Microglia can take up soluble Aβ from the extracellular milieu and degrade it with a combination of lyzosomal enzymes, a process that contributes to the maintenance of normal levels of Aβ in the brain. The authors investigated whether ApoE has any influence on this process. They found that when human ApoE was added to murine microglia cultured in the presence of soluble Aβ, the rate of clearance of internalized Aβ was increased in a dose-dependent manner. The rate of Aβ uptake was unaffected, and thus elevation of ApoE enhanced intracellular Aβ degradation. Furthermore, the loss of ApoE in Apoe-null microglia impaired Aβ degradation, showing that ApoE is essential for microglial Aβ breakdown.
The expression of ApoE, and that of ABCA1, the protein that loads ApoE with lipid, is upregulated by liver X receptors (LXRs; ligand-activated transcription factors). The authors showed that Aβ degradation could be manipulated by altering the activity of LXRs: incubating microglia with an LXR-specific agonist raised intracellular ApoE levels and ApoE lipid content and increased Aβ degradation. This effect was not observed in Apoe-null microglia, confirming that ApoE is necessary for the modulating effect of LXR activity. Additional experiments with Abca1-knockout microglia confirmed that the lipidation state of ApoE is important: a greater lipid load resulted in greater Aβ breakdown.
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