期刊
HUMAN MOLECULAR GENETICS
卷 13, 期 17, 页码 1959-1968出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddh199
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资金
- NCI NIH HHS [CA 43703] Funding Source: Medline
- NHLBI NIH HHS [R01 HL32868] Funding Source: Medline
- NIA NIH HHS [R01 AG14451, P50 AG08012] Funding Source: Medline
- NIGMS NIH HHS [GM08613] Funding Source: Medline
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.
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