ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models

被引：865

作者：

Cramer, Paige E. ^{[1
]}

Cirrito, John R. ^{[2
]}

Wesson, Daniel W. ^{[1
,3
,4
]}

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

Karlo, J. Colleen ^{[1
]}

Zinn, Adriana E. ^{[1
]}

Casali, Brad T. ^{[1
]}

Restivo, Jessica L. ^{[2
]}

Goebel, Whitney D. ^{[2
]}

James, Michael J. ^{[5
]}

Brunden, Kurt R. ^{[5
]}

Wilson, Donald A. ^{[3
,4
]}

Landreth, Gary E. ^{[1
]}

机构：

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

[2] Washington Univ, Knight Alzheimers Dis Res Ctr, Hope Ctr Neurol Disorders, Dept Neurol,Sch Med, St Louis, MO 63110 USA

[3] Nathan S Kline Inst Psychiat Res, Emot Brain Inst, Orangeburg, NY 10962 USA

[4] NYU, Sch Med, Orangeburg, NY 10962 USA

[5] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Ctr Neurodegenerat Dis Res, Philadelphia, PA 19104 USA

来源：

SCIENCE | 2012年 / 335卷 / 6075期

关键词：

ALZHEIMERS-DISEASE; COMMON VARIANTS; DYSFUNCTION; BURDEN; MICE; METABOLISM; RECEPTORS; PATHOLOGY; MEMORY; CD2AP;

D O I：

10.1126/science.1217697

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Alzheimer's disease (AD) is associated with impaired clearance of beta-amyloid (A beta) from the brain, a process normally facilitated by apolipoprotein E (apoE). ApoE expression is transcriptionally induced through the action of the nuclear receptors peroxisome proliferator-activated receptor gamma and liver X receptors in coordination with retinoid X receptors (RXRs). Oral administration of the RXR agonist bexarotene to a mouse model of AD resulted in enhanced clearance of soluble A beta within hours in an apoE-dependent manner. A beta plaque area was reduced more than 50% within just 72 hours. Furthermore, bexarotene stimulated the rapid reversal of cognitive, social, and olfactory deficits and improved neural circuit function. Thus, RXR activation stimulates physiological A beta clearance mechanisms, resulting in the rapid reversal of a broad range of A beta-induced deficits.

引用

页码：1503 / 1506

页数：4

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