ApoE promotes the proteolytic degradation of Aβ

被引：738

作者：

Jiang, Qingguang ^{[1
]}

Lee, C. Y. Daniel ^{[1
]}

Mandrekar, Shweta ^{[1
]}

Wilkinson, Brandy ^{[1
]}

Cramer, Paige ^{[1
]}

Zelcer, Noam ^{[2
]}

Mann, Karen ^{[3
]}

Lamb, Bruce ^{[3
]}

Willson, Timothy M. ^{[4
]}

Collins, Jon L. ^{[4
]}

Richardson, Jill C. ^{[5
]}

Smith, Jonathan D. ^{[6
]}

Comery, Thomas A. ^{[7
]}

Riddell, David ^{[7
]}

Holtzman, David M. ^{[8
]}

Tontonoz, Peter ^{[2
]}

Landreth, Gary E. ^{[1
]}

机构：

[1] Case Western Reserve Univ, Sch Med, Dept Neurosci, Alzheimers Res Lab, Cleveland, OH 44106 USA

[2] Univ Calif Los Angeles, Howard Hughes Med Inst, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA

[3] Cleveland Clin Fdn, Lerner Res Inst, Dept Neurosci, Cleveland, OH 44195 USA

[4] GlaxoSmithKline, Discovery Res, Res Triangle Pk, NC 27709 USA

[5] GlaxoSmithKline, Harlow CM19 5AW, Essex, England

[6] Cleveland Clin Fdn, Lerner Res Inst, Dept Cell Biol, Cleveland, OH 44195 USA

[7] Wyeth Ayerst Res, Discovery Neurosci, Princeton, NJ 08543 USA

[8] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA

来源：

NEURON | 2008年 / 58卷 / 05期

关键词：

D O I：

10.1016/j.neuron.2008.04.010

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页码：681 / 693

页数：13

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