApoE exis ts in different isoforms of which the apoE3 genotype is the most frequ ent. Notably, the apoE4 genotype has been linked to late-onset Alzheim er's disease. This study presents evidence that apoE3 as well as apoE4 bind NAC, but the binding to apoE4 is about twice as strong as to apo E3. The isoform-specific binding of NAC to apoE may thus play an impor tant role in amyloidogenesis and in the sequestering of apoE in senile plaques during the progress of Alzheimer's disease.