In our laboratory, we seek to elucidate the mechanisms underlying Alzheimer’s disease (AD) and to translate our findings into approaches to prevent or treat AD. We are primarily focused on AD genetics because genetic risk factors drive the majority of AD risk. Also, since genetic variants modulate AD risk, then by definition, drugs that act similarly will also modulate AD risk. Hence, we interpret the pathways identified by genetics as validated drug targets.
Our experimental approach begins by noting that high throughput genome wide association studies have identified a series of single nucleotide polymorphisms (SNP)s that are robustly associated with AD risk. Hence our goal is to perform molecular genetic studies to identify the mechanisms of action underlying these SNPs. The primary actions of these SNPs, or their co-inherited proxy SNPs, is to (i) alter amino acid sequence, (ii) alter gene expression or (iii) alter mRNA splicing. For each of the AD-associated SNPs, we are working through this process. For example, a CD33 SNP has been associated with AD risk. We found that this SNP acts through a co-inherited proxy SNP to modulate the splicing efficiency of the second exon in CD33. The allele that protects from AD risk acts to reduce the inclusion of exon 2. The CD33 isoform lacking exon 2 is predicted to produce a non-functional CD33. Hence, our findings suggest that CD33 inhibition will protect from AD risk. We are currently pursuing this hypothesis at multiple levels, including the study of CD33 inhibitors.
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.
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?”
2014-2018 NIH R01AG045775. “Translating CD33 genetic mechanism into a novel
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
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, Wilfred BR, Fardo DW, Nelson PT, and Estus S. CD33 Alzheimer’s risk-altering polymorphism, CD33 expression and exon 2 splicing. J. Neurosci. 33: 13320-05 (2013). PMC3742922
Vasquez JB, Fardo, DW and Estus, S. ABCA7 expression is associated with Alzheimer’s disease polymorphism and disease status. Neurosci. Lett. 556: 58-62 (2013) PMC3863933
Tai LM, Mehra S, Shete V, Estus S, Rebeck GW, Bu G, LaDu MJ. Soluble apoE/Aβ complex: mechanism and therapeutic target for APOE4-induced AD risk. Mol Neurodegener. 10: 1750-1326-9-2 (2014). PMC3897976
Parikh I, Fardo DW, Estus S. Genetics of PICALM Expression and Alzheimer's Disease. PLoS One. 9(3):e91242 (2014). PMC3949918