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, T0901317 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
Acknowledged several hypotheses associated with liver X receptors (LXRs)/retinoid X receptors (RXRs) agonism that were not addressed in this study
We recognize that LXR/RXR agonism may affect the pathology of AD in other ways (e.g. increased phagocytic clearance of amyloid deposits (Savage 2015) or may directly affect the cognitive decline via non-Abetadependent mechanisms not yet fully understood (Jack 2016)
Summary
Alzheimer’s disease (AD) is a debilitating neurodegenerative disease and the leading cause of dementia in the elderly. The pathological hallmarks of AD are the presence of extracellular amyloid plaques and intracellular neurofibrillary tangles in the hippocampus and cortical areas of the brain[1]. Aggregation of Aβ into soluble, multimeric assemblies and insoluble amyloid fibrils is hypothesized to contribute directly to the pathogenesis of AD; therapeutic strategies aimed at lowering soluble Aβ levels in the brain would be predicted to have a disease-modifying effect[2]. The presence of a single copy of E4 increases the risk for Alzheimer’s disease 3-fold and individuals with 2 copies are 15 times more likely to develop AD3. 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 APOE on Aβ production, turnover and/or clearance from the central nervous system (CNS)
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