Role of Apolipoprotein E in β-Amyloidogenesis ISOFORM-SPECIFIC EFFECTS ON PROTOFIBRIL TO FIBRIL CONVERSION OF Aβ IN VITRO AND BRAIN Aβ DEPOSITION IN VIVO

Human APOE beta 4 allele is a strong genetic risk factor of Alzheimer disease. Neuropathological and genetic studies suggested that apolipoprotein E4 (apoE4) protein facilitates deposition of amyloid beta peptide (A beta) in the brain, although the mechanism whereby apoE4 increases amyloid aggregates remains elusive. Here we show that injection of A beta protofibrils induced A beta deposition in the brain of APP transgenic mice, suggesting that A beta protofibrils acted as a seed for aggregation and deposition of A beta in vivo. Injection of A beta protofibrils together with apoE3 significantly attenuated A beta deposition, whereas apoE4 did not have this effect. In vitro assays revealed that the conversion of A beta protofibrils to fibrils progressed more slowly upon coincubation with apoE2 or apoE3 compared with that with apoE4. A beta protofibrils complexed with apoE4 were less stable than those with apoE2 or apoE3. These data suggest that the suppression effect of apoE2 or apoE3 on the structural conversion of A beta protofibrils to fibrils is stronger than those of apoE4, thereby impeding beta-amyloid deposition.