ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models

Paige E. Cramer; John R. Cirrito; Daniel W. Wesson; C. Y.Daniel Lee; J. Colleen Karlo; Adriana E. Zinn; Brad T. Casali; Jessica L. Restivo; Whitney D. Goebel; Michael J. James; Kurt R. Brunden; Donald A. Wilson; Gary E. Landreth

doi:10.1126/science.1217697

ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models

Paige E. Cramer, John R. Cirrito, Daniel W. Wesson, C. Y.Daniel Lee, J. Colleen Karlo, Adriana E. Zinn, Brad T. Casali, Jessica L. Restivo, Whitney D. Goebel, Michael J. James, Kurt R. Brunden, Donald A. Wilson, Gary E. Landreth

Research output: Contribution to journal › Article › peer-review

918 Scopus citations

Abstract

Alzheimer's disease (AD) is associated with impaired clearance of β-amyloid (Aβ) 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 Aβ within hours in an apoE-dependent manner. Aβ 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 Aβ clearance mechanisms, resulting in the rapid reversal of a broad range of Aβ-induced deficits.

Original language	English
Pages (from-to)	1503-1506
Number of pages	4
Journal	Science
Volume	335
Issue number	6075
DOIs	https://doi.org/10.1126/science.1217697
State	Published - Mar 23 2012

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@article{e5078ece3c6740d6b60c5f68131c116b,

title = "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models",

abstract = "Alzheimer's disease (AD) is associated with impaired clearance of β-amyloid (Aβ) 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 Aβ within hours in an apoE-dependent manner. Aβ 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 Aβ clearance mechanisms, resulting in the rapid reversal of a broad range of Aβ-induced deficits.",

author = "Cramer, {Paige E.} and Cirrito, {John R.} and Wesson, {Daniel W.} and Lee, {C. Y.Daniel} and Karlo, {J. Colleen} and Zinn, {Adriana E.} and Casali, {Brad T.} and Restivo, {Jessica L.} and Goebel, {Whitney D.} and James, {Michael J.} and Brunden, {Kurt R.} and Wilson, {Donald A.} and Landreth, {Gary E.}",

year = "2012",

month = mar,

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doi = "10.1126/science.1217697",

language = "English",

volume = "335",

pages = "1503--1506",

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T1 - ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models

AU - Cramer, Paige E.

AU - Cirrito, John R.

AU - Wesson, Daniel W.

AU - Lee, C. Y.Daniel

AU - Karlo, J. Colleen

AU - Zinn, Adriana E.

AU - Casali, Brad T.

AU - Restivo, Jessica L.

AU - Goebel, Whitney D.

AU - James, Michael J.

AU - Brunden, Kurt R.

AU - Wilson, Donald A.

AU - Landreth, Gary E.

PY - 2012/3/23

Y1 - 2012/3/23

N2 - Alzheimer's disease (AD) is associated with impaired clearance of β-amyloid (Aβ) 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 Aβ within hours in an apoE-dependent manner. Aβ 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 Aβ clearance mechanisms, resulting in the rapid reversal of a broad range of Aβ-induced deficits.

AB - Alzheimer's disease (AD) is associated with impaired clearance of β-amyloid (Aβ) 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 Aβ within hours in an apoE-dependent manner. Aβ 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 Aβ clearance mechanisms, resulting in the rapid reversal of a broad range of Aβ-induced deficits.

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SN - 0036-8075

VL - 335

SP - 1503

EP - 1506

JO - Science

JF - Science

IS - 6075

ER -

ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models

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