C-terminal-truncated apolipoprotein (apo) E4 inefficiently clears amyloid-β (Aβ) and acts in concert with Aβ to elicit neuronal and behavioral deficits in mice

Apolipoprotein (apo) E4 is the major known genetic risk factor for Alzheimer's disease (AD). We have shown in vitro and in vivo that apoE4 preferentially undergoes aberrant cleavage in neurons, yielding neurotoxic C-terminal-truncated fragments. To study the effect of these fragments on amyloid-beta (A beta) clearance/deposition and their potential synergy with A beta in eliciting neuronal and behavioral deficits, we cross-bred transgenic mice expressing apoE3, apoE4, or apoE4(Delta 272-299) with mice expressing human amyloid protein precursor (APP) harboring familial AD mutations (hAPP(FAD)). At 6-8 mo of age, hAPP(FAD) mice expressing apoE3 or apoE4 had lower levels of hippocampal A beta (94% and 89%, respectively) and less A beta deposition (89% and 87%) than hAPP(FAD) mice without apoE, whereas hAPP(FAD) mice expressing mouse apoE had higher A beta levels. Thus, human apoE stimulates A beta clearance, but mouse apoE does not. Expression of apoE4(Delta 272-299) reduced total A beta levels by only 63% and A beta deposition by 46% compared with hAPP(FAD) mice without apoE. Unlike apoE3 and apoE4, the C-terminaltruncated apoE4 bound poorly with A beta peptides, leading to decreased A beta clearance and increased A beta deposition. Despite their lower levels of A beta and A beta deposition, hAPP(FAD)/apoE4(Delta 272-299) mice accumulated pathogenic A beta oligomers and displayed neuronal and behavioral deficits similar to or more severe than those in hAPP(FAD) mice. Thus, the C-terminal-truncated apoE4 fragment inefficiently clears A beta peptides and acts in concert with low levels of A beta to elicit neuronal and behavioral deficits in mice.