ApoAI deficiency results in marked reductions in plasma cholesterol but no alterations in amyloid-beta pathology in a mouse model of Alzheimer's disease-like cerebral amyloidosis.
Epidemiological studies suggest links between cholesterol metabolism and Alzheimer's disease (AD), with hypercholesterolemia associated with increased AD risk, and use of cholesterol-lowering drugs associated with decreased risk. Animal models using cholesterol-modifying dietary or pharmacological interventions demonstrate similar findings. Proposed mechanisms include effects of cholesterol on the metabolism of amyloid-beta (Abeta), the protein that deposits in AD brain. To investigate the effect of genetic alterations in plasma cholesterol on Abeta pathology, we crossed the PDAPP transgenic mouse model of AD-like cerebral amyloidosis to apolipoprotein AI-null mice that have markedly reduced plasma cholesterol levels due to a virtual absence of high density lipoproteins, the primary lipoprotein in mice. Interestingly and in contrast to models using non-physiological high fat diets or cholesterol-lowering drugs to modify plasma cholesterol, we observed no differences in Abeta pathology in PDAPP mice of the various apoAI genotypes despite robust differences in plasma cholesterol levels between the groups. Absence of apoAI also resulted in reductions in brain but not cerebrospinal fluid cholesterol, but had no effect on brain apolipoprotein E levels. These and other data suggest that it is perhaps the level of brain apolipoprotein E, not cholesterol per se, that plays a primary role in brain Abeta metabolism.
Fagan
Anne M
AM
Department of Neurology and Center for the Study of Nervous System Injury, Alzheimer's Disease Research Center, Washington University School of Medicine, 660 S. Euclid Ave., Box 8111, St. Louis, MO 63110, USA. fagana@neuro.wustl.edu.
Christopher
Erin
E
Taylor
Jennie W
JW
Parsadanian
Maia
M
Spinner
Michael
M
Watson
Melanie
M
Fryer
John D
JD
Wahrle
Suzanne
S
Bales
Kelly R
KR
Paul
Steven M
SM
Holtzman
David M
DM
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000686:Amyloidosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D016632:Apolipoprotein A-I / Q000172:deficiency* / Q000235:genetics; D015153:Blotting, Western; D001927:Brain Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002784:Cholesterol / Q000032:analysis / Q000378:metabolism*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005838:Genotype; D051379:Mice; D008822:Mice, Transgenic
D016229:Amyloid beta-Peptides; D016632:Apolipoprotein A-I; D002784:Cholesterol