Abstract
Alzheimer's disease (AD) is characterized pathologically by the presence of amyloid plaques and neurofibrillary tangles. The amyloid hypothesis contends that the abnormal accumulation of Aβ, the principal component of amyloid plaques, plays an essential role in initiating the disease. Impaired clearance of soluble Aβ from the brain, a process facilitated by apolipoprotein E (APOE), is believed to be a contributing factor in plaque formation. APOE expression is transcriptionally regulated through the action of a family of nuclear receptors including the peroxisome proliferator-activated receptor gamma and liver X receptors (LXRs) in coordination with retinoid X receptors (RXRs). It has been previously reported that various agonists of this receptor family can influence brain Aβ levels in rodents. In this study we investigated the effects of LXR/RXR agonism on brain and cerebrospinal fluid (CSF) levels of Aβ40 in naïve rats. Treatment of rats for 3 days or 7 days with the LXR agonist, TO901317 or the RXR agonist, Bexarotene did not result in significant changes in brain or CSF Aβ40 levels.
Highlights
Alzheimer’s disease (AD) is a debilitating neurodegenerative disease and the leading cause of dementia in the elderly
Data showing that APOE4 carriers begin to accumulate amyloid deposits earlier in life relative to non-carriers[4] has led to the hypothesis that increased risk associated with an E4 genotype may be the result of the effects of apolipoprotein E (APOE) on amyloid-β peptide (Aβ) production, turnover and/or clearance from the central nervous system (CNS)
Our aim in this study was to investigate the effects of retinoid X receptors (RXRs)/liver X receptors (LXRs) agonism on Aβ homeostasis in the CNS of non-transgenic rats using the RXR agonist, Bexarotene and the LXR agonist, TO901317
Summary
Alzheimer’s disease (AD) is a debilitating neurodegenerative disease and the leading cause of dementia in the elderly. The expression of genes encoding lipid-transport proteins, including APOE is transcriptionally regulated by the ligand-activated nuclear receptors, peroxisome proliferator-activated receptor gamma (PPARγ) and liver X receptors (LXRs) which form obligate heterodimers with retinoid X receptors (RXRs)[5]. Activation of these receptors has been shown to affect the activation state of macrophage and microglia[6]. Several groups have demonstrated that agonism of the LXR receptor resulted in reduced amyloid plaque burden and/or soluble Aβ levels in amyloid precursor protein (APP) transgenic mouse models[7,8,9]. We sought to examine the effects of LXR/RXR agonism on Aβ homeostasis in the CNS of non-transgenic rats using the RXR agonist, Bexarotene and the LXR agonist, TO901317
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