Oksana Berezovska, PhD

Dr. Berezovska is an Assistant Professor of Neurology at Harvard Medical School. She has a lab at Massachusetts General Hospital at the MassGeneral Institute for Neurodegenerative Disease that focuses on the cellular and molecular events underlying neuropathological changes in Alzheimer’s disease (AD).

Deposition of amyloid beta (A beta) containing plaques in the brain is one of the major neuropathological hallmarks of Alzheimer’s disease (AD). The final enzymatic step in generating Aß (A beta ₄₀ and A beta₄₂ as the major species) via intramembranous cleavage of the amyloid precursor protein (APP) is performed by the presenilin (PS1) dependent gamma-secretase complex. Changes in the precision of PS1/ gamma-cleavage of the APP substrate, therefore, result in a change in A beta _42/40 ratio. An increase in A beta _42/40 ratio potentially leads to A beta oligomerization (neurotoxic species), fibrillization, and ultimately AD.

Our goal is to study the cellular and molecular mechanisms of AD pathology. We focus on the analysis of gamma-secretase and APP interactions, and examine mechanisms by which various genetic and pharmacological factors modulate Abeta production and/or regulate the precision of APP cleavage by gamma-secretase that leads to a change in A beta _42/40 ratio.

Our laboratory employs state-of-the-art molecular imaging approaches (e.g. FRET, Fluorescence Lifetime Imaging Microscopy) to monitor the conformational changes of a single molecule, or molecular complexes, in different subcellular compartments in intact and/or live cells, both in vitro and in vivo. Novel fluorescence microscopy approaches (e.g., Bi-molecular Fluorescence Complementation, photoactivatable GFP) are complemented by conventional cell biology, and biochemistry approaches, to study molecular mechanisms leading to AD pathology. Current areas of interest include but are not limited to: 1) The effect of familial AD mutations in PS1, PS2, and APP genes on PS conformation and PS-APP interactions and trafficking. 2) The mechanism of action of pharmacological compounds affecting A beta production. 3) The assembly of the gamma-secretase complex and the role of individual components in interactions with a substrate, subcellular distribution, and trafficking. 4) The effect of neuronal activation/inhibition on Abeta production, PS1 conformation, and PS1-APP interactions at synaptic terminals.

FLIM - shows subcellular distribution of PS1 protein

Selected Publications

Ramdya P., J.Skoch, Bacskai BJ., Hyman BT, and Berezovska O. Activated Notch associates with a Presenilin1/gamma-secretase docking site. 2003, J.Neurochem, 87, 843-850.

Berezovska O., Bacskai BJ., Hyman BT. Monitoring proteins in intact cells. Sci SAGE KE, 2003, pe14 (11 June); http://sageke.sciencemag.org

Berezovska O., Ramdya P., Wolfe M.S., Bacskai BJ., Hyman BT. APP associates with a Nicastrin dependent docking site on the PS1/gamma-secretase complex in cells demonstrated by Fluorescence Lifetime Imaging. J. Neurosci., 2003, 23(11), 4560-4566.

Lleo A, Berezovska O, Herl L, Raju S, Deng A, Frosch MP, Irizarry M, and Hyman BT "Nonsteroidal anti-inflammatory drugs (NSAIDs) lower Abeta42 and change presenilin 1 conformation in vitro and in vivo" 2004, Nature Med. 10 (10), 1065-1066.

Berezovska O., Lleo A., Herl LD., Frosch MP., Stern EA., Bacskai BJ., and Hyman BT. Familial Alzheimer’s Disease presenilin 1 mutations cause alterations in the conformation of presenilin and intarections with amyloid precursor protein. 2005 J.Neurosci, 25(11), 3009-3017.

Lleo A., Waldron E, von Arnim CA, Herl L, Tangredi MM, Peltan ID, Strickland DK, Koo EH, Hyman BT, Pietrzik CU, and Berezovska O. "Low density lipoprotein receptor-related protein (LRP) interacts with presenilin 1 and is a competitive substrate of the amyloid precursor protein (APP) for gamma-secretase" J. Biol Chem. 2005, 280(29):27303-9.