The inheritance of 54 allele of APOE is a major genetic risk factor for late-onset AD. APOE is under the transcriptional control of Liver X receptors, LXR1 and LXR2. LXR are transcription factors that control the expression of genes involved in cholesterol metabolism. In brain, in addition to normal neuronal function, cholesterol metabolism is of utmost importance for secretase activities, APP cleavage, A? aggregation and its clearance from the brain. Recently we, and others, reported that deletion of Abca1 - an LXR target gene, in APP transgenic mice decreases endogenous mouse ApoE level and increases amyloid deposition. Compared with APOE3 carriers, higher incidence of AD and increased amyloid deposition in APOE4 carriers might be a result of lower ApoE protein levels observed in these patients. Thus, ApoE4 isoform provides less protection against the accumulation of toxic A? species. It is conceivable that additional genetic factors such as impaired transcriptional regulation by LXR in response to strong metabolic signals, like high fat diet, influence this risk and precipitate the development of dementia. We hypothesize that transcriptional control of ApoE by LXR is critical for ameliorating the detrimental effect of ApoE4 isoform on amyloid deposition and cognitive decline. The hypothesis is based on the following observations: First, our preliminary data demonstrate that in human ApoE targeted replacement mice, ApoE4 protein levels are lower than ApoE3 and this correlates with increased amyloid load. In addition, treatment with the synthetic LXR ligand, T0901317 (T0), increases ApoE4 levels in vitro and in vivo thus reducing the quantitative differences between the two isoforms. Second, studies from our and other groups indicated that treatment of APP transgenic mice with T0 increases ApoE protein level and inhibits A? deposition. Third, our recent study demonstrated that T0 treatment alleviates the deleterious effects of high fat diet on amyloid deposition and cognitive decline in older APP23 mice suggesting that the effect of T0 on AD phenotype is a result of facilitated A? clearance mediated through increased ApoE protein level.
Two Specific aims are designed to test the hypothesis:
Specific aim 1 : To examine how the activated LXR ligands modify the effect of ApoE3 and ApoE4 isoforms on A? aggregation and clearance.
Specific aim 2 : To characterize the effects of LXR ligand T0901317 on AD phenotype in APP/PS1dE9 mice on ApoE3 and EpoE4 background fed normal and Western type of diets.

Public Health Relevance

This study will address questions that are important for continuing research in a field highly relevant to human health - Alzheimer's disease and the strongest risk factor - Apolipoprotein E. The result from this study will help us to understand the interplay between important genes and proteins involved in cholesterol transport in brain, and how the knowledge about disturbed function of those proteins can help in developing new therapeutic strategies for slowing AD progression.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Cell Death in Neurodegeneration Study Section (CDIN)
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Petanceska, Suzana
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University of Pittsburgh
Public Health & Prev Medicine
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Nam, Kyong Nyon; Mounier, Anais; Wolfe, Cody M et al. (2017) Effect of high fat diet on phenotype, brain transcriptome and lipidome in Alzheimer's model mice. Sci Rep 7:4307
Castranio, Emilie L; Mounier, Anais; Wolfe, Cody M et al. (2017) Gene co-expression networks identify Trem2 and Tyrobp as major hubs in human APOE expressing mice following traumatic brain injury. Neurobiol Dis 105:1-14
Fitz, Nicholas F; Carter, Alexis Y; Tapias, Victor et al. (2017) ABCA1 Deficiency Affects Basal Cognitive Deficits and Dendritic Density in Mice. J Alzheimers Dis 56:1075-1085
Carter, Alexis Y; Letronne, Florent; Fitz, Nicholas F et al. (2017) Liver X receptor agonist treatment significantly affects phenotype and transcriptome of APOE3 and APOE4 Abca1 haplo-deficient mice. PLoS One 12:e0172161
Sweet, Robert A; MacDonald, Matthew L; Kirkwood, Caitlin M et al. (2016) Apolipoprotein E*4 (APOE*4) Genotype Is Associated with Altered Levels of Glutamate Signaling Proteins and Synaptic Coexpression Networks in the Prefrontal Cortex in Mild to Moderate Alzheimer Disease. Mol Cell Proteomics 15:2252-62
Nam, Kyong Nyon; Mounier, Anais; Fitz, Nicholas F et al. (2016) RXR controlled regulatory networks identified in mouse brain counteract deleterious effects of A? oligomers. Sci Rep 6:24048
Fitz, Nicholas F; Tapias, Victor; Cronican, Andrea A et al. (2015) Opposing effects of Apoe/Apoa1 double deletion on amyloid-? pathology and cognitive performance in APP mice. Brain 138:3699-715
Lefterov, Iliya; Schug, Jonathan; Mounier, Anais et al. (2015) RNA-sequencing reveals transcriptional up-regulation of Trem2 in response to bexarotene treatment. Neurobiol Dis 82:132-140
Mounier, Anais; Georgiev, Danko; Nam, Kyong Nyon et al. (2015) Bexarotene-Activated Retinoid X Receptors Regulate Neuronal Differentiation and Dendritic Complexity. J Neurosci 35:11862-76
Fitz, Nicholas F; Castranio, Emilie L; Carter, Alexis Y et al. (2014) Improvement of memory deficits and amyloid-? clearance in aged APP23 mice treated with a combination of anti-amyloid-? antibody and LXR agonist. J Alzheimers Dis 41:535-49

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