Role of apolipoprotein E in {beta}-amyloidogenesis: isoform-specific effects on protofibril to fibril conversion of A{beta} in vitro and brain A{beta} deposition in vivo. [Neurobiology]

April 27th, 2015 by Hori, Y., Hashimoto, T., Nomoto, H., Hyman, B. T., Iwatsubo, T.

Human APOE ϵ4 allele is a strong genetic risk factor of Alzheimer disease (AD). Neuropathological and genetic studies suggested that apolipoprotein E4 (apoE4) protein facilitates deposition of amyloid β peptide (Aβ) in the brain, although the mechanism whereby apoE4 increases amyloid aggregates remains elusive. Here we show that injection of Aβ protofibrils induced Aβ deposition in the brain of APP transgenic mice, suggesting that Aβ protofibrils acted as a seed for aggregation and deposition of Aβ in vivo. Injection of Aβ protofibrils together with apoE3 significantly attenuated Aβ deposition, whereas apoE4 did not have this effect. In vitro assays revealed that the conversion of Aβ protofibrils to fibrils progressed slower upon co-incubation with apoE2 or apoE3 compared to that with apoE4. Aβ 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 Aβ protofibrils to fibrils is stronger than those of apoE4, thereby impeding β-amyloid deposition.
  • Posted in Journal of Biological Chemistry, Publications
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