ApoE4 disrupts sterol and sphingolipid metabolism in Alzheimer's but not normal brain.
The epsilon 4 allele of ApoE is associated with an earlier onset and faster progression of Alzheimer's disease in patients with the familial form of this neurodegenerative condition. Although ApoE4 has been repeatedly associated with altered sphingomyelin and cholesterol levels in tissue culture and rodent models, there has not been a direct quantification of sphingomyelin or sterol levels in the brains of patients with different forms of ApoE. We measured the sphingolipid and sterol content of human brain tissues and found no evidence of perturbed sterol or sphingolipid biochemistry in the brains of individuals expressing ApoE4 who did not have a preexisting neurodegenerative condition. Nevertheless, ApoE4 was associated with gross abnormalities in the sterol and sphingolipid content of numerous brain regions in patients with Alzheimer's disease. The findings suggest that ApoE4 may not by itself alter sterol or sphingolipid metabolism in the brain under normal conditions, but that other neuropathologic changes of Alzheimer's are required to unmask the effect of ApoE4, and to perturb sterol and sphingolipid biochemistry.
Bandaru
Veera Venkata Ratnam
VV
Department of Neurology, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, USA.
Troncoso
Juan
J
Wheeler
David
D
Pletnikova
Olga
O
Wang
Jessica
J
Conant
Kathy
K
Haughey
Norman J
NJ
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001923:Brain Chemistry / Q000235:genetics; D002518:Ceramides / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009448:Neurochemistry / Q000379:methods; D013107:Sphingolipids / Q000378:metabolism*; D013261:Sterols / Q000378:metabolism*
D053327:Apolipoprotein E4; D002518:Ceramides; D013107:Sphingolipids; D013261:Sterols; D002784:Cholesterol