| First Author | Wang C | Year | 2023 |
| Journal | J Clin Invest | Volume | 133 |
| Issue | 14 | PubMed ID | 37279069 |
| Mgi Jnum | J:354484 | Mgi Id | MGI:7511382 |
| Doi | 10.1172/JCI169131 | Citation | Wang C, et al. (2023) APOE-epsilon4 synergizes with sleep disruption to accelerate Abeta deposition and Abeta-associated tau seeding and spreading. J Clin Invest 133(14) |
| abstractText | Alzheimer's disease (AD) is the most common cause of dementia. The APOE-epsilon4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset AD. The APOE genotype modulates the effect of sleep disruption on AD risk, suggesting a possible link between apoE and sleep in AD pathogenesis, which is relatively unexplored. We hypothesized that apoE modifies Abeta deposition and Abeta plaque-associated tau seeding and spreading in the form of neuritic plaque-tau (NP-tau) pathology in response to chronic sleep deprivation (SD) in an apoE isoform-dependent fashion. To test this hypothesis, we used APPPS1 mice expressing human APOE-epsilon3 or -epsilon4 with or without AD-tau injection. We found that SD in APPPS1 mice significantly increased Abeta deposition and peri-plaque NP-tau pathology in the presence of APOE4 but not APOE3. SD in APPPS1 mice significantly decreased microglial clustering around plaques and aquaporin-4 (AQP4) polarization around blood vessels in the presence of APOE4 but not APOE3. We also found that sleep-deprived APPPS1:E4 mice injected with AD-tau had significantly altered sleep behaviors compared with APPPS1:E3 mice. These findings suggest that the APOE-epsilon4 genotype is a critical modifier in the development of AD pathology in response to SD. |
