期刊
NEURON
卷 58, 期 5, 页码 681-693出版社
CELL PRESS
DOI: 10.1016/j.neuron.2008.04.010
关键词
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资金
- Howard Hughes Medical Institute Funding Source: Medline
- NHLBI NIH HHS [HL30568, R01 HL066088, R01 HL066082, HL66088, P01 HL030568] Funding Source: Medline
- NIA NIH HHS [F32AG24031, R37 AG013956, R01 AG030482-01, AG020202, R01 AG013956, R01 AG020202, R01 AG030482, AG13956, F32 AG024031] Funding Source: Medline
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.
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