| First Author | Zhao W | Year | 2014 |
| Journal | Front Aging Neurosci | Volume | 6 |
| Pages | 210 | PubMed ID | 25177293 |
| Mgi Jnum | J:289663 | Mgi Id | MGI:6433173 |
| Doi | 10.3389/fnagi.2014.00210 | Citation | Zhao W, et al. (2014) Aging reduces glial uptake and promotes extracellular accumulation of Abeta from a lentiviral vector. Front Aging Neurosci 6:210 |
| abstractText | We used a lentiviral system for expressing secreted human Abeta in the brains of young and old APOE knock-in mice. This system allowed us to examine Abeta metabolism in vivo, and test the effects of both aging and APOE genotype, two of the strongest risk factors for Alzheimer's disease. We injected the Abeta1-42 lentivirus into the motor cortex of young (2 month old) and old (20-22 month old) APOE3 and APOE4 mice. After 2 weeks of lentiviral expression, we analyzed the pattern of Abeta accumulation, glial activation, and phosphor-tau. In young mice, Abeta accumulated mainly within neurons with no evidence of extracellular Abeta. Significantly higher levels of intraneuronal Abeta were observed in APOE4 mice compared to APOE3 mice. In old mice, APOE4 predisposed again to higher levels of Abeta accumulation, but the Abeta was mainly in extracellular spaces. In younger mice, we also observed Abeta in microglia but not astrocytes. The numbers of microglia containing Abeta were significantly higher in APOE3 mice compared to APOE4 mice, and were significantly lower in both genetic backgrounds with aging. The astrocytes in old mice were activated to a greater extent in the brain regions where Abeta was introduced, an effect that was again increased by the presence of APOE4. Finally, phospho-tau accumulated in the region of Abeta expression, with evidence of extracellular phospho-tau increasing with aging. These data suggest that APOE4 predisposes to less microglial clearance of Abeta, leading to more intraneuronal accumulation. In older brains, decreased clearance leads to more extracellular Abeta, and more downstream consequences relating to astrocyte activation and phospho-tau accumulation. We conclude that both aging and APOE genotype affect pathways related to Abeta metabolism by microglia. |
