ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models.
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.
Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Paige E
PE
Cramer
John R
JR
Cirrito
Daniel W
DW
Wesson
C Y Daniel
CY
Lee
J Colleen
JC
Karlo
Adriana E
AE
Zinn
Brad T
BT
Casali
Jessica L
JL
Restivo
Whitney D
WD
Goebel
Michael J
MJ
James
Kurt R
KR
Brunden
Donald A
DA
Wilson
Gary E
GE
Landreth
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000686:Amyloidosis / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D000077610:Bexarotene; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009812:Odorants; D009833:Olfactory Pathways / Q000187:drug effects / Q000502:physiology; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D010587:Phagocytosis; D058225:Plaque, Amyloid / Q000188:drug therapy; D047488:Retinoid X Receptors / Q000819:agonists / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000494:pharmacology* / Q000627:therapeutic use*
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D000077610:Bexarotene