Independent effects of APOE on cholesterol metabolism and brain Aβ levels in an Alzheimer disease mouse model

Karen M. Mann, Fayanne E. Thorngate, Yuko Katoh-Fukui, Hiroki Hamanaka, David L. Williams, Shinobu Fujita, Bruce Lamb

Research output: Contribution to journalArticle

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Abstract

The APOE E4 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 E4 alleles affects both the age of onset and the severity of pathology development. Dosage of APOE E2 and E3 alleles, however, appear to be protective against the effects of E4. 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 Aβ 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 Aβ 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 Aβ 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 Aβ metabolism in a mouse model of Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)1959-1968
Number of pages10
JournalHuman Molecular Genetics
Volume13
Issue number17
DOIs
StatePublished - Sep 1 2004
Externally publishedYes

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Apolipoproteins E
Alzheimer Disease
Cholesterol
Brain
Alleles
Apolipoprotein E2
Apolipoprotein E3
Pathology
Apolipoproteins A
Apolipoprotein E4
Age of Onset
Epidemiologic Studies
Genotype

ASJC Scopus subject areas

  • Genetics

Cite this

Mann, K. M., Thorngate, F. E., Katoh-Fukui, Y., Hamanaka, H., Williams, D. L., Fujita, S., & Lamb, B. (2004). Independent effects of APOE on cholesterol metabolism and brain Aβ levels in an Alzheimer disease mouse model. Human Molecular Genetics, 13(17), 1959-1968. https://doi.org/10.1093/hmg/ddh199

Independent effects of APOE on cholesterol metabolism and brain Aβ levels in an Alzheimer disease mouse model. / Mann, Karen M.; Thorngate, Fayanne E.; Katoh-Fukui, Yuko; Hamanaka, Hiroki; Williams, David L.; Fujita, Shinobu; Lamb, Bruce.

In: Human Molecular Genetics, Vol. 13, No. 17, 01.09.2004, p. 1959-1968.

Research output: Contribution to journalArticle

Mann, KM, Thorngate, FE, Katoh-Fukui, Y, Hamanaka, H, Williams, DL, Fujita, S & Lamb, B 2004, 'Independent effects of APOE on cholesterol metabolism and brain Aβ levels in an Alzheimer disease mouse model', Human Molecular Genetics, vol. 13, no. 17, pp. 1959-1968. https://doi.org/10.1093/hmg/ddh199
Mann KM, Thorngate FE, Katoh-Fukui Y, Hamanaka H, Williams DL, Fujita S et al. Independent effects of APOE on cholesterol metabolism and brain Aβ levels in an Alzheimer disease mouse model. Human Molecular Genetics. 2004 Sep 1;13(17):1959-1968. https://doi.org/10.1093/hmg/ddh199
Mann, Karen M. ; Thorngate, Fayanne E. ; Katoh-Fukui, Yuko ; Hamanaka, Hiroki ; Williams, David L. ; Fujita, Shinobu ; Lamb, Bruce. / Independent effects of APOE on cholesterol metabolism and brain Aβ levels in an Alzheimer disease mouse model. In: Human Molecular Genetics. 2004 ; Vol. 13, No. 17. pp. 1959-1968.
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