PMID- 25777514
OWN - NLM
STAT- MEDLINE
DCOM- 20160711
LR  - 20181202
IS  - 1875-8908 (Electronic)
IS  - 1387-2877 (Linking)
VI  - 46
IP  - 2
DP  - 2015
TI  - The Continuing Failure of Bexarotene in Alzheimer's Disease Mice.
PG  - 471-82
LID - 10.3233/JAD-150029 [doi]
AB  - Alzheimer's disease (AD) is the most common form of dementia characterized by 
      synaptic dysfunction, memory loss, neuroinflammation, and neuronal cell death. 
      Amyloid-beta (Abeta), recognized as the main culprit of AD, aggregates and accumulates 
      in the extracellular compartment as neuritic plaques, after deregulation of its 
      production or clearance. Apolipoprotein E (ApoE) plays a major role in Abeta 
      clearance and its expression is transcriptionally regulated by the liver X 
      receptor and retinoid X receptors (RXRs) system. Bexarotene (BEXA), an RXR 
      agonist that increases ApoE expression and microglia phagocytosis has been 
      proposed as a promising therapy for AD, resolving both the amyloid pathology and 
      memory loss. Despite the first compelling report, however, multiple failures have 
      been documented, raising concern about whether BEXA could in fact become a novel 
      disease-modifying strategy for AD. To help clarify this, we investigated the 
      effect of BEXA in vivo at multiple levels in TASTPM transgenic mice. Seven-day 
      oral administration of BEXA to these mice did not achieve any significant memory 
      improvement, plaque reduction, or enhancement of microglial cell activation. No 
      differences were found when specifically investigating the microglial phagocytic 
      state in vivo. In addition, a brain structural analysis with magnetic resonance 
      did not detect any BEXA-mediated change in the volume reduction of the main 
      affected brain areas in our mice. These results suggest that BEXA has no 
      beneficial effects on the multi-factorial pathologic phenotype of AD mice.
FAU - Balducci, Claudia
AU  - Balducci C
AD  - Laboratory of Biology of Neurodegenerative Disorders, Department of Neuroscience, 
      IRCCS Mario Negri Institute for Pharmacological Research, Milano, Italy.
FAU - Paladini, Alessandra
AU  - Paladini A
AD  - Laboratory of Biology of Neurodegenerative Disorders, Department of Neuroscience, 
      IRCCS Mario Negri Institute for Pharmacological Research, Milano, Italy.
FAU - Micotti, Edoardo
AU  - Micotti E
AD  - Laboratory of Biology of Neurodegenerative Disorders, Department of Neuroscience, 
      IRCCS Mario Negri Institute for Pharmacological Research, Milano, Italy.
FAU - Tolomeo, Daniele
AU  - Tolomeo D
AD  - Laboratory of Biology of Neurodegenerative Disorders, Department of Neuroscience, 
      IRCCS Mario Negri Institute for Pharmacological Research, Milano, Italy.
FAU - La Vitola, Pietro
AU  - La Vitola P
AD  - Laboratory of Biology of Neurodegenerative Disorders, Department of Neuroscience, 
      IRCCS Mario Negri Institute for Pharmacological Research, Milano, Italy.
FAU - Grigoli, Emanuele
AU  - Grigoli E
AD  - Laboratory of Biology of Neurodegenerative Disorders, Department of Neuroscience, 
      IRCCS Mario Negri Institute for Pharmacological Research, Milano, Italy.
FAU - Richardson, Jill C
AU  - Richardson JC
AD  - Neurosciences Therapeutic Unit, GlaxoSmithKline, Gunnels Wood Road, Stevenage, 
      Herts, UK.
FAU - Forloni, Gianluigi
AU  - Forloni G
AD  - Laboratory of Biology of Neurodegenerative Disorders, Department of Neuroscience, 
      IRCCS Mario Negri Institute for Pharmacological Research, Milano, Italy.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Netherlands
TA  - J Alzheimers Dis
JT  - Journal of Alzheimer's disease : JAD
JID - 9814863
RN  - 0 (Apolipoproteins E)
RN  - 0 (Liver X Receptors)
RN  - 0 (Orphan Nuclear Receptors)
RN  - 0 (Retinoid X Receptors)
RN  - 0 (Tetrahydronaphthalenes)
RN  - A61RXM4375 (Bexarotene)
SB  - IM
MH  - Alzheimer Disease/*drug therapy
MH  - Animals
MH  - Apolipoproteins E/metabolism
MH  - Bexarotene
MH  - Brain/*pathology
MH  - Disease Models, Animal
MH  - Female
MH  - Liver X Receptors
MH  - Maze Learning/drug effects
MH  - Mice
MH  - Mice, Transgenic
MH  - Microglia/drug effects
MH  - Orphan Nuclear Receptors/*agonists
MH  - Retinoid X Receptors/*agonists
MH  - Tetrahydronaphthalenes/*administration & dosage
MH  - Treatment Failure
OTO - NOTNLM
OT  - Alzheimer's disease
OT  - TASTPM mice
OT  - amyloid-beta
OT  - apolipoprotein E
OT  - bexarotene
OT  - magnetic resonance imaging
OT  - memory
OT  - therapy
EDAT- 2015/03/18 06:00
MHDA- 2016/07/12 06:00
CRDT- 2015/03/18 06:00
PHST- 2015/03/18 06:00 [entrez]
PHST- 2015/03/18 06:00 [pubmed]
PHST- 2016/07/12 06:00 [medline]
AID - P100767RG0U86352 [pii]
AID - 10.3233/JAD-150029 [doi]
PST - ppublish
SO  - J Alzheimers Dis. 2015;46(2):471-82. doi: 10.3233/JAD-150029.