| First Author | Hudry E | Year | 2013 |
| Journal | Sci Transl Med | Volume | 5 |
| Issue | 212 | Pages | 212ra161 |
| PubMed ID | 24259049 | Mgi Jnum | J:213540 |
| Mgi Id | MGI:5585247 | Doi | 10.1126/scitranslmed.3007000 |
| Citation | Hudry E, et al. (2013) Gene transfer of human Apoe isoforms results in differential modulation of amyloid deposition and neurotoxicity in mouse brain. Sci Transl Med 5(212):212ra161 |
| abstractText | Inheritance of the epsilon4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor associated with the sporadic form of Alzheimer's disease (AD), whereas the rare APOE epsilon2 allele has the opposite effect. However, the mechanisms whereby APOE confers risk and protection remain uncertain. We used a gene transfer approach to bathe the cortex of amyloid plaque-bearing transgenic mice with virally expressed human APOE. We monitored amyloid-beta (Abeta) with multiphoton imaging, in vivo microdialysis, and postmortem array tomography to study the kinetics of human APOE-mediated changes in Abeta-related neurotoxicity in a mouse model of AD. We observed that human APOE4 increased the concentrations of oligomeric Abeta within the interstitial fluid and exacerbated plaque deposition; the converse occurred after exposure to human APOE2. Peri-plaque synapse loss and dystrophic neurites were also worsened by APOE4 or attenuated by APOE2. Egress of Abeta from the central nervous system (CNS) into the plasma was diminished by APOE3 and APOE4 compared to APOE2, in accord with isoform-specific retention of Abeta in the CNS. Overall, our data show a differential effect of human APOE isoforms on amyloid deposition and clearance in transgenic mice and, more importantly, on Abeta-mediated synaptotoxicity. These results suggest that the APOE genetic risk is mediated by Abeta, and that therapeutic approaches aimed at decreasing APOE4, or increasing APOE2, may be beneficial in AD. |
