The Role of ApoE and Liver X Receptors in Alzheimer's Disease
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Case Western Reserve University School of Graduate Studies / OhioLINK
2008
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| Online Access: | http://rave.ohiolink.edu/etdc/view?acc_num=case1212161307 |
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ndltd-OhioLink-oai-etd.ohiolink.edu-case12121613072021-08-03T05:32:35Z The Role of ApoE and Liver X Receptors in Alzheimer's Disease Jiang, Qingguang Biomedical Research ApoE LXR ABCA1 A&946 APP Alzheimer's disease NF&954 B inflammation microglia astrocyte IDE neprilysin HDL GW3965 p65 acetylation HDAC3 SMRT p300 pCAF lipidation <p>Apolipoprotein E (ApoE) is associated with age-related risk for Alzheimer's disease and plays critical roles in Aβ metabolism. ApoE is the major apolipoprotein present in high-density lipoproteins (HDL) and plays an essential role in cholesterol homeostasis in the brain. The ATP-binding cassette A1 (ABCA1) mediates the efflux of cholesterol and phospholipids into ApoE HDL. Liver X receptors regulate the expression of ApoE and ABCA1. ApoE plays a previously unappreciated role in facilitating the proteolytic clearance of soluble Aβ from the brain. The endolytic degradation of Aβ peptides within microglia by neprilysin and related enzymes is dramatically enhanced by ApoE. Similarly, Aβ degradation extracellularly by insulin degrading enzyme is facilitated by ApoE. The capacity of ApoE to promote Aβ degradation is dependent upon the ApoE isoform and its lipidation status. The enhanced expression of lipidated ApoE, through the activation of liver X receptors, stimulates Aβ degradation. In vivo, aged Tg2576 mice treated with the LXR agonist GW3965 exhibited a dramatic reduction in brain Aβ load. Significantly, GW3965 treatment also reversed contextual memory deficits. In N2a.Swe cells, LXR activation induced ABCA1 expression and reduced steady state Aβ levels. However, it did not affect the levels of holo-APP, the generation of secreted α-APP or C-terminal fragment. LXR did not affect the distribution of APP or its processing machinery, supporting the conclusion that LXR-mediated reduction of Aβ is due to enhanced clearance but not altered APP processing.</p><p> Amyloid plaques are associated with a chronic inflammatory environment. LXR activation inhibited microglia-mediated inflammation both in vitro and in vivo. This inhibition is due to its regulation of NFκB transcriptional activity by actively stimulating the nuclear export of p65. The effect of the LXR agonist on p65 nuclear export correlates with its effect on the dynamic exchange of the SMRT/HDAC3 corepressor complex for the p300/pCAF coactivator complex upon LXR activation. Furthermore, LXR activation reverses the inhibition of fibrillar Aβ-stimulated phagocytosis by pro-inflammatory stimuli in microglia and ameliorates plaque-associated microglial inflammation in aged Tg2576 mice. Altogether, our results suggest that LXR agonists may represent a novel therapy for AD through its effects on both Aβ homeostasis and inflammation.</p> 2008-06-23 English text Case Western Reserve University School of Graduate Studies / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=case1212161307 http://rave.ohiolink.edu/etdc/view?acc_num=case1212161307 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
| collection |
NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Biomedical Research ApoE LXR ABCA1 A&946 APP Alzheimer's disease NF&954 B inflammation microglia astrocyte IDE neprilysin HDL GW3965 p65 acetylation HDAC3 SMRT p300 pCAF lipidation |
| spellingShingle |
Biomedical Research ApoE LXR ABCA1 A&946 APP Alzheimer's disease NF&954 B inflammation microglia astrocyte IDE neprilysin HDL GW3965 p65 acetylation HDAC3 SMRT p300 pCAF lipidation Jiang, Qingguang The Role of ApoE and Liver X Receptors in Alzheimer's Disease |
| author |
Jiang, Qingguang |
| author_facet |
Jiang, Qingguang |
| author_sort |
Jiang, Qingguang |
| title |
The Role of ApoE and Liver X Receptors in Alzheimer's Disease |
| title_short |
The Role of ApoE and Liver X Receptors in Alzheimer's Disease |
| title_full |
The Role of ApoE and Liver X Receptors in Alzheimer's Disease |
| title_fullStr |
The Role of ApoE and Liver X Receptors in Alzheimer's Disease |
| title_full_unstemmed |
The Role of ApoE and Liver X Receptors in Alzheimer's Disease |
| title_sort |
role of apoe and liver x receptors in alzheimer's disease |
| publisher |
Case Western Reserve University School of Graduate Studies / OhioLINK |
| publishDate |
2008 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=case1212161307 |
| work_keys_str_mv |
AT jiangqingguang theroleofapoeandliverxreceptorsinalzheimersdisease AT jiangqingguang roleofapoeandliverxreceptorsinalzheimersdisease |
| _version_ |
1719421530504429568 |