ApoE promotes the proteolytic degradation of Aβ

Apolipoprotein E is associated with age-related risk for Alzheimer's disease and plays critical roles in A beta homeostasis. We report that ApoE plays a role in facilitating the proteolytic clearance of soluble A beta from the brain. The endolytic degradation of A beta peptides within microglia by neprilysin and related enzymes is dramatically enhanced by ApoE. Similarly, A beta degradation extracellularly by insulin-degrading enzyme is facilitated by ApoE. The capacity of Apo to promote A beta degradation is dependent upon the ApoE isoform and its lipidation status. The enhanced expression of lipidated ApoE, through the activation of liver X receptors, stimulates A beta degradation. Indeed, aged Tg2576 mice treated with the LXR agonist GW3965 exhibited a dramatic reduction in brain A beta load. GW3965 treatment also reversed contextual memory deficits. These data demonstrate a mechanism through which ApoE facilitates the clearance of A beta from the brain and suggest that LXR agonists may represent a novel therapy for A beta.