Affiliations: [a] Laboratory of Biology of Neurodegenerative Disorders, Department of Neuroscience, IRCCS Mario Negri Institute for Pharmacological Research, Milano, Italy | [b] Neurosciences Therapeutic Unit, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts, UK
Correspondence:
[*]
Correspondence to: Dr. Gianluigi Forloni, IRCCS Istituto di Ricerche Farmacologiche “Mario Negri”, via G. La Masa 19, 20156 Milano, Italy. Tel.: +39 02 39014462; Fax: +39 02 354 6277; forloni@marionegri.it
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 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.
Keywords: Alzheimer’s disease, amyloid-β, apolipoprotein E, bexarotene, magnetic resonance imaging, memory, TASTPM mice, therapy
