科研之友
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摘要
We used a lentiviral system for expressing secreted human A beta in the brains of young and old APOE knock-in mice. This system allowed us to examine A beta 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 A beta(1-42) 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 A beta accumulation, glial activation, and phosphor-tau. In young mice, A beta accumulated mainly within neurons with no evidence of extracellular A beta. Significantly higher levels of intraneuronal A beta were observed in APOE4 mice compared to APOE3 mice. In old mice, APOE4 predisposed again to higher levels of A beta accumulation, but the A beta was mainly in extracellular spaces. In younger mice, we also observed A beta in microglia but not astrocytes. The numbers of microglia containing A beta 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 A beta was introduced, an effect that was again increased by the presence of APOE4. Finally, phospho-tau accumulated in the region of A beta expression, with evidence of extracellular phospho-tau increasing with aging. These data suggest that APOE4 predisposes to less microglial clearance of A beta, leading to more intraneuronal accumulation. In older brains, decreased clearance leads to more extracellular A beta, and more downstream consequences relating to astrocyte activation and phospho-tau accumulation. We conclude that both aging and APOE genotype affect pathways related to A beta metabolism by microglia.
