Dora M. Kovacs, PhD. Associate Professor of Neurology E-Mail Address: kovacs@helix.mgh.harvard.edu Office Address: Neurobiology of Disease Laboratory Genetics and Aging Research Unit Massachusetts General Hospital East Building 114, Room 3010 114 16th Street Charlestown, MA 02129 Phone: 617-726-3668 Fax: 617-724-1823

Biography:

Dora M. Kovacs, Ph.D. Associate Professor of Neurology at Harvard Medical School and Assistant in Genetics at Massachusetts General Hospital, Genetics and Aging Research Unit, has over 15 years of molecular and cell biology research experience and has been directing her own laboratory for the past 3 years. She joined the Genetics and Aging Research Unit in 1993 as a postdoctoral fellow, to study the role of the amyloid precursor protein (APP) in Alzheimer's disease. She has since co-authored over 15 original articles in peer-reviewed journals, over 10 chapters or reviews, and is co-inventor on 3 patents. She has served for several years on the Review board of the Medical and Scientific Advisory Council of the Alzheimer's Association, and most recently on the Editorial Board of The Scientific World. She has been invited to present her work at numerous international symposia and conferences. For her contributions to research on the molecular basis of Alzheimer's disease, she received the Britton Fellowship for Research in Alzheimer's disease, the French Foundation for Alzheimer Research Fellowship, and the Neurosciences Education and Research Foundation Award. Dr. Kovacs received a summa cum laude BS-MS degree in Biology from the University of Bologna, Italy, and a Ph.D. in Pharmacology and Toxicology from the University of Padova, Italy, in 1991. While earning her Ph.D. degree in Italy, she performed her research at the Division of Neuropathology, Case Western Reserve University, Cleveland. Prior to joining MGH, she worked as a research fellow at the Department of Molecular Neurobiology at the University of Pittsburgh School of Medicine on transcription factors regulating the expression of the tyrosine hydroxylase gene.

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Publications:

Original Articles:

1. Palmert, M.R., Golde, T.E., Cohen, M.L., Kovacs, D.M., Tanzi, R.E., Gusella, J.F., Usiak, M.F., Younkin, L.H., Younkin, S.G. Amyloid protein precursor messenger RNAs: differential expression in Alzheimer's disease. Science 1988; 241:1080-1084.

2. Autilio-Gambetti, L., Morandi, A., Tabaton, M., Schaetzle, B., Kovacs, D.M., Perry, G., Greenberg, B., Gambetti, P. The amyloid precursor protein of Alzheimer disease is expressed as a 130 kDa polypeptide in various cultured cell types. Febs Lett. 1988; 241:94-98.

3. Palmert, M.R., Podlisny, M.B., Golde, T.E., Cohen, M.L., Kovacs, D.M., Tanzi, R.E., Gusella, J.F., Whitehouse, P.J., Witker, D.S., Oltersdorf, T., Younkin, L.H., Selkoe, D.J., Younkin, S.G. Analysis of the beta-amyloid protein precursor of Alzheimer's disease: mRNAs and protein products. Advances in Neurology 1990; 51:181-184.

4. LeBlanc, A.C., Kovacs, D.M., Chen, H.J., Villari, F., Tykocinski, M.L., Autilio-Gambetti, L., Gambetti, P. Role of amyloid precursor protein: Study with anti-sense transfection of human neuroblastoma cells. J. Neurosci. Res. 1992; 31:635-645.

5. Miner, L.L., Pandalai, S.P., Weisberg, E.P., Sell, S., Kovacs, D.M., Kaplan, B.B. Cold-induced alterations in the binding of adrenomedullary nuclear proteins to the promoter region of the tyrosine hydroxylase gene. J. Neurosci. Res. 1992; 33:10-18.

6. Kovacs, D.M., Kaplan, B.B. Discordant estimates of TPA-induced CMV promoter activity as determined by reporter gene mRNA levels and enzymatic activity. Biochem. Biophys. Res. Commun. 1992; 189:912-918.

7. Kovacs, D.M., Wasco, W., Witherby, J., Felsenstein, K.M., Brunel, F., Roeder, R.G., Tanzi, R.E. The upstream stimulatory factor functionally interacts with the Alzheimer amyloid B-protein precursor gene. Hum. Mol. Gen. 1995; 4:1527-1533.

8. Kovacs, D.M., Fausett, H.J., Page, K.J., Kim, T.-W., Moir, R.D., Merriam, D.E., Hollister, R.D., Hallmark, O.G., Mancini, R., Felsenstein, K.M., Hyman, B.T., Tanzi, R.E., Wasco, W. Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and localization to intracellular membranes in mammalian cells. Nature Medicine 1996; 2:224-229.

9. Tanzi, R.E., Kovacs, D.M., Kim, T.-W., Moir, R.D., Guenette, Y.S., Wasco, W. The gene defects responsible for familial Alzheimer's disease. Neurobiology of Disease , 3, 159-168 (1996).

10. Seeger, M., Nordstedt, C., Petanceska, S., Kovacs, D.M., Gouras G.K., Hahne, S., Fraser, P., Levesque. L., Czernik, A.J., St George-Hyslop, P., Sisodia, S.S., Thinakaran, G., Tanzi, R.E., Greengard, P., Gandy S. Evidence for phosphorylation and oligomeric assembly of presenilin 1. Proc. Natl. Acad. Sci. (USA) 1997; 94, 5090-5094.

11. Kim, T.-W., Pettingell, W.H., Jung, Y.K., Kovacs, D.M., Tanzi, R.E. Alternative cleavage of Alzheimer-associated presenilins during apoptosis by a caspase-3 family protease. Science. 1997; 277, 373-376.

12. Kovacs, D.M., Na, S., Tanzi, R.E. Presenilin mutations in Alzheimer's Disease. Clin. Neurosc. 1998; 51, 24-25.

13. Kovacs, D.M., Mancini, R., Henderson, J., Schmidt, S.D., Na, S.J., Kim, T.-W., Tanzi, R.E. Staurosporine-induced activation of caspase 3 is potentiated by presenilin 1 FAD mutations in human neuroglioma cells. J. Neurochem., 1999; 73, 2278-2285.

14. Abbenante, G., Kovacs, D.M., Leung, D.L., Craik, D.J., Tanzi, R.E., Fairlie, D.P. Inhibitors of b-amyloid formation based on the b-secretase cleavage site. Biochem. Biophys. Res. Comm. 2000; 268, 133-135.

15. Puglielli, L., Konopka, G., Chang, T.Y., Tanzi, R.E., Kovacs, D.M. Acyl-coenzyme A:cholesterol acyltransferase modulates the generation of the amyloid b-peptide. Nat. Cell Biol. 2001, 3, 905-912.

16. Kim, D.Y, MacKenzie Ingano, L.A., Kovacs, D.M. Nectin-1 a, an immunoglobulin-like receptor involved in the formation of synapses, is a substrate for presenilin/ g-secretase cleavage. J. Biol. Chem. 2002, 277, 49976-81.

17. Puglielli, L., Ellis, B.C., Saunders, A.J., Kovacs, D.M. Ceramide stabilizes BACE1 and promotes amyloid b-peptide biogenesis. J. Biol. Chem. 2003, 278:19777-83.

18. Xie, Z., Moir, R.D., Romano, D.M., Tesco, G., Kovacs, D.M., Tanzi, R.E. Hypocapnia induces caspase-3 activation and increases A b production. Neurodegenerative Dis. 2004, 1:29-37.

19. Xie, Z., Romano, D.M., Kovacs, D.M., Tanzi R.E. Effects of RNA interference-mediated silencing of gamma-secretase complex components on cell sensitivity to caspase-3 activation. J. Biol. Chem. 2004, 279:34130-34137.

20. Hutter-Paier, B., Huttunen, H.J., Puglielli, L., Eckman, C.B., Kim, D.Y., Hofmeister, A., Moir, R.D., Domnitz, S.B., Frosch, M.P., Windisch, M., Kovacs, D.M. The ACAT inhibitor CP-113,818 markedly reduces amyloid pathology in a mouse model of Alzheimer’s disease. Neuron, 2004, 44:227-238.

21. Kim, D.Y, MacKenzie Ingano, L.A., Carey, W.B., Pettingell, W., Kovacs, D.M. Presenilin/ g-secretase-mediated cleavage of the voltage-gated sodium channel b2 subunit regulates cell adhesion and migration. J. Biol. Chem. 2005, 280:23251-23261.

22. Puglielli, L., Friedlich A.L., Setchell, K.D., Nagano, S., Opazo, C., Cherny, R.A., Barnham, K.J., Wade, J.D., Melov, S., Kovacs, D.M., Bush, A.I. Alzheimer disease beta-amyloid activity mimics cholesterol oxidase. J. Clin. Invest., 2005, 115:2556-2563.

23. Kovacs, I., Lentini, K.M., MacKenzie Ingano, L.A., Kovacs, D.M. Presenilin1 forms aggresomal deposits in response to heat shock. J. Mol. Neurosci., 2006 (in press)

24. Zhang, M., Haapasalo, A., Kim, D.Y., MacKenzie Ingano, L.A., Pettingell, W.H., Kovacs, D.M. Presenilin/ g -secretase activity regulates protein clearance from the endocytic recycling compartment. Faseb J., 2006 (in press)

Reviews, Chapters, and Editorials:

1. Autilio-Gambetti, L., Morandi, A., Kovacs, D.M., Tabaton, M., Schaetzle, B., Hauer, C., Groger, D.K., Tykocinski, M.L., Perry, G., Greenberg, B.D., Satish, S., Cornette, J., Gambetti, P. Amyloid precursor protein in cell cultures: a 130 kDa polypeptide. Prog. Clin. Biol. Res. (US) In: Alzheimer's Disease and Related Disorders, (eds) Iqbal, K. and Wisniewski, H.M. 1989; 317:985-990.

2. Palmert M.R., Podlisny M.B., Golde T.E., Cohen, M.L., Kovacs, D.M., Tanzi, R.E., Gusella, J.F., Whitehouse P.J., Witker, D.S., Oltersdorf, T., Younkin L.H., Selkoe, D.J., Younkin, S.G. The B amyloid protein precursor: mRNAs, membrane associated forms, and soluble derivatives. Prog. Clin. Biol. Res. (US) In: Alzheimer's Disease and Related Disorders, (eds) Iqbal, K. and Wisniewski, H.M. 1989; 317:971-984.

3. Tanzi, R.E., Romano, D., Gaston, S., Crowley, A., Bush, A., Peppercorn, J., Paradis, M., Pettingell, W., Gurubhagavatula, S., Kovacs, D.M., Haines, J., St George-Hyslop, P., Wasco, W. The diverse molecular nature of Alzheimer's disease. In: Amyloid Protein Precursor in Development, Aging and Alzheimer's Disease. Masters, C.L. et al. (eds) Springer-Verlag, Heidelberg. 1994; 181-189.

4. Tanzi, R.E., Kovacs, D.M., Kim, T.-W., Moir, R., Guenette, S., Wasco, W. The Presenilin genes and their role in early-onset familial Alzheimer's disease. Alzheimer's Disease Review, 1996, 1:91-98.

5. Tanzi, R.E., Kim, T.-W., Kovacs, D.M., Guenette, Y.S., Moir, R.D., Hyman, B.T, Wasco, W. The genes responsible for familiar Alzheimer's disease: toward a common etiological pathway. In: Iqbal, K. et al. (eds) Alzheimer's disease: Biology, Diagnosis and Therapeutics. John Wiley & Sons Ltd., 1997; 63-69.

6. Tanzi, R.E., Kim, T.-W. , Kovacs, D.M., Wasco, W., Moir, R.D., Pettingell, W., Henderson, J. and Mancini, R. Alternative endoproteolysis of the presenilins and familial Alzheimer's disease. In: Presenilins and Alzheimer's disease. (Younkin, S.G., Tanzi, R.E. and Christen, Y., eds), Springer-Verlag, New York, NY., 1998:19-26.

7. Kovacs, D.M. and Tanzi, R.E. Molecular determinants of FAD: Presenilin 1 mutations. Cell. Mol. Life Sciences. 1998; 54, 902-909.

8. Kovacs, D.M., Mancini, R., Na, S., Kim, T.-W., Tanzi, R.E. Caspase cleavage of presenilin 1 is increased in apoptotic cells as a result of familial Alzheimer's disease mutations. In: Iqbal, K. et al. (eds) Alzheimer's disease: Biology, Diagnosis and Therapeutics. John Wiley & Sons Ltd., 1999:607-612.

9. Kovacs, D.M. Alpha2-macroglobulin in late-onset Alzheimer’s disease. Exp. Geron. 2000, 35:473-479.

10. MacKenzie Ingano, L., Lentini, K.M., Kovacs, I., Tanzi, R.E., Kovacs, D.M. Cytoplasmic presenilin aggregates in proteasome inhibitor treated cells. Ann. NY Acad. Sci. 2000, 920:259-260.

12. Puglielli, L., MacKenzie Ingano, L.A., Tanzi, R.E., Kovacs, D.M. The amyloid precursor protein V717I mutation increases susceptibility to cell death in a cholesterol-dependent manner. In: Iqbal, K. et al. (eds) Alzheimer's disease: Advances in Etiology, Pathogenesis and Therapeutics. John Wiley & Sons Ltd., 2001, 469-477.

13. Puglielli, L. and Kovacs, D.M. Alzheimer's disease: 100 years later. Revista Medica de Chile, 2001, 129:569-575.

14. Tanzi, R.E. and Kovacs, D.M. Alpha2-macroglobulin. Wiley Encyclopedia of Mol. Med., 2002, 5:142-143.

15. Kimberly, W.T., Kovacs, D.M., Walsh, D., Lashuel, H., Lemere, C.A. The 8 th International Conference on Alzheimer's Disease and Related Disorders July 20-25, 2002, Stockholm, Sweden. Meeting report. Amyloid. 2003, 10:51-61.

16. Puglielli, L., Tanzi, R.E., Kovacs, D.M. Alzheimer’s disease: the cholesterol connection. Nat. Neurosci., 2003, 6:345-351.

17. Puglielli, L., Ellis, B.C., MacKenzie Ingano, L.A., Kovacs, D.M. Role of acyl-coenzyme A: cholesterol acyltransferase activity in the processing of the amyloid precursor protein. J. Mol. Neurosci., 2004, 24:93-96.