Physiology

STEVEN ESTUS, Ph.D. Professor, Case Western Reserve Univ., 1989 Vice Chairman, Department of Physiology Associate, Sanders-Brown Center on Aging Office: SB-332, Sanders Brown Center on Aging 0230 Tel: (859) 257-1412 Office Ext.: 264; Lab Ext.: 262, 263, 265 E-mail: sestus2@email.uky.edu

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, noting that variants in APOE itself are major genetic regulators of AD risk, as well as genetic variants implicated in recent AD genome wide association studies, particularly those within CLU and PICALM.

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.

Current Funding:

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

Recent Manuscripts:

Ling, I-F. and S. Estus. Role of SFRS13A in low density lipoprotein receptor splicing. Hum. Mutat. 31:702-9 (2010). PMC Journal – In Process.

Ling, I-F. and S. Estus. Critical exonic splicing enhancers modulate low density lipoprotein receptor exon 12 splicing. J. Neurochem. 115(3):614-24 (2010). PMCID: PMC2998065

Dieter, L.S. and S. Estus. Isoform of APOE with retained intron 3; quantitation and identification of an associated single nucleotide polymorphism. Molec. Neurodeg. 5: 34 (2010). PMCID: PMC2940878

Simmons CR, Zou F, Younkin SG, Estus S. Rheumatoid arthritis-associated polymorphisms are not protective against Alzheimer's disease. Mol Neurodegener. 2011 May 19;6:33. PMC3120711

Other Publications