Carmela R. Abraham
Boston University School of Medicine
Silvio Conte Building, K304
72 E. Concord Street
Boston, MA. 02118
Lab Phone: 617-638-4315
BSc, Biology, Tel Aviv University
PhD, Neuroscience, Harvard University, Cambridge, MA
Research Assistant Professor
Our laboratory studies the molecular mechanisms leading to normal brain aging and the pathological processes that culminate in Alzheimer’s disease and multiple sclerosis. 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 on neurons and oligodendrocytes. 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.
Dubal DB, Zhu L, Sanchez PE, Worden K, Broestl L, Johnson E, Ho K, Yu GQ, Kim D, Betourne A, Kuro-O M, Masliah E, Abraham CR, Mucke L. Life Extension Factor Klotho Prevents Mortality and Enhances Cognition in hAPP Transgenic Mice. J Neurosci. 2015 Feb 11; 35(6):2358-71.View in: PubMed
Chen CD, Tung TY, Liang J, Zeldich E, Tucker Zhou TB, Turk BE, Abraham CR. Identification of cleavage sites leading to the shed form of the anti-aging protein klotho. Biochemistry. 2014 Sep 2; 53(34):5579-87. View in: PubMed
Jun G, Asai H, Zeldich E, Drapeau E, Chen C, Chung J, Park JH, Kim S, Haroutunian V, Foroud T, Kuwano R, Haines JL, Pericak-Vance MA, Schellenberg GD, Lunetta KL, Kim JW, Buxbaum JD, Mayeux R, Ikezu T, Abraham CR, Farrer LA. PLXNA4 is associated with Alzheimer disease and modulates tau phosphorylation. Ann Neurol. 2014 Sep; 76(3):379-92. View in: PubMed
Zeldich E, Chen CD, Colvin TA, Bove-Fenderson EA, Liang J, Tucker Zhou TB, Harris DA, Abraham CR. The Neuroprotective Effect of Klotho is Mediated via Regulation of Members of the Redox System. J Biol Chem. 2014 Aug 29; 289(35):24700-15.View in: PubMed
- The Anti-Aging and Tumor Suppressor Protein Klotho Enhances Differentiation of a Human Oligodendrocytic Hybrid Cell Line. Chen CD, Li H, Liang J, Hixson K, Zeldich E, Abraham CR. J Mol Neurosci. 2014
- Life extension factor klotho enhances cognition. Dubal DB, Yokoyama JS, Zhu L, Broestl L, Worden K, Wang D, Sturm VE, Kim D, Klein E, Yu GQ, Ho K, Eilertson KE, Yu L, Kuro-o M, De Jager PL, Coppola G, Small GW, Bennett DA, Kramer JH, Abraham CR, Miller BL, Mucke L. Cell Rep. 2014 May 22;7(4):1065-76
- Biochemical and functional characterization of the klotho-VS polymorphism implicated in aging and disease risk. Tucker Zhou TB, King GD, Chen C, Abraham CR. J Biol Chem. 2013 Dec 20;288(51):36302-11.
- MicroRNA-339 and microRNA-556 regulate Klotho expression in vitro. Mehi SJ, Maltare A, Abraham CR, King GD. Age (Dordr). 2014 Feb;36(1):141-9.
- Comparable dimerization found in wildtype and familial Alzheimer’s disease amyloid precursor protein mutants. So PP, Khodr CE, Chen CD, Abraham CR. Am J Neurodegener Dis. 2013;2(1):15-28. Epub 2013 Mar 8.
- The antiaging protein Klotho enhances oligodendrocyte maturation and myelination of the CNS. Chen CD, Sloane JA, Li H, Aytan N, Giannaris EL, Zeldich E, Hinman JD, Dedeoglu A, Rosene DL, Bansal R, Luebke JI, Kuro-o M, Abraham CR. J Neurosci. 2013 Jan 30;33(5):1927-39. doi: 10.1523/JNEUROSCI.2080-12.2013.
- The spectrum of disease in chronic traumatic encephalopathy. McKee AC, Stein TD, Nowinski CJ, Stern RA, Daneshvar DH, Alvarez VE, Lee HS, Hall G, Wojtowicz SM, Baugh CM, Riley DO, Kubilus CA, Cormier KA, Jacobs MA, Martin BR, Abraham CR, Ikezu T, Reichard RR, Wolozin BL, Budson AE, Goldstein LE, Kowall NW, Cantu RC. Brain. 2013 Jan;136(Pt 1):43-64. doi: 10.1093/brain/aws307. Epub 2012 Dec
- Small-molecule Klotho enhancers as novel treatment of neurodegeneration. Abraham CR, Chen C, Cuny GD, Glicksman MA, Zeldich E. Future Med Chem. 2012 Sep;4(13):1671-9. doi: 10.4155/fmc.12.134.
- Lowering of amyloid beta peptide production with a small molecule inhibitor of amyloid-β precursor protein dimerization. So PP, Zeldich E, Seyb KI, Huang MM, Concannon JB, King GD, Chen CD, Cuny GD, Glicksman MA, Abraham CR. Am J Neurodegener Dis. 2012 May 30;1(1):75-87.
- King GD, Huang, MM, Schuman ER, Chen CD, Cuny GD, Glicksman, MA, Abraham CR. (2012) Identification of novel small molecules to modulate transcription of Klotho. Biochem. J. 441:453-61.
- Abraham, CR and Nagle, MW (2011) Acylaminoacyl-peptidase in Handbook of Proteolytic Enzymes, 3rd Edition.
- Abraham, CR (2011) Amyloid beta peptide and the Amyloid cascade hypothesis. In The Handbook of Alzheimer’s Disease and Other Dementias, First Edition. Edited by Andrew E. Budson, Neil W. Kowall. Published by Blackwell Publishing Ltd.
- King, GD, Rosene, DL and Abraham, CR (2011) Promoter methylation and age-related downregulation of klotho in rhesus monkey. AGE, Sept. 16. Epub.
- So, P, Chen, C-D, and Abraham, CR (2011) Detection of Wild Type and Mutant Amyloid Precursor Protein Dimerization Using Beta-Galactosidase Enzyme Fragment Complementation. J. Alz Dis. 26:647-55.
- Porat, ME, Lunetta, KL, Cupples, LA, Abraham, CR, Green, RC, Baldwin, CT and Farrer, LA (2010) Serum paraoxonase activity is associated with variants in the PON gene cluster and risk of Alzheimer disease. Neurobiol. Aging. Oct. 25.
- Oh, S-Y, Chen, C-D, and Abraham, CR (2010) Cell-type Dependent Modulation of Notch Signaling by the Amyloid Precursor Protein. J. Neurochem. 113:262-74.
- Zhao, Yamin R, O’Connor, Peter B, McKee, Ann C, Abraham, CR. (2009) Acyl Peptide Hydrolase Degrades Monomeric and Oligomeric Amyloid-Beta Peptide. Molecular Neurodegeneration. 4:33.
- Cordy, JM, Zerbinatti, CV, Chen, C-D,Guillily, M, Suon, S, Ray, WJ, Seabrook, GR, Abraham, CR, and Wolozin, B. (2008) Oxysterol-binding protein-1 (OSBP-1) modulates processing and trafficking of the amyloid precursor protein. Molecular Neurodgeneration. 3:5.
- Hinman, JD, Oh, S-Y, Chen, C-D, Hollander, W and Abraham, CR. (2008) Age-dependent accumulation of ubiquitinated CNP in myelin lipid rafts. Glia. 56:118-33.
- Duce, JA, Podvin, S, Hollander, W, Kipling, D, Rosene, DL and Abraham, CR. (2008) Gene profile analysis implicates Klotho as an important contributor to aging changes in brain white matter of the rhesus monkey. Glia. 56:106-17.
- Chen, C-D, Podvin, S, Gillespie, E, Leeman, S and Abraham, CR. (2007) Insulin Stimulates the Cleavage and Release of the Extracellular Domain of Klotho via ADAM10 and ADAM17, PNAS. 104:19796-19801.
- Hinman, JD and Abraham, CR (2007) What’s behind the decline? – The role of white matter in brain aging. Neurochem. Res. 32:2023-31.
- Yamin, R, Bagchi, S, Hildebrant, R, Scaloni, A, Widom, RL, and Abraham, CR. (2007) Acyl Peptide Hydrolase, a serine proteinase isolated from conditioned medium of neuroblastoma cells, degrades the amyloid ß peptide. J. Neurochem. 100:458-467.
- Chen, C-D, Oh, SY, Hinman, JD and Abraham, CR. (2006) Visualization of APP dimerization and APP-Notch heterodimerization in living cells using bimolecular fluorescence complementation. J. Neurochem, 97:30-43.
- Duce, JA, Hollander, W, Jaffe, R. and Abraham, CR. (2006) Early complement activation targets myelin and oligodendrocytes in the aged rhesus monkey brain. Neurobiol Aging. 27:633-644.
- Oh, SY, Ellenstein, A, Chen, C-D, Hinman, JD, Berg, EA, Costello, CE, Yamin, R, Neve, RL and Abraham, CR (2005) The Amyloid Precursor Protein interacts with Notch receptors. J. Neurosci. Res. 82:32-42.
- Hinman, JD, Peters, A, Rosene, DL, Hollander, W, Rasband, M and Abraham, CR. (2005) Age-related molecular reorganization at the node of Ranvier. J. Comp. Neurol. 495:351-362.
- Hinman, JD, Duce, JA, Siman, R, Hollander, W and Abraham, C.R. (2004) Activation of calpain-1 in myelin and microglia in the white matter of the aged rhesus monkey. J. Neurochem. 89:430-441.