Directory Calendar News Careers Alumni Giving

Dr. Radosveta P Koldamova, MD, PhD

Associate Professor, Environmental and Occupational Health

Contact

130 De Soto Street, PUBHL, Room 4135, Lab4060.5-4060.10, Pittsburgh 15261
R-znvy: enqnx@cvgg.rqh
Primary Phone: 967-838-2642
Web site:

Assistant(s): 
Lynette Clark, yipynex@cvgg.rqh, 967-179-4255

Personal Statement

Our work is focused mainly on the role of Apolipoprotein E as
the major genetic risk factor for Alzheimer disease and its regulators, cholesterol
transporter ABCA1 and transcription factor Liver X Receptors (LXRa and LXRb). Since
2001, this program has been continually funded by NIH and private foundations. The
investigation of the cellular and molecular mechanisms by which ABCA1 and LXR
regulate amyloid deposition, its clearance and cognitive decline in AD model
mice has been he common theme throughout the funding. The research in my lab,
in collaboration with Dr. Lefterov, was instrumental and is still leading in
revealing the role of LXR and ABCA1 in progression of AD-like pathology in
mouse models. In 2005 we were the first to report that global deletion of mouse

 Abca1 dramatically worsens AD phenotype in mouse model for AD, which was independently confirmed by other research teams using different AD mouse models. Similarly, we were the first to propose the use of agonists for LXR and RXR receptors for treatment of AD. These two articles have generated a lot of interest and each one has been cited more than 200 times. Our research has gained national and international recognition and has been published in top tier biomedical and neuroscience journals such as Science, the Journal of Neuroscience and recently in Brain. Currently we are using Next Generation Sequencing (ChIP-seq and mRNA-seq) to identify molecular targets of transcription factors RXR and LXR and study the role of microglia in aging brain and neurodegeneration. For the last four years our group has been working on the role of gene-environment interactions in the pathogenesis of AD. In collaboration with Drs. Lefterov and Barchowsky we have been working on epigenetic mechanism of arsenic toxicity in WT and genetically modified mice.


Research

Cellular and molecular mechanisms that affect the risk of
Alzheimer’s disease are the main topics of my current research. Alzheimer’s
disease (AD) is a multifactorial neurodegenerative disorder that is affected by
genetic and environmental risk factors, such as inheritance of e4 allele of APOE
(APOE4), sex, diet and toxicants.
The inheritance of APOE4 allele is a major genetic risk factor
for late-onset Alzheimer’s disease but the mechanisms underlying this association
remain elusive. Currently we examine immune responses in brain against acute
and chronic amyloid-beta (Aβ) insults/deposition, in the context of expressed APOE
isoforms and aging. We use different transgenic mouse models and postmortem human
Alzheimer disease brain tissue and conduct multi-omics
profiling (lipidomics and transcriptomics analyses) that identifies APOE-allele
dependent lipid and gene expression patterns in Alzheimer’s brain. In this
research we are exploiting the newest methodologies including FACS and
MACS sorting of different brain cell type followed by single cell transcriptome
analysis.

My current work on the above topic is mostly centered on the
therapeutic effects of LXR and RXR agonists in APP mice expressing human APOE3
and APOE4 isoforms. Our ongoing translational research on APOE4 inheritance and phenotype is based on the hypothesis that ligand
activated nuclear receptors LXR and RXR ameliorate the unfavorable effect of APOE4
isoform on Ab aggregation in vitro and AD phenotype in model mice.
This line of research encompasses several projects and is the basis of my R01
grant that ended this year. Together, the results of our experiments examining
the effect of nuclear LXR receptors and their ligands in AD models and thus, a
better understanding of the molecular mechanisms controlling their effects have
opened a new direction in the translational AD science, swiftly followed by
studies conducted by other researchers. Our study published in PLoS One (PLoS One. 2017 Feb 27) demonstrated
that LXR treatment significantly
affects phenotype and transcriptome of APOE3 and APOE4 expressing, Abca1 haplo-deficient mice. Furthermore,
our results demonstrated that LXR ligand treatment causes a significant
reduction of memory deficits and amyloid pathology.

Our group has invested substantial effort researching the
effect of the synthetic RXR agonist, Bexarotene on the phenotype of AD mouse
models. Bexarotene is FDA approved drug for
treatment of Cutaneous
T Cell Lymphoma. Recently our and other groups have been exploring its
effects on memory and Ab clearance in
AD animal models. The initial result of our work were published in Science (2013 May 24;340(6135):924-c) and have generated a lot of publicity including the
press. Currently we are using Next Generation Sequencing (ChIP-seq and
RNA-seq) to identify molecular targets of RXR and LXR that resulted in three
recent publications in Neurobiology of Disease (2015 Jun 10. pii:
S0969-9961(15)00194), Journal of Neuroscience (J
Neurosci. 2015 Aug 26 ) and Nature Scientific Reports (Sci
Rep. 2016 Apr 7).

The primary motivation for moving to the Department of EOH
was to expand my research capabilities, translational research particularly and
specifically directed towards the effect of the environment and environmental
factors on AD phenotype and disease progression. AD is a complex disease and ever
increasing scientific interest
has been now focused on gene-environment
interactions that determine responses to diet, medication, lifestyle and
other factors   that are likely to impact AD pathogenesis,
progression and if understood, will provide opportunities to intervene. In our study
published in The Journal of Neuroscience (J Neurosci. 2010 May
19;30(20):6862-72) we revealed the effect of high fat/high cholesterol diet
on amyloid phenotype in APP transgenic mice. Our data demonstrated that in middle
aged mice high fat diet exacerbates the AD phenotype evaluated by behavioral,
morphological, and biochemical assays. We have recently expanded this research
to examine the effect of HFD on brain transcriptome and lipidome in the same
mice and the manuscript was published in Scientific Reports (Sci Rep. 2017 Jun 27;7). RNA-seq results
revealed that in mice fed HFD there was an increased expression of genes
related to innate immune response, such as Trem2 and Tyrobp and we found a
significant increase of TREM2 immunoreactivity in HFD. Down-regulated by HFD
were genes related to neuron projections and synaptic transmission in agreement
to the significantly deteriorated neurite morphology and cognition in these
mice. To examine the effect of the diet on the brain lipidome, we performed
Shotgun Lipidomics and revealed that the levels of 24 lipid molecular species
in the mouse brain were significantly modulated by HFD. Network visualization
of correlated lipids demonstrated overall imbalance with most prominent effect
on cardiolipin molecular species. This integrative approach demonstrates that
HFD elicits a complex response at molecular, cellular and system levels in the
CNS. At present we are testing the effects of diet on the epigenetic changes in
the brain using Next Generation Sequencing technology. In our most recent
article (Biochim Biophys Acta. 2018
Jan;1864(1):152-161.) we used AD model mice expressing human APOE isoforms
and revealed that high fat diet affected microglia response in combination with
APOE genotype and sex. We used RNA-sequencing to identify differentially
expressed genes and gene-networks correlated to diet, APOE isoform and sex.
Correspondingly, we found that in female APP/E4-HFD mice, microglia coverage
around plaques, particularly of larger size, was significantly reduced. This
suggests altered containment of the plaque growth and sex-dependent
vulnerability in response to diet. The results of our study show concurrent
impact of diet, APOE isoform and sex on the brain transcriptome and AD-like
phenotype.


Education

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


Teaching


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

 

EOH and Molecular Toxicology Journal Club


Selected Publications

  • Castranio EL, Wolfe CM, Letronne F, Nam KN, Fitz NF, Koldamova R, Lefterov I. ABCA1 haplodeficiency affects the brain transcriptome following traumatic brain injury in mice expressing human APOE isoforms. Accepted in Acta neuropathologica communications on July 8 2018.

    Nam KN, Wolfe C, Fitz NF, , Letronne F, Carter AY, Castranio EL, Schug J, Lefterov I, Koldamova R. Integrated approach reveals diet, APOE genotype and gender affect immune
    response in APP mice. Biochim Biophys Acta. 2017 Oct 14

    Nam KN, Mounier A, Wolfe C, Fitz NF, Carter AY, Castranio EL, Kamboh HI, Reeves
    VL, Wang J, Han X, Schug J, Lefterov I, Koldamova R. Effect of high fat diet on phenotype, brain transcriptome and lipidome in Alzheimer's model mice. Sci Rep. 2017 Jun 27;7.

    Castranio EL, Mounier A, Wolfe CM, Nam KN, Fitz NF, Letronne F, Schug J, Koldamova R, Lefterov I. Gene co-expression networks identify Trem2 and Tyrobp as major hubs in human APOE expressing mice following traumatic brain injury. Neurobiol Dis. 2017 Sep;105:1-14.

    Carter AY et al. Liver X receptor agonist treatment significantly affects phenotype and transcriptome of APOE3 and APOE4 Abca1 haplo-deficient mice. PLoS One. 2017 Feb 27;1 (2).

    Fitz, N. F., et al. (2017) “Abca1 deficiency affects dendritic density and cognitive function in mice”. Journal of Alzheimer's Disease, doi:10.3233/jad-161056 (2017).

    Kyong Nyon Nam, Anais Mounier, Nicholas F. Fitz, Cody Wolfe, Jonathan Schug, Iliya
    Lefterov and Radosveta Koldamova. RXR controlled regulatory networks identified in mouse brain counteract deleterious effects of Aβ oligomers. Sci Rep. 2016 Apr 7;6:24048.

    Nicholas F. Fitz, Victor Tapias, Andrea A. Cronican , Emilie Castranio, Muzamil Salem, Alexis Y. Carter, Martina Lefterova,  Iliya Lefterov  & Radosveta Koldamova, Opposing effects of Apoe/Apoa1 double deletion on amyloid β pathology and cognitive performance in APP mice. Brain. 2015 Dec;138(Pt 12):3699-715.

    Anais Mounier, Danko Georgiev, Kyong Nyon Nam, Nicholas F. Fitz, Emilie Castranio, Cody Wolfe, Andrea Cronican, Jonathan Schug, Iliya Lefterov and Radosveta Koldamova, Bexarotene activated Retinoid X Receptors regulate neuronal differentiation and dendritic complexity. J Neurosci. 2015 Aug 26;35(34):11862-76.

    Lefterov, I., Jonathan Schug, Anais Mounier, Kyong Nyon Nam, Nicholas
    F. Fitz, and Radosveta Koldamova, Neurobiology of Disease “RNA-sequencing
    reveals transcriptional up-regulation of Trem2 in response to bexarotene
    treatment” (2015 Jun 10. pii: S0969-9961(15)00194-1).

    Koldamova R., Fitz FN, Lefterov I, ATP-binding cassette transporter A1: from metabolism to
    neurodegeneration. Neurobiol Dis.  2014 Dec;72 Pt A:13-21.

    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.

    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.

    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

     

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

Login  |  Sitemap