Sanders-Brown Faculty

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Steven Estus, Ph.D.

Professor

Departmental Affiliation(s):

Physiology

Research Focus:

Genetics of cholesterol and Alzheimer’s

In the lab:

Jim Simpson (Research Associate)

I-Fang Ling (Ph.D. Student)

Chris Simmons (Ph.D./M.D Student)

Laura Stephens (Masters Student).

Research Interests:

In our laboratory, we seek to elucidate the molecular and cellular mechanisms underlying neurodegenerative disease. Over the past several years, the focus of our laboratory has been the use of molecular genetics to identify genetic variants, or polymorphisms, that alter gene expression or RNA splicing and thereby increase the risk of Alzheimers disease (AD). Since cholesterol is emerging as a possible AD modulator, we are currently evaluating polymorphisms in genes that encode proteins critical to cholesterol homeostasis. As we identify these polymorphisms, we are expressing the genes in cells in vitro to evaluate their function, and evaluating mice deficient for these genes for issues relevant to AD, e.g., amyloid-beta levels. Overall, our work is facilitated by the Sanders-Brown Center on Aging and Alzheimers Disease Center (ADC). Our ADC has been critical in providing hundreds of DNA samples from well-characterized AD and control individuals, which are necessary for genotyping polymorphisms, as well as autopsy-derived CSF and brain samples, that has allowed us to quantify the levels of the gene products and genetic variant proteins of interest in a rapid and human-disease relevant fashion. In summary, the overall goal of our laboratory is to use human genetics to investigate hypotheses evaluating pathways critical to AD risk and progression. These studies contribute to the fight against AD by identifying individuals at risk, identifying possible novel therapies, and tailoring therapy to individuals.

Recent Publications:

Q. Liu, J. Zhang, H. Tran, M. M. Verbeek, K. Reiss, S. Estus and Guojun Bu. LRP1shedding in human brain: roles of ADAM10 and ADAM17.  Molec. Neurodegen. 4:17 (2009).

 F. Zou, R. K. Gopalraj, J. Lok, H. Zhu, I-F. Ling, J. F. Simpson, H. M. Tucker, J. F. Kelly, S. G. Younkin, D. W. Dickson, R. C. Petersen, N. R. Graff-Radford, D. A. Bennett, J. E. Crook, S. G. Younkin and S. Estus. Sex-dependent Association of a Common Low Density Lipoprotein Receptor Polymorphism with RNA Splicing Efficiency in the Brain and Alzheimers Disease.  Hum Molec. Genet.  17:929-935 (2008).

H. Zhu, J.W. Taylor, D.A. Bennett, S.G. Younkin and S. Estus. Lack of association of hepatic lipase polymorphisms with late-onset Alzheimer's disease. In Press, Neurobiol. Aging. (2007).

H. Zhu, H.M. Tucker, K. Grear, J. F. Simpson, A. K. Manning, L. A. Cupples and S. Estus. A common polymorphism decreases low-density lipoprotein receptor exon 12 splicing efficiency and associates with increased cholesterol. Hum. Molec. Genet. 16: 1765-1772 (2007).

G.W. Rebeck, M.J. LaDu, S. Estus, G. Bu, and E.J. Weeber. The generation and function of soluble apoE receptors in the CNS. Molec. Neurodegen. 1:15 (2006).

H. Zhu, R. K.Gopalra, J. F. Kelly, D. A. Bennett and S. Estus. Lack of genetic association of cholesteryl ester transfer protein polymorphisms with late onset Alzheimers disease. Neurosci. Lett. 381:36-41 (2005).

R. K. Gopalraj, H. Zhu, J. F. Kelly, M. Mendiondo, J. F. Pulliam, D. A. Bennett and S. Estus. Genetic association of low density lipoprotein receptor and Alzheimer’s Disease. Neurobiol. Aging. 26: 1-7 (2005).

N Ertekin-Taner, J. Ronald. L. Feuk, J. Prince, M. Tucker, L. Younkin, M. Hella, S. Jain, A. Hackett, L. Scanlin, J. Kelly, M. Kihiko-Ehman, M. Neltner, L. Hersh, M. Kindy, W. Markesbery, M. Hutton, M. de Andrade, R.C. Petersen, N. Graff-Radford, S. Estus, A.J. Brookes, S.G. Younkin. Elevated amyloid beta protein (Abeta42) and late onset Alzheimer's disease are associated with single nucleotide polymorphisms in the urokinase-type plasminogen activator gene. Hum. Mol. Genet. 14: 447-460 (2005).