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(American Journal of Pathology. 2004;165:1413-1422.)
© 2004 American Society for Investigative Pathology

ApoAI Deficiency Results in Marked Reductions in Plasma Cholesterol But No Alterations in Amyloid-ß Pathology in a Mouse Model of Alzheimer’s Disease-Like Cerebral Amyloidosis

Anne M. Fagan^*, Erin Christopher^*, Jennie W. Taylor^*, Maia Parsadanian^*, Michael Spinner^*, Melanie Watson^*, John D. Fryer^*, Suzanne Wahrle^*, Kelly R. Bales, Steven M. Paul^¶ and David M. Holtzman^*||

From the Center for the Study of Nervous System Injury,^* Alzheimer’s Disease Research Center, and the Departments of Neurology and Molecular Biology and Pharmacology,|| Washington University School of Medicine, St. Louis, Missouri; Neuroscience Discovery Research, Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana; and the Department of Pharmacology,^¶ Toxicology, and Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana

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-ß (Aß), the protein that deposits in AD brain. To investigate the effect of genetic alterations in plasma cholesterol on Aß 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 Aß 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 Aß metabolism.

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