Room 332, Sanders-Brown Center On Aging
800 South Limestone Street
Lexington, KY 40536-0230
Genetics of cholesterol and Alzheimer’s
Left to right: Carson van Sandford, Steve Estus, Ishita Parikh, Jim Simpson, Manasi Malik.
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.
L. S. Dieter andS. Estus.Isoform of APOE with retained intron 3; quantitation and identification of an associated single nucleotide polymorphism.Molec. Neurodeg. 5: 34 (2010).
Ling, I-F. andS. Estus.Critical exonic splicing enhancers modulate low density lipoprotein receptor exon 12 splicing.J. Neurochem.115(3):614-24(2010).
Ling, I-F. andS. Estus.Role of SFRS13A in low density lipoprotein receptor splicing. Hum. Mutat.31:702-9(2010). PMC Journal – In Process.
Grear, K. E., I-F. Ling, J. F. Simpson, J. L. Furman, C. R. Simmons, S. L. Peterson, F. A. Schmitt, W. R. Markesbery, Q. Liu, J. E. Crook, S. G.Younkin, G. Bu andS.Estus. Expression of SORL1 and a novel SORL1 splice variant in normal and Alzheimers disease brain.Molec. Neurodegen.4: 46 (2009).PMC2776013
Q. Liu, J. Zhang, H. Tran, M. M. Verbeek, K. Reiss,S. Estusand Guojun Bu. LRP1shedding in human brain: roles of ADAM10 and ADAM17. Molec. Neurodegen. 4:17 (2009).PMC2672942
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. YounkinandS. 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).PMC2361153
H. Zhu, J.W. Taylor, D.A. Bennett, S.G. Younkin andS. Estus. Lack of association of hepatic lipase polymorphisms with late-onset Alzheimer's disease.Neurobiol.Aging.29: 793-4 (2008). PMC2361133
H. Zhu, J.W. Taylor, D.A. Bennett, S.G. Younkin andS. 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 andS.Estus. A common polymorphism decreases low-density lipoprotein receptorexon 12 splicing efficiency and associates with increased cholesterol.Hum.Molec. Genet. 16: 1765-1772 (2007).
J. Tangpong, M.P. Cole, R. Sultana, G. Joshi,S. Estus, M. Vore, W. St. Clair, S. Ratanachaiyavong, D.K. St. Clair and D.A. Butterfield. Adriamycin-induced, TNF-alpha-mediated central nervous system toxicity.Neurobiol Dis.23: 127-139 (2006).