Role of Liver X Receptor in AD Pathophysiology

Abstract

Alzheimer's disease (AD) is the major cause of dementia worldwide. The pharmacological activation of nuclear receptors (Liver X receptors: LXRs or Retinoid X receptors: RXR) has been shown to induce overexpression of the ATP-Binding Cassette A1 (ABCA1) and Apolipoprotein E (ApoE), changes that are associated with improvement in cognition and reduction of amyloid beta pathology in amyloidogenic AD mouse models (i.e. APP, PS1: 2tg-AD). Here we investigated whether treatment with a specific LXR agonist has a measurable impact on the cognitive impairment in an amyloid and Tau AD mouse model (3xTg-AD: 12-months-old; three months treatment). The data suggests that the LXR agonist GW3965 is associated with increased expression of ApoE and ABCA1 in the hippocampus and cerebral cortex without a detectable reduction of the amyloid load. We also report that most cells overexpressing ApoE (86±12%) are neurons localized in the granular cell layer of the hippocampus and entorhinal cortex. In the GW3965 treated 3xTg-AD mice we also observed reduction in astrogliosis and increased number of stem and proliferating cells in the subgranular zone of the dentate gyrus. Additionally, we show that GW3965 rescued hippocampus long term synaptic plasticity, which had been disrupted by oligomeric amyloid beta peptides. The effect of GW3965 on synaptic function was protein synthesis dependent. Our findings identify alternative functional/molecular mechanisms by which LXR agonists may exert their potential benefits as a therapeutic strategy against AD.

Therapeutic potential of nuclear receptor agonists in Alzheimer's disease

“…Recently, it was reported that activation of LXRs in a triple transgenic mouse model of AD (3xTg-AD) leads to a change in the DNA methylation status of genes related to synaptic function (Syp, Syn1, and Dlg3) and neurogenesis (Hmgb3 and Rbbp7), suggesting an increase in their expression, which was, in fact, confirmed for Syn1 (76). These results are in line with previous work published by the same authors, demonstrating that the beneficial effect of LXR on synaptic function in 3xTg-AD mice is dependent on synaptic-related protein synthesis, which is disrupted by A (77). Another recent study reported that the activation of PPAR by simvastatin is able to improve memory function in 5XFAD mice, which is likely underlined by an increase in cAMP-response element binding protein (CREB) and brain-derived neurotrophic factor (34).…”

LXR Regulation of Brain Cholesterol: From Development to Disease

“…Previous evidence has suggested that RXR and its heterodimer partners are able to regulate the transcription of neuronal genes important for neurogenesis and neurite extension [67–70], synaptic function [71], and neuronal survival [1]. A recent study from Sandoval-Hernandez et al reports that treatment of 3xTg-AD mice with LXR agonist GW3965 increases proliferation of neural precursors in the subgranular zone and rescues Aβ-induced deficits in long-term potentiation (LTP) in a protein-synthesis dependent manner [72]. In a later study, Sandoval-Hernandez et al determined that GW3965 treatment was able to effect improved performance on cognitive tests in aged 3xTg-AD mice coincident with reduced DNA methylation in the hippocampus [73].…”

ABCA1/ApoE/HDL Pathway Mediates GW3965-Induced Neurorestoration After Stroke

“…Deficiency of ABCA1 also decreases ApoE level and impairs ApoE metabolism in brain 3, 5, 25–27 . Both ABCA1 and ApoE play a vital role in cholesterol homeostasis, neuronal repair and synaptic plasticity 28, 29 . ABCA1 −B/−B mice are generated by crossing loxP-flanked (floxed) ABCA1 mice with transgenic mice expressing Cre recombinant under the control of the neuronal and glial specific nestin promoter 25 .…”

“…GW3965 crosses the blood-brain barrier and stimulates expression of many target genes, including ABCA1/ApoE 6 . GW3965 treatment raises HDL-level in plasma, liver and macrophages 10, 32, 38, 39 , and increases expression of ABCA1/ApoE in the hippocampus and cerebral cortex and rescues hippocampus long-term synaptic plasticity in an Alzheimer’s disease mouse model 29 . In the present study, we found that GW3965-treatment of ABCA1 fl/fl -stroke mice significantly increased the levels of brain-ABCA1/ApoE and blood-HDL, increased gray/WM-remodeling as well as improved functional-outcome.…”