The nuclear retinoid X receptor agonist, bexarotene, has been implicated in recovery of cognitive function in mouse models of Alzheimer's disease (AD). Since AD genetic mouse models also show abnormal neural hyperexcitability, which may play a destructive role in memory storage and retrieval, we studied whether bexarotene exerted dynamic network effects on electroencephalography cortical spike discharge rate and spectral frequency in an AD (hAPP J20 model) and non-AD (Kv1.1 null) mouse models of epilepsy. We find that oral treatment with bexarotene over 1 week acutely reduced spike discharges in both models and seizures in the Kv1.1 null mouse model without major alterations in the background frequency of brain rhythms. The effect was reversible and exhibited a similar rapid onset in hippocampal slices. While the exact mechanisms are unknown, bexarotene counteracts both amyloid-β-induced and amyloid-β-independent increases in cortical network hyperexcitability.
The retinoid X receptor (RXR) agonist, bexarotene increases apolipoprotein E (ApoE) expression and exerts a striking improvement in cognitive function in an Alzheimer's disease (AD) mouse model (Cramer et al., 2012). Salient effects include reduction in amyloid-β (Aβ) plaque burden, clearance of soluble Aβ within 72 hours of treatment, and improvement in neural network activity and cognitive behaviors within 1 week. Recent studies confirmed the reduction in soluble forms of Aβ, including Aβ oligomers, in response to bexarotene treatment (Bachmeier et al., 2013, Fitz et al., 2013, Price et al., 2013, Tesseur et al., 2013, Ulrich et al., 2013 and Veeraraghavalu et al., 2013) and improved cognition and memory (Fitz et al., 2013 and Tesseur et al., 2013), however, plaque loss was not confirmed (Fitz et al., 2013, Laclair et al., 2013, Price et al., 2013, Tesseur et al., 2013 and Veeraraghavalu et al., 2013). These data support an accumulating body of evidence linking soluble forms of Aβ, rather than plaque deposition, with memory decline.
The cellular mechanisms leading to the dynamic and potentially reversible component of dementia in Aβ-overexpression models of AD and their amelioration by bexarotene remain poorly understood. There is ample evidence at the single cell level for Aβ-linked defects in synaptic plasticity, and these are accompanied by circuit level network discharges and seizures in most experimental genetic models of AD (Blanchard et al., 2002, Minkeviciene et al., 2009 and Mucke and Selkoe, 2012). Network hyperexcitability may arise from changes in intrinsic membrane properties as well as synaptic and connectivity defects and all have been described in AD models (Palop and Mucke, 2010). Clearance of Aβ from the brain is facilitated by ApoE, and ApoE expression is transcriptionally induced through the action of the nuclear peroxisome proliferator activated receptor and liver X receptors in coordination with RXRs. The primary mechanism of action of RXR receptors is to alter gene expression (Boehm et al., 1995, Hurst, 2000 and Lalloyer et al., 2009), but the extent and time course of its effects on neuronal excitability mechanisms are unknown, particularly in the early stages of its exposure to central nervous system pathways.
In this pilot study, we sought evidence for early changes in brain excitability that might correlate with the improvement in cognitive function because of bexarotene, as well as to determine whether this effect was strictly dependent on Aβ pathology by comparing 2 distinct mutant mouse models of neural hyperexcitability, 1 AD and 1 non-AD model.
