Role of Liver X Receptor in AD Pathophysiology.

Adrián G Sandoval-Hernández,Herman Moreno,Gloria Patricia Cardona-Gómez,Gonzalo Arboleda,Luna Buitrago,Emmanuel Planel

doi:10.1371/journal.pone.0145467

Adrián G Sandoval-Hernández, Herman Moreno + Show 4 more

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https://doi.org/10.1371/journal.pone.0145467

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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.

Highlights

Alzheimer's disease (AD) is an age-dependent neurodegenerative disorder and a major publichealth problem
When 3xTg-AD mice were treated with GW3965, there was no significant difference with wild-type littermates (WT) in these tasks
In retention task (Fig 1B), untreated WT had significantly less time of latency to step through the platform than untreated 3xTg-AD mice (p

Summary

Introduction

Alzheimer's disease (AD) is an age-dependent neurodegenerative disorder and a major publichealth problem. The hallmark of the disease is the formation of two types of protein aggregates: extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs) which are composed mainly of hyper-phosphorylated tau protein, both of which are necessary for the definitive diagnosis of AD in humans [1]. Role of LXR in AD Pathophysiology begins with an accumulation of amyloid beta peptides (Aβ1–42 and Aβ1–40) that promotes the subsequent events—including neuroinflammation, kinase deregulation, tangles formation, neurite dystrophy, synaptic deficits—which leads to neuronal death and dementia [2]. The hippocampal formation, one of the brain areas involved in learning and memory, is the earliest affected structure in AD [3]. The dentate gyrus (DG), has been described as one of the main areas where adult neurogenesis occurs and neurogenesis has been proposed to be affected in AD [4]

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