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Dr. Radosveta P Koldamova, MD, PhD

Associate Professor, Environmental and Occupational Health


Bridgeside Point Bldg, 100 Technology Drive, Pittsburgh 15219
R-znvy: enqnx@cvgg.rqh
Primary Phone: 967-838-2642
Web site:

Lynette Clark, yipynex@cvgg.rqh, 967-179-4255

Personal Statement

R. KOLDAMOVA AND I. LEFTEROV LAB: CELLULAR AND MOLECULAR MECHANISMS OF NEURODEGENERATION USE OF GENETICALLY MODIFIED MOUSE MODELS TO EXPLORE THE ROLE OF LIPID ASSOCIATED GENES IN PATHOGENESIS OF ALZHEIMER’S DISEASE. Our laboratory uses broad approaches to dissect regulatory networks and to explore the role of lipid associated genes and proteins in molecular pathogenesis of Alzheimer disease. Our areas of research are: LXR regulated transcriptional control in brain and Alzheimer disease. Recent studies have linked cholesterol metabolism and AD pathogenesis but the molecular and physiological mechanisms remain elusive. The , are transcription factors that control?liver X receptors (LXRs), LXRa and LXR the expression of genes involved in cholesterol metabolism and lipoprotein remodelling. Compared to other tissues, the regulatory functions of LXRs in brain remain largely unexplored and our knowledge so far is limited to the cholesterol transporters and apoE. Remarkably apoE, a proven risk factor for sporadic AD, is an LXR target gene. Studies on LXR activation in brain, have focused so far on APP models at young ages. In a recent study by using Affymetrix gene array assays we have revealed gene and protein expression in brain of 6-month old APP23 mice subjected to LXR ligand treatment for extended in brain we identified a?times. Along with a decreased level of deposited A wide spectrum of upregulated genes related to lipid metabolism/transport, metabolism of xenobiotics and detoxification. Amongst downregulated were genes involved in immune response and inflammation, cell death and apoptosis. To learn about LXR controlled regulatory networks in brain as well as age dependent and disease related changes in LXR function we are using chromatin immunoprecipitation and ChIP-chip approach. We will be using these methodologies in AD model mice and AD brain samples to dissect LXR dependent transcriptional circuitry and to understand the role of these transcription factors in aging and disease progression. Role of ABCA1 and brain lipoproteins in neurodegeneration ATP-binding cassette transporter A1 (ABCA1), a major regulator of cholesterol efflux and generation of high density lipoproteins (HDL), is one of the most important LXR targets. It has been demonstrated that if ABCA1 is functionally impaired, poorly lipidated apoA-I in the periphery becomes unstable and is hyper-catabolized. In brain, ABCA1 is considered essential for regulation of the internal cycling of cholesterol between glia and neurons. Recent data suggest that ABCA1 is essential also for apoE lipidation and for maintaining of its normal CNS concentration. Lack of ABCA1 in mice results in dramatically decreased CNS levels of apoE and abnormal structure of poorly lipidated lipoprotein complexes subjected to rapid degradation. Recently we and two other groups have shown independently that ABCA1 deficiency increases Adeposition in different lines of APP transgenic mice accompanied by a substantial decrease in the level of brain apoE. Keeping in mind the role of apoE in amyloid deposition, one explanation for this phenotype could be that insufficient and poorly lipidated apoA-I and apoE either decrease Aclearance or facilitate (apoE in particular) Aaggregation. To learn more about ABCA1-ApoE-ApoA-I regulatory axis in brain and its role in Adeposition-clearance we are using genetically modified complex animal models that overexpress human APP and at the same time with global deletion of ABCA1, apoE or ApoA-I. Important aspect of this research area in our lab is the role of ABCA1 and brain apolipoproteins in Afibril formation and generation of Aoligomeric structures Molecular library screening and identification of novel Alzheimer disease therapeutic agents Despite the enormous efforts in academia and in - and -secretase inhibitors are still?pharmaceutical industry, Avaccination, far from clinical use. Drugs that ameliorate AD phenotypes by interfering cholesterol metabolism have been also suggested, but the rationale for using those is poorly defined and in all of the cases the molecular mechanisms which account for their beneficial effects are poorly understood. Therefore . We have found?there remains a great need for other strategies of lowering A that activated LXRs regulate metabolic pathways of brain cholesterol intra- and -amyloid deposition and?extracellular transport that influence APP processing, its clearance from brain. Moreover, we and others have shown, that treatments of neuronal cell lines and primary neurons with natural or synthetic LXR ligands secretion, and that in vivo treatment of young AD model mice with a?decrease A synthetic LXR ligand, increased the expression of LXR responsive genes in CNS -amyloid levels in their brains. We have also found that?and decreased soluble the application of LXR ligands inhibited secretion of inflammatory cytokines and increased neuronal survival following Aor LPS treatment. The ultimate beneficial outcome of LXR ligand treatment on AD phenotype in vivo is a combination of effects mediated by genes expressed in neurons and astrocytes influencing -amyloid formation and clearance, and by genes expressed in?Ageneration, microglia which are tightly related to both – Aclearance and inflammation. The data therefore substantiate a drug discovery program for identification of LXR activators/agonists and their systematic evaluation in well established in vitro and in vivo model systems. This study is conducted in collaboration with John S. Lazo at UPitt Drug Discovery Institute. During the screening, the activated status of LXR is evaluated by their ability to increase dramatically the transcription of ABCA1 – a major LXR response gene. Thus, the increased amount of ABCA1 mRNA following in vitro application of a given compound serves as a reporter for LXR activation. Compounds that meet the criteria for LXR activation are be further screened for their ability to reduce Aproduction in vitro and ultimately in AD transgenic model mice.


1979 Medical Academy  Sofia, BULGARIA. Medical doctor
1994 Medical Academy & Bulgarian Academy of Sciences, Sofia, BULGARIA, PhD


Human genetics: Biochemical and Molecular genetics of complex disease (Epigenetic mechanisms
in human pathology)

Selected Publications

Koldamova R, Fitz NF, Lefterov I. “ATP-Binding Cassette Transporter A1: From metabolism to Neurodegeneration” Neurobiol Dis. 2014 May 17. pii: S0969-9961(14)00125-9. doi: 10.1016/j.nbd.2014.05.007. [Epub ahead of print]

Nicholas F. Fitz, Emilie L. Castranio, Alexis Y. Carter, Ravindra Kodali, Iliya Lefterov & Radosveta Koldamova: Improvement of memory deficits and Aβ clearance in aged APP23 mice treated
with a combination of anti-Aβ antibody and LXR agonist. J Alzheimer's Disease 2014 Mar 18. [Epub ahead of print]

Koldamova R, Schug J, Lefterova M, Cronican AA, Fitz NF, Davenport FA, Carter A, Castranio EL, Lefterov I: “Genome-wide approaches reveal EGR1-controlled regulatory networks associated with neurodegeneration”. Neurobiology Dis 2014 Mar;63:107-14. doi: 10.1016/j.nbd.2013.11.005. Epub 2013 Nov 20.

Fitz NF, Cronican AA, Lefterov I, Koldamova R. Comment on "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models". Science. 2013 May 24;340(6135):924-c. doi: 10.1126/science.123580

Cronican AA, Fitz NF, Carter A, Saleem M, Shiva S, Barchowsky A, Koldamova R, Schug J,
Lefterov I. Genome-wide alteration of histone H3K9 acetylation pattern in mouse offspring prenatally exposed to arsenic.  PLoS One. 2013;8(2):e53478. doi:10.1371/journal.pone.0053478. Epub 2013 Feb 6

Fitz NF, Cronican AA, Saleem M, Fauq AH, Chapman R, Lefterov I, Koldamova R. Abca1 deficiency affects Alzheimer's disease-like phenotype in human ApoE4 but not in ApoE3-targeted replacement mice. J Neuroscience. 2012 Sep 19;32(38):13125-36

Lefterov I, Fitz NF, Cronican AA, Fogg A, Kodali R, Wetzel R, Radosveta Koldamova (2010) Apolipoprotein A-I deficiency increases cerebral amyloid angiopathy and cognitive deficits in APP/PS1dE9 mice. J Biol Chem. 285: 36945-36957

Fitz Nicholas, Andrea Cronican, Tam Pham, Allison Fogg, Abdul H. Fauq, Robert Chapman, Iliya
Lefterov & Radosveta Koldamova (2010). LXR agonist treatment ameliorates amyloid pathology and memory deficits caused by high fat diet in APP23 mice. J Neuroscience, 30: 6862-72.

Radosveta P Koldamova
© 2018 by University of Pittsburgh Graduate School of Public Health

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