UCSF

Among the common apolipoprotein (apo) E isoforms (apoE2, apoE3, and apoE4), apoE4 is the major known genetic risk factor for Alzheimer's disease (AD). Previous in vitro and in vivo experiments showed that apoE4 preferentially undergoes aberrant cleavage in neurons, yielding neurotoxic C-terminal-truncated fragments. To study the effect of these fragments on amyloid-beta (Abeta) clearance/deposition and their potential synergy with Abeta in eliciting neuronal and behavioral deficits, transgenic mice expressing human apoE3, apoE4, or apoE4(delta272-299) were cross-bred with mice expressing human amyloid precursor protein harboring familial AD mutations (hAPPFAD). At 6-8 months of age, hAPPFAD mice expressing human apoE3 or apoE4 had 94% and 89% less hippocampal Abeta(1-x), respectively, than hAPPFAD mice lacking apoE, while hAPPFAD mice expressing mouse apoE had the highest Abeta levels. Abeta deposition in hAPPFAD mice expressing human apoE3 or apoE4 was 89% and 87% less than hAPPFAD mice without apoE, respectively. Thus, human apoE stimulates Abeta clearance, but mouse apoE does not. Expression of apoE4(delta272-299) reduced total Abeta levels by only 63% and Abeta deposition by 46%, compared to hAPPFAD mice without apoE. Unlike apoE3 and apoE4, the C-terminal-truncated apoE4 bound Abeta peptides poorly, leading to decreased Abeta clearance and increased Abeta deposition. Despite their lower levels of Abeta and Abeta deposition, hAPPFAD/apoE4(delta272-299) mice accumulated potential pathogenic Abeta oligomers and displayed neuronal and behavioral deficits similar to or more severe than those in hAPPFAD mice lacking apoE. Thus, the C-terminal-truncated apoE4 fragment inefficiently clears Abeta peptides and has enhanced toxicity in the presence of low levels of Abeta to elicit neuronal and behavioral deficits in mice.