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S3‐02–05: APOE expression in different types of cells in the CNS: Roles in neurobiology and Alzheimer's disease
Author(s) -
Huang Yadong
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.382
Subject(s) - apolipoprotein e , neurogenesis , biology , choroid plexus , neuroscience , cell type , microbiology and biotechnology , pathology , central nervous system , disease , medicine , cell , genetics
expressing mice with LXR ligand T0901317 increases ABCA1 expression in CNS, inhibits A-beta levels in the brain and has a beneficial effect on their cognitive performance. In vitro data from our and other groups suggest that the upregulation of ABCA1 mRNA expression and inhibition of A-beta production is a direct effect of natural or synthetic LXR ligands applied to cultured neuronal cell lines and primary neurons. Our goal was to examine the effect of LXR agonists on gene expression and A-beta aggregation in vivo and in vitro. Methods: We applied LXR ligands to APP transgenic mice for various times and examined gene and protein expression. We also performed a series of experiments with primary brain cells derived from ABCA1 and LXR knockout mice subjected to various LXR agonist treatments. Results: Our data demonstrate an upregulation of genes related to lipid metabolism and transport, and a downregulation of genes involved in immune response and inflammation. Additional treatment experiments demonstrated an increase of apolipoprotein E and a decreased amyloid deposition in APP transgenic mice. LXR agonists suppressed the inflammatory response induced by fibrillar and oligomeric A-beta in primary LXR wild type but not in LXR knockout glial cells. Furthermore, activated LXR increased the secretion and lipidation of apoE in primary astrocytes and decreased A-beta aggregation in vitro. Conclusions: These results show that LXR agonists could alleviate AD pathology by acting on amyloid deposition and brain inflammation. An increased understanding of the LXR controlled regulation of A-beta aggregation will lead to the development of more specific and powerful agonists targeting LXR for the treatment of AD.