Neurobiology of Disease Laboratory: Dora M. Kovacs, PhD

Overview

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.

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.

Another 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 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 Projects

wACAT Inhibitors and New Alzheimer's Disease Drug Therapies

Therapies already developed for atherocyltransferase (ACAT) inhibitors, drugs specifically targeting one step of the cholesterol pathway, are currently being considered for AD.

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.

Presenilin/Gamma-secretase and BACE1, and Sodium Channel Dysfunction

This 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 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 Positions

Read about and apply for residency, fellowship and observership programs in neurology.

All applicants should register with the Massachusetts General Hospital Careers website.

Publications

NCBI PubMed 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.

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.