Introduction
Apolipoprotein E ε ApoE4 (apoE4) is the strongest genetic risk factor for Alzheimer's disease (AD). It increases the risk of ad in Europe by 15 times, and its impact on the risk of ad in Asia is much higher than that in Europe. Previous studies have found that apoE has a positive effect on a β The production and clearance of tau and tau dependent neurodegeneration are affected, but its mechanism in specific cells is still unclear.
A study of Boston University School of medicine BUSM has made some breakthroughs in this regard, that is, apoE4 activates glial cell specific disorders and non cellular autonomic regulation disorders, aggravating ad. these findings were recently published in the journal Cell (influencing factor 66.85).
Research related
The researchers analyzed the global transcriptome of hiPSC model, human brain and apoE tr mice, confirmed the characteristics and role of apoE4 gene, and further revealed some mechanisms of apoE4 on the induction of AD.
1. The presence of multiple haplotypes containing apoE loci depends on the APOE genotype.
2. The regulatory mechanism or structural sites near apoE vary from species to species, and lipid metabolic dysfunction is unique to human apoE4 glial cells (cell-specific disorder).
Stromal related, ECM related, interferon and cytokine signaling pathways in mouse microglia and astrocytes, but lack of post functional lipid related disorders.
3. ApoE4 microglia and astrocytes cause lipid metabolism disorders and inflammatory stromal disorders, which promote each other, leading to the aggravation of AD.
ApoE4 can drive lysosomal cholesterol chelation in astrocytes, increase cholesterol biosynthesis and reduce efflux, eventually leading to lipid imbalance.
ApoE4 induces proinflammatory stromal disorders (non cellular autonomic disorders) through astrocyte neuron communication, exacerbating lipid disorders including cholesterol biosynthesis and reduced efflux.
ApoE4 inhibits microglia apoe-trem2-plc γ 2 signal transduction. The reduction of apoe-trem2 signal transduction in microglia will accelerate the imbalance of lipid metabolism and inflammatory state.
Summary
This study demonstrates the human specificity of apoE4 and the type dependent transcription and cell phenotype of AD brain cells, revealing the main defects of lipid homeostasis and glial activation. This suggests that in apoE4 carriers, restoring glial lipid homeostasis and regulating inflammation may become a new method for the treatment of AD. Studies have also confirmed that LXR (liver X receptor) agonists can save the dysregulated lipid / cholesterol metabolism in ApoE 4 astrocytes and restore the efflux to apoE3 (normal gene) level.
