In our laboratory, we seek to elucidate the mechanisms underlying the actions of genetic polymorphisms that modulate the risk of disease, especially Alzheimer’s disease (AD). Our goal is to translate these findings into novel approaches to prevent or treat human disease. 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. We have similar projects that focus upon other AD-related polymorphisms, as well as pilot studies to evaluate the actions of polymorphisms that modulate the risk of multiple sclerosis, migraine, and ALS.
In summary, the overall goal of our laboratory is to use human genetics to identify molecular mechanisms that modulate the risk of human disease, especially AD. 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
2014-2016 Bright Focus. “Genomic Editing to Elucidate CD33 Function”.
Malik M, Chiles J 3rd, Xi HS, Medway C, Simpson J, Potluri S, Howard D, Liang Y, Paumi CM, Mukherjee S, Crane P, Younkin S, Fardo DW, Estus S. Genetics of CD33 in Alzheimer's Disease and Acute Myeloid Leukemia Hum Mol Genet. (2015) [Epub ahead of print]
Liu CC, Tsai CW, Deak F, Rogers J, Penuliar M, Sung YM, Maher JN, Fu Y, Li X, Xu H, Estus S, Hoe HS, Fryer JD, Kanekiyo T, Bu G. Deficiency in LRP6-Mediated Wnt Signaling Contributes to Synaptic Abnormalities and Amyloid Pathology in Alzheimer's Disease. Neuron. 84:63-77 (2014) PMC4199382
Parikh I, Medway C, Younkin S, Fardo DW, Estus S. An intronic PICALM polymorphism, rs588076, is associated with allelic expression of a PICALM isoform. Mol Neurodegener. 9(1):32 (2014). PMC4150683
Nelson PT, Estus S, Abner EL, Parikh I, Malik M, Neltner JH, Ighodaro E, Wang WX, Wilfred BR, Wang LS, Kukull WA, Nandakumar K, Farman ML, Kofler JK, Poon WW, Corrada MM, Kawas CH, Cribbs DH, Bennett DA, Schneider JA, Larson EB, Crane PK, Valladares O, Schmitt FA, Kryscio RJ, Jicha GA, Smith CD, Scheff SW, Sonnen JA, Haines JL, Pericak-Vance MA, Mayeux R, Farrer LA. Van Eldik LJ, Horbinski C, Green RC, Gearing M, Poon LW, Kramer PL, Woltjer RL, Kamboh IL, Montine TJ, Partch AB, Richmire KR, Monsell SE, Alzheimer' Disease Genetic Consortium, Schellenberg GD, Fardo DW. ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology. Acta Neuropathol. 127: 825-843 (2014). PMC4113197
Parikh I, Fardo DW, Estus S. Genetics of PICALM Expression and Alzheimer's Disease. PLoS One. 9(3):e91242 (2014). PMC3949918
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
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
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
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
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