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Independent effects of APOE on cholesterol metabolism and brain Abeta levels in an Alzheimer disease mouse model.
Hum Mol Genet 2004; 13(17):1959-68HM

Abstract

The APOE epsilon4 allele is the most significant genetic risk factor associated with Alzheimer's disease to date. Epidemiological studies have demonstrated that inheritance of one or more epsilon4 alleles affects both the age of onset and the severity of pathology development. Dosage of APOE epsilon2 and epsilon3 alleles, however, appear to be protective against the effects of epsilon4. Although much of the biology of APOE in peripheral cholesterol metabolism is understood, its role in brain cholesterol metabolism and its impact on AD development is less defined. Several APOE transgenic models have been generated to study the effects of APOE alleles on APP processing and Abeta pathology. However, these models have potential limitations that confound our understanding of the effects of apolipoprotein E (APOE) levels and cholesterol metabolism on disease development. To circumvent these limitations, we have taken a genomic-based approach to better understand the relationship between APOE alleles, cholesterol and Abeta metabolism. We have characterized APOE knock-in mice, which express each human allele under the endogenous regulatory elements, on a defined C57BL6/J background. These mice have significantly different serum cholesterol levels and steady-state brain APOE levels, and yet have equivalent brain cholesterol levels. However, the presence of human APOE significantly increases brain Abeta levels in a genomic-based model of AD, irrespective of genotype. These data indicate an independent role for APOE in cholesterol metabolism in the periphery relative to the CNS, and that the altered levels of cholesterol and APOE in these mice are insufficient to influence Abeta metabolism in a mouse model of Alzheimer's disease.

Authors+Show Affiliations

Department of Genetics, Case Western Reserve University, Cleveland, OH 44106, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15229191

Citation

Mann, Karen M., et al. "Independent Effects of APOE On Cholesterol Metabolism and Brain Abeta Levels in an Alzheimer Disease Mouse Model." Human Molecular Genetics, vol. 13, no. 17, 2004, pp. 1959-68.
Mann KM, Thorngate FE, Katoh-Fukui Y, et al. Independent effects of APOE on cholesterol metabolism and brain Abeta levels in an Alzheimer disease mouse model. Hum Mol Genet. 2004;13(17):1959-68.
Mann, K. M., Thorngate, F. E., Katoh-Fukui, Y., Hamanaka, H., Williams, D. L., Fujita, S., & Lamb, B. T. (2004). Independent effects of APOE on cholesterol metabolism and brain Abeta levels in an Alzheimer disease mouse model. Human Molecular Genetics, 13(17), pp. 1959-68.
Mann KM, et al. Independent Effects of APOE On Cholesterol Metabolism and Brain Abeta Levels in an Alzheimer Disease Mouse Model. Hum Mol Genet. 2004 Sep 1;13(17):1959-68. PubMed PMID: 15229191.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Independent effects of APOE on cholesterol metabolism and brain Abeta levels in an Alzheimer disease mouse model. AU - Mann,Karen M, AU - Thorngate,Fayanne E, AU - Katoh-Fukui,Yuko, AU - Hamanaka,Hiroki, AU - Williams,David L, AU - Fujita,Shinobu, AU - Lamb,Bruce T, Y1 - 2004/06/30/ PY - 2004/7/2/pubmed PY - 2005/3/19/medline PY - 2004/7/2/entrez SP - 1959 EP - 68 JF - Human molecular genetics JO - Hum. Mol. Genet. VL - 13 IS - 17 N2 - The APOE epsilon4 allele is the most significant genetic risk factor associated with Alzheimer's disease to date. Epidemiological studies have demonstrated that inheritance of one or more epsilon4 alleles affects both the age of onset and the severity of pathology development. Dosage of APOE epsilon2 and epsilon3 alleles, however, appear to be protective against the effects of epsilon4. Although much of the biology of APOE in peripheral cholesterol metabolism is understood, its role in brain cholesterol metabolism and its impact on AD development is less defined. Several APOE transgenic models have been generated to study the effects of APOE alleles on APP processing and Abeta pathology. However, these models have potential limitations that confound our understanding of the effects of apolipoprotein E (APOE) levels and cholesterol metabolism on disease development. To circumvent these limitations, we have taken a genomic-based approach to better understand the relationship between APOE alleles, cholesterol and Abeta metabolism. We have characterized APOE knock-in mice, which express each human allele under the endogenous regulatory elements, on a defined C57BL6/J background. These mice have significantly different serum cholesterol levels and steady-state brain APOE levels, and yet have equivalent brain cholesterol levels. However, the presence of human APOE significantly increases brain Abeta levels in a genomic-based model of AD, irrespective of genotype. These data indicate an independent role for APOE in cholesterol metabolism in the periphery relative to the CNS, and that the altered levels of cholesterol and APOE in these mice are insufficient to influence Abeta metabolism in a mouse model of Alzheimer's disease. SN - 0964-6906 UR - https://www.unboundmedicine.com/medline/citation/15229191/Independent_effects_of_APOE_on_cholesterol_metabolism_and_brain_Abeta_levels_in_an_Alzheimer_disease_mouse_model_ L2 - https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddh199 DB - PRIME DP - Unbound Medicine ER -