Our laboratory studies the molecular mechanisms leading to normal brain aging and the pathological processes that culminate in Alzheimer’s disease. We utilize the rhesus monkey as a model for understanding changes that occur during non-pathological aging. With microarray analysis we identified genes that play crucial roles in brain dysfunction leading to cognitive decline. An example is Klotho, a cytoprotective, anti-aging protein. We found that Klotho expression is considerably decreased in the aged brains of monkeys, rats, and mice. We are now working to comprehensively characterize the role of Klotho in normal aging and disease. Our projects are to identify Klotho receptors in the brain and define the signaling pathways by which Klotho exerts its protective effects. We are also studying Klotho’s transcriptional regulation and have identified compounds to therapeutically exploit these protective effects. Another line of investigation in our lab is to understand the biology of the amyloid precursor protein (APP), the parent protein of the amyloid beta peptide (Abeta), which accumulates in the brains of Alzheimer’s disease patients and causes irreversible neurodegeneration. Certain mutations in APP result in autosomal dominant, early onset familial Alzheimer’s disease due to the increased production of Abeta. Since APP homodimerization is believed to be involved in Abeta formation in the brain we searched and identified molecules capable of intervening in this process to reduce the levels of toxic Abeta peptide in the brain.
- Professor, Pharmacology & Experimental Therapeutics, Boston University School of Medicine
- Member, Evans Center for Interdisciplinary Biomedical Research, Boston University
- Graduate Faculty (Primary Mentor of Grad Students), Boston University School of Medicine, Graduate Medical Sciences
- Harvard University, PhD
- Tel Aviv University (TAU), BSc
- Published on 4/29/2020
Chen CD, Rudy MA, Zeldich E, Abraham CR. A method to specifically activate the Klotho promoter by using zinc finger proteins constructed from modular building blocks and from naturally engineered Egr1 transcription factor backbone. FASEB J. 2020 Jun; 34(6):7234-7246. PMID: 32347987.
- Published on 4/13/2020
Wolf EJ, Logue MW, Zhao X, Daskalakis NP, Morrison FG, Escarfulleri S, Stone A, Schichman SA, McGlinchey RE, Milberg WP, Chen C, Abraham CR, Miller MW. PTSD and the klotho longevity gene: Evaluation of longitudinal effects on inflammation via DNA methylation. Psychoneuroendocrinology. 2020 Jul; 117:104656. PMID: 32438247.
- Published on 1/13/2020
Chen CD, Li Y, Chen AK, Rudy MA, Nasse JS, Zeldich E, Polanco TJ, Abraham CR. Identification of the cleavage sites leading to the shed forms of human and mouse anti-aging and cognition-enhancing protein Klotho. PLoS One. 2020; 15(1):e0226382. PMID: 31929539.
- Published on 12/23/2019
Delitsikou V, Jarad G, Rajaram RD, Ino F, Rutkowski JM, Chen CD, Santos CXC, Scherer PE, Abraham CR, Shah AM, Feraille E, Miner JH, de Seigneux S. Klotho regulation by albuminuria is dependent on ATF3 and endoplasmic reticulum stress. FASEB J. 2020 Feb; 34(2):2087-2104. PMID: 31907991.
- Published on 6/27/2019
Zeldich E, Chen CD, Boden E, Howat B, Nasse JS, Zeldich D, Lambert AG, Yuste A, Cherry JD, Mathias RM, Ma Q, Lau NC, McKee AC, Hatzipetros T, Abraham CR. Klotho Is Neuroprotective in the Superoxide Dismutase (SOD1G93A) Mouse Model of ALS. J Mol Neurosci. 2019 Oct; 69(2):264-285. PMID: 31250273.
- Published on 3/4/2019
McGrath ER, Himali JJ, Levy D, Conner SC, Pase MP, Abraham CR, Courchesne P, Satizabal CL, Vasan RS, Beiser AS, Seshadri S. Circulating fibroblast growth factor 23 levels and incident dementia: The Framingham heart study. PLoS One. 2019; 14(3):e0213321. PMID: 30830941.
- Published on 1/1/2019
Chen CD, Zeldich E, Khodr C, Camara K, Tung TY, Lauder EC, Mullen P, Polanco TJ, Liu YY, Zeldich D, Xia W, Van Nostrand WE, Brown LE, Porco JA, Abraham CR. Small Molecule Amyloid-ß Protein Precursor Processing Modulators Lower Amyloid-ß Peptide Levels via cKit Signaling. J Alzheimers Dis. 2019; 67(3):1089-1106. PMID: 30776010.
- Published on 3/7/2018
Ikezu T, Chen C, DeLeo AM, Zeldich E, Fallin MD, Kanaan NM, Lunetta KL, Abraham CR, Logue MW, Farrer LA. Tau Phosphorylation is Impacted by Rare AKAP9 Mutations Associated with Alzheimer Disease in African Americans. J Neuroimmune Pharmacol. 2018 06; 13(2):254-264. PMID: 29516269.
- Published on 1/22/2018
Robinson AA, Abraham CR, Rosene DL. Candidate molecular pathways of white matter vulnerability in the brain of normal aging rhesus monkeys. Geroscience. 2018 02; 40(1):31-47. PMID: 29357021.
- Published on 1/19/2018
Chen CD, Zeldich E, Li Y, Yuste A, Abraham CR. Activation of the Anti-Aging and Cognition-Enhancing Gene Klotho by CRISPR-dCas9 Transcriptional Effector Complex. J Mol Neurosci. 2018 Feb; 64(2):175-184. PMID: 29352444.
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