QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, November 16, 2005, 25(46):10658-10663; doi:10.1523/JNEUROSCI.1922-05.2005

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Ramaswamy, G. Articles by Weisgraber, K. H. Search for Related Content PubMed PubMed Citation Articles by Ramaswamy, G. Articles by Weisgraber, K. H.

 Previous Article  |  Next Article 

Neurobiology of Disease
Effect of Domain Interaction on Apolipoprotein E Levels in Mouse Brain

Gayathri Ramaswamy,¹ Qin Xu,¹ Yadong Huang,^1,2,3 and Karl H. Weisgraber^1,2,4

¹Gladstone Institute of Neurological Disease, Departments of ²Pathology and ³Neurology, and ⁴Cardiovascular Research Institute, University of California, San Francisco, California 94158

Apolipoprotein (apo) E4 is a risk factor for heart disease, Alzheimer's disease, and other forms of neurodegeneration, but the underlying mechanisms are unknown. Domain interaction, a structural property that distinguishes apoE4 from apoE2 and apoE3, results in more rapid turnover and lower plasma levels of apoE4. To determine whether domain interaction affects brain apoE levels, we analyzed brain homogenates from human apoE3 and apoE4 knock-in mice, wild-type mice, and Arg-61 apoE mice, in which domain interaction was introduced by gene targeting. As determined on Western blots, the hemibrain, cortex, hippocampus, and cerebellum of knock-in mice had 30-40% lower levels of apoE4 than apoE3, and Arg-61 mice had 25-50% lower apoE levels than wild-type mice. In the CSF, Arg-61 apoE level was 40% lower than the wild-type level. Arg-61 apoE mRNA levels were similar to or slightly higher than wild-type apoE mRNA levels. Thus, the lower Arg-61 apoE levels were not attributable to decreased mRNA levels. In culture medium from heterozygous Arg-61/wild-type and apoE4/apoE3 primary astrocytes, Arg-61 apoE and apoE4 levels were lower than wild-type apoE and apoE3, respectively, suggesting that primary astrocytes secrete lower amounts of Arg-61 apoE and apoE4. These results demonstrate that domain interaction is responsible for the lower levels of both human apoE4 and mouse Arg-61 apoE in mouse brain. Cells may recognize apoE4 and Arg-61 apoE as misfolded proteins and target them for degradation or accumulation. Thus, degradation/accumulation or lower levels of apoE4 may contribute to the association of apoE4 with Alzheimer's disease.

Key words: apolipoprotein E; Alzheimer's disease; domain interaction; knock-in mice; wild-type mice; Arg-61 apoE mice

---

Received May 13, 2005; revised September 19, 2005; accepted October 1, 2005.

This article has been cited by other articles:

				N. Zhong, G. Ramaswamy, and K. H. Weisgraber Apolipoprotein E4 Domain Interaction Induces Endoplasmic Reticulum Stress and Impairs Astrocyte Function J. Biol. Chem., October 2, 2009; 284(40): 27273 - 27280. [Abstract] [Full Text] [PDF]

				K. R. Bales, F. Liu, S. Wu, S. Lin, D. Koger, C. DeLong, J. C. Hansen, P. M. Sullivan, and S. M. Paul Human APOE Isoform-Dependent Effects on Brain {beta}-Amyloid Levels in PDAPP Transgenic Mice J. Neurosci., May 27, 2009; 29(21): 6771 - 6779. [Abstract] [Full Text] [PDF]

				N. Zhong and K. H. Weisgraber Understanding the Association of Apolipoprotein E4 with Alzheimer Disease: Clues from Its Structure J. Biol. Chem., March 6, 2009; 284(10): 6027 - 6031. [Abstract] [Full Text] [PDF]

				D. R. Riddell, H. Zhou, K. Atchison, H. K. Warwick, P. J. Atkinson, J. Jefferson, L. Xu, S. Aschmies, Y. Kirksey, Y. Hu, et al. Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels J. Neurosci., November 5, 2008; 28(45): 11445 - 11453. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help