Steven Estus

Research Description: 

In our laboratory, we seek to elucidate the mechanisms underlying Alzheimer’s disease (AD). Since genetics drives the majority of AD risk, we are currently using molecular genetics coupled with cell biology, i.e., identifying single nucleotide polymorphisms (SNP)s in AD-related genes that alter gene expression or splicing, and then evaluating the resultant effects at the cellular level on AD-related mechanisms. Our goal is to identify pharmacologic agents that mimic the effects of the protective alleles and thereby reduce AD risk. For example, since cholesterol represents a possible AD modulator, we recently evaluated polymorphisms implicated in cholesterol homeostasis for their association with AD. We found several positive results, most notably in the gene that encodes HMGCR, the target of the common statin class of cholesterol-lowering drugs. The AD-protective allele acts to reduce splicing of a critical HMGCR exon, effectively reducing HMGCR activity; this action is similar to the effect of statins. Since this SNP may have confounded recent statin trials to reduce AD, we are currently genotyping DNA samples from a statin trial to evaluate this possibility. We have similar projects underway evaluating SNPs within the members of the ApoE receptor class of genes as well as genetic variants implicated in recent AD genome wide association studies, particularly those within inflammation pathways.

Overall, our work is facilitated by our association with the Sanders-Brown Center on Aging and its 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, which 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 responsive individuals.

Grants: 

2009-2014 NIH, P01 AG030128 “ApoE Receptor Biology and Neurodegeneration”, Ladu, PL, S. Estus, PI Project 2 “- ApoE Receptor Splicing, genetics, and AD”

2011-2012 University of Kentucky CTSS Grant “Safety and Target Engagement of
Clusterin by Valproic Acid in Subjects with Intact Cognition: Proof of Concept for the Development of a Prevention Trail for Alzheimer’s Disease”.

2013-2014 Alzheimers Drug Discovery Foundation “Translating genetics into pharmacology: does valproic acid "super-size" AD-protective SNPs in CLU and ABCA7?”

Selected Publications: 

Simmons CR, Zou F, Younkin SG, Estus S. Rheumatoid arthritis-associated polymorphisms are not protective against Alzheimer's disease. Mol Neurodegener. 6:33 (2011).  PMC3120711

Burchett ME, Ling IF, Estus S. FBN1 isoform expression varies in a tissue and development-specific fashion. Biochem Biophys Res Commun. 411: 323-8 (2011) PMC3148416

 Simmons CR, Zou F, Younkin S, Estus S. Evaluation of the global association between cholesterol-associated polymorphisms and Alzheimer's disease suggests a role for rs3846662 and HMGCR splicing in disease risk.  Mol Neurodegener. 6:62  (2011) PMID:  21867541

Ling,  I-F, Bhongsatiern J,  Simpson, JL, Fardo, DW and Estus S.  Genetics of clusterin isoform expression and Alzheimer’s disease risk.  PLoS ONE 7(4):e33923.  (2012) PMC3323613

Youmans KL, Tai LM, Nwabuisi-Heath E, Jungbauer L, Kanekiyo T, Gan M, Kim J, Eimer WA, Estus S, Rebeck GW, Weeber EJ, Bu G, Yu C, Ladu MJ.  APOE4-specific changes in Aβ accumulation in a new transgenic model of Alzheimer's Disease.  J Biol Chem. 2012 PMID: 23060451

Nelson PT, Pious NM, Jicha GA, Wilcock DM, Fardo DW, Estus S, Rebeck GW. APOE-E2 and APOE-E4 Correlate With Increased Amyloid Accumulation in Cerebral Vasculature. J Neuropathol Exp Neurol. 72:708-15 (2013). PMID: 23771217

 Malik M, Simpson JF, Parikh I, WilfredBR, Fardo, DW, NelsonPT, and EstusS.  CD33 Alzheimer’s risk-altering polymorphism, CD33 expression and exon 2 splicing.  J. Neurosci. In Press 2013.

 

Other Publications

X
Enter your College of Medicine username.
Enter the password that accompanies your username.
Loading