Implication of apoE isoforms in cholesterol metabolism by primary rat hippocampal neurons and astrocytes.
Apolipoprotein E (apoE) has been genetically linked to late-onset Alzheimer's disease. From the three common alleles (epsilon2, epsilon3 and epsilon4), epsilon4 has been suggested to promote amyloid beta (Ass) plaque fibrillation, one hallmark of Alzheimer's disease. It has been demonstrated that altered lipid content of hippocampal plasma membrane coincides with the disease. In this study, we show for the first time that the apoE dependent cholesterol metabolism in hippocampal neurons is higher than that of hippocampal astrocytes. Further, apoE-bound cholesterol is highly incorporated in membranous compartments in hippocampal neurons, whereas hippocampal astrocytes show higher intracellular distribution. This is an effect that coincides with cell-type dependent difference of low density lipoprotein receptor (LDLR) family member expression. Hippocampal neurons express high levels of the LDLR related protein (LRP), whereas hippocampal astrocytes are highly positive for LDLR. We could also demonstrate an apoE isoform (apoE2, apoE3 and apoE4) dependent cholesterol uptake in both cells types. In hippocampal neurons, we could find a decreased apoE4-bound cholesterol uptake. In contrast, hippocampal astrocytes show decreased internalization of apoE2-bound cholesterol. In addition, lipidated apoE4 is little associated with neurites in hippocampal neurons in comparison to the other two isoforms. In contrary, hippocampal astrocytes show faint apoE2 immunocytostaining intensity. Data presented indicate that the role of apoE4 in cholesterol homeostasis and apolipoprotein cell association is more pronounced in hippocampal neurons, showing significant alterations compared to the other two isoforms, suggesting that hippocampal neurons are affected by apoE4 associated altered cholesterol metabolism compared to hippocampal astrocytes.
Rapp
Alfred
A
Department of Medical Chemistry, MedUniWien, Center of Physiology and Pathophysiology, Medical University of Vienna, Währingerstrasse 10, 1090 Vienna, Austria. alfredrapp@yahoo.com
Gmeiner
Bernhard
B
Hüttinger
Manfred
M
D000818:Animals; D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D001253:Astrocytes / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism* / Q000493:pharmacokinetics; D008078:Cholesterol, LDL / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D006624:Hippocampus / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D007150:Immunohistochemistry; D050356:Lipid Metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000032:analysis; D009474:Neurons / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D011485:Protein Binding; D020033:Protein Isoforms / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism
D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D008078:Cholesterol, LDL; D005904:Glial Fibrillary Acidic Protein; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008869:Microtubule-Associated Proteins; D020033:Protein Isoforms; D011973:Receptors, LDL; D002784:Cholesterol