| First Author | Bien-Ly N | Year | 2011 |
| Journal | Proc Natl Acad Sci U S A | Volume | 108 |
| Issue | 10 | Pages | 4236-41 |
| PubMed ID | 21368138 | Mgi Jnum | J:170827 |
| Mgi Id | MGI:4947456 | Doi | 10.1073/pnas.1018381108 |
| Citation | Bien-Ly N, et al. (2011) C-terminal-truncated apolipoprotein (apo) E4 inefficiently clears amyloid-beta (Abeta) and acts in concert with Abeta to elicit neuronal and behavioral deficits in mice. Proc Natl Acad Sci U S A 108(10):4236-41 |
| abstractText | 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 (Abeta) clearance/deposition and their potential synergy with Abeta in eliciting neuronal and behavioral deficits, we cross-bred transgenic mice expressing apoE3, apoE4, or apoE4(Delta272-299) 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 Abeta (94% and 89%, respectively) and less Abeta deposition (89% and 87%) than hAPP(FAD) mice without apoE, whereas hAPP(FAD) mice expressing mouse apoE had higher Abeta levels. 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 with hAPP(FAD) mice without apoE. Unlike apoE3 and apoE4, the C-terminal-truncated apoE4 bound poorly with Abeta peptides, leading to decreased Abeta clearance and increased Abeta deposition. Despite their lower levels of Abeta and Abeta deposition, hAPP(FAD)/apoE4(Delta272-299) mice accumulated pathogenic Abeta 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 Abeta peptides and acts in concert with low levels of Abeta to elicit neuronal and behavioral deficits in mice. |
