ApoAI deficiency results in marked reductions in plasma cholesterol but no alterations in amyloid-β 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, David M. Holtzman

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)1413-1422
Number of pages10
JournalAmerican Journal of Pathology
Volume165
Issue number4
DOIs
StatePublished - Oct 2004

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Fagan, A. M., Christopher, E., Taylor, J. W., Parsadanian, M., Spinner, M., Watson, M., Fryer, J. D., Wahrle, S., Bales, K. R., Paul, S. M., & Holtzman, D. M. (2004). ApoAI deficiency results in marked reductions in plasma cholesterol but no alterations in amyloid-β pathology in a mouse model of Alzheimer's disease-like cerebral amyloidosis. American Journal of Pathology, 165(4), 1413-1422. https://doi.org/10.1016/S0002-9440(10)63399-8