Science DOI: 10.1126/science.1217697
ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models
+ Author Affiliations
- 1Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
- 2Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
- 3Emotional Brain Institute, Nathan Kline Institute for Psychiatric Research and the New York University School of Medicine, Orangeburg, NY 10962, USA.
- 4Center of Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Alzheimer's disease is associated with impaired clearance of β-amyloid 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 (PPARγ) and liver X receptors (LXR) in coordination with retinoid X receptors (RXR). Oral administration of the RXR agonist, bexarotene, to a murine model of Alzheimer's disease resulted in enhanced clearance of soluble Aβ within hours in an apoE-dependent manner. Aβ plaque area was reduced >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 very rapid reversal of a broad range of Aβ-induced deficits.
- Received for publication 9 December 2011.
- Accepted for publication 20 January 2012.