Absence of ApoE upregulates murine brain ApoD and ABCA1 levels, but does not affect brain sterol levels, while human ApoE3 and human ApoE4 upregulate brain cholesterol precursor levels.
Apolipoprotein E (apoE) is a regulator of peripheral cholesterol homeostasis, and the apoE-isoform E4 is a major risk factor for the development of Alzheimer's disease (AD). Accumulating evidence suggests a key role for aberrant cholesterol metabolism in AD. We hypothesized that apoE-deficiency in mice not only affects cholesterol homeostasis in the periphery, but also in the brain, and that this can be restored by astrocyte-specific expression of human apoE3, but not apoE4. Using gas-chromatography mass-spectrometry, we found that absence of apoE in mice does not affect brain cholesterol homeostasis although serum sterol levels increase dramatically, especially when the apoE-knockout mice are fed a high fat diet. We provide evidence suggesting that apoD and the ATP-binding Cassette Transporter A1 (ABCA1) play a compensatory role in the apoE-deficient brain. Surprisingly, astrocyte-specific expression of human apoE3 or apoE4 in brains of apoE-knockout mice significantly increases brain levels of cholesterol and its precursors compared to control mice, indicative of an increased cholesterol synthesis rate in the brain. This increase is independent of the apoE-isoform, suggesting that the detrimental effect of apoE4 on the pathogenesis of AD is unlikely to be due to an apoE-isoform effect on brain cholesterol homeostasis.
Jansen
Paula J
PJ
Department of Molecular Cell Biology, Research Institute Brain and Behaviour (EURON), University of Maastricht, Maastricht, The Netherlands.
Lütjohann
Dieter
D
Thelen
Karin M
KM
von Bergmann
Klaus
K
van Leuven
Fred
F
Ramaekers
Frans C S
FC
Monique
Monique
M
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D053318:Apolipoprotein E3 / Q000235:genetics / Q000378:metabolism; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism; D053399:Apolipoproteins D / Q000145:classification / Q000378:metabolism*; D001057:Apolipoproteins E / Q000172:deficiency*; D001921:Brain / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D013261:Sterols / Q000378:metabolism*
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D053399:Apolipoproteins D; D001057:Apolipoproteins E; D009419:Nerve Tissue Proteins; D013261:Sterols; D002784:Cholesterol