Massachusetts General Hospital

Research Investigator Profile

Dora M. Kovacs, PhD

• Associate Professor of Neurology,
  Harvard Medical School
• Associate Neuroscientist,
  Massachusetts General Hospital
• Director, Neurobiology of Disease Laboratory
  

Research Description

My research focuses on the molecular events underlying neurodegeneration in Alzheimer’s disease (AD). Among other neuropathological features, cortical deposition of an insoluble material, called amyloid, occurs in both the aging and the AD-afflicted brain. I am interested in identifying the cellular pathways regulating the generation of the toxic beta-amyloid protein (Abeta), and the factors involved in the subsequent neurodegenerative process associated with this peptide.

Therapies already developed for atherosclerosis and cardiovascular disease are currently being considered for AD. Acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors, drugs specifically targeting one step of the cholesterol pathway, are being actively developed for treatment of cardiovascular disease. We have shown that ACAT inhibitors have reduced generation of Abeta in cell-based models of AD and dramatically improved brain pathology in a transgenic mouse model of AD. We are currently synthesizing and testing novel ACAT inhibitors. Our overarching goal is to provide evidence that would strongly encourage clinical trial of ACAT inhibitors for AD.

Our second major project concerns the physiological functions of presenilin/gamma-secretase and BACE1, the two enzymes that play a pivotal role in the generation of Abeta. Most recently, we established a signaling pathway involving both of these enzymes and regulating the activity of voltage-gated sodium channels in the brain.  We are now examining how sodium channel dysfunction may contribute to AD pathology.

Research interests	Alzheimer's, Amyloid beta (Abeta), presenilin/gamma-secretase, BACE/beta-secretase, cholesterol and Abeta generation, subcellular trafficking of APP, processing and trafficking of voltage-gated sodium channels in Alzheimer’s
Research techniques	Molecular biology, cell biology, cell and primary neuronal cultures, protein biochemistry, immunocytochemistry, basic cholesterol analyses
Diseases studied	Alzheimer’s disease
Selected publications	Huttunen, H.J., Peach, C., Bhattacharyya, R., Barren, C,. Pettingell, W., Hutter-Paier, B., Windisch, M., Berezovska, O., Kovacs, D.M. Inhibition of acyl-coenzyme A: cholesterol acyl transferase modulates amyloid precursor protein trafficking in the early secretory pathway. FASEB J., 2009, 23:3819-28. Kim, D.Y., Carey, W.B., MacKenzie Ingano, L.A., Wang, H., Yang, L.B., Pettingell, W.H., Lee, V. M.-Y., Woolf, C.J., Kovacs, D.M. BACE1 regulates voltage-gated sodium channel levels and activity. Nat. Cell Biol., 2007 9:755-764. 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. 4    Puglielli, L., Tanzi, R.E., Kovacs, D.M. Alzheimer’s disease: the cholesterol connection. Nat. Neurosci., 2003, 6:345-351. Puglielli, L., Konopka, G., Chang, T.Y., Tanzi, R.E., Kovacs, D.M. Acyl-coenzyme A:cholesterol acyltransferase modulates the generation of the amyloid beta-peptide. Nat. Cell Biol. 2001, 3, 905-912.
NCBI PubMed link	NCBI PubMed Publications
NIH biosketch	Dora M. Kovacs, PhD (PDF)
Contact Information	Building 114, Charlestown Navy Yard 114 16th Street, Room 3010 MassGeneral Inst. for Neurodegenerative Disease Charlestown, MA 02129 Phone: 617-726-3668 Fax: 617-724-1823 Email: dora_kovacs@hms.harvard.edu