The continuing failure of bexarotene in alzheimer's disease mice

Claudia Balducci, Alessandra Paladini, Edoardo Micotti, Daniele Tolomeo, Pietro La Vitola, Emanuele Grigoli, Jill C. Richardson, Gianluigi Forloni

Research output: Contribution to journalArticle

Abstract

Alzheimer's disease (AD) is the most common form of dementia characterized by synaptic dysfunction, memory loss, neuroinflammation, and neuronal cell death. Amyloid-β (Aβ), 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 Aβ clearance and its expression is transcriptionally regulated by the liverXreceptor and retinoidXreceptors (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 BEXAmediated 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.

Original languageEnglish
Pages (from-to)471-482
Number of pages12
JournalJournal of Alzheimer's Disease
Volume46
Issue number2
DOIs
Publication statusPublished - 2015

Fingerprint

Alzheimer Disease
Memory Disorders
Apolipoproteins E
Amyloid
Amyloid Plaques
Brain
Microglia
Phagocytosis
Transgenic Mice
Oral Administration
Dementia
Cell Death
Magnetic Resonance Spectroscopy
bexarotene
Pathology
Phenotype
Therapeutics

Keywords

  • Alzheimer's disease
  • amyloid-β
  • apolipoprotein E
  • bexarotene
  • magnetic resonance imaging
  • memory
  • TASTPM mice
  • therapy

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Geriatrics and Gerontology
  • Clinical Psychology

Cite this

The continuing failure of bexarotene in alzheimer's disease mice. / Balducci, Claudia; Paladini, Alessandra; Micotti, Edoardo; Tolomeo, Daniele; La Vitola, Pietro; Grigoli, Emanuele; Richardson, Jill C.; Forloni, Gianluigi.

In: Journal of Alzheimer's Disease, Vol. 46, No. 2, 2015, p. 471-482.

Research output: Contribution to journalArticle

Balducci, Claudia ; Paladini, Alessandra ; Micotti, Edoardo ; Tolomeo, Daniele ; La Vitola, Pietro ; Grigoli, Emanuele ; Richardson, Jill C. ; Forloni, Gianluigi. / The continuing failure of bexarotene in alzheimer's disease mice. In: Journal of Alzheimer's Disease. 2015 ; Vol. 46, No. 2. pp. 471-482.
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