Radosveta Koldamova, MD, PhD
- 1994 PhD in Biology, Experimental Cancer Therapy, Bulgarian Academy of Sciences, Sofia, Bulgaria
- 1979 MD, Medical Academy, Sofia, Bulgaria
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 Alzheimer’s disease (AD) pathogenesis but the molecular and physiological mechanisms remain elusive. There exist transcription factors that control liver X receptors (LXRs), the expression of genes involved in cholesterol metabolism and lipoprotein remodeling. Compared to other tissues, the regulatory functions of LXRs in the 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 mouse models at young ages. In a recent study 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. Along with a decreased level of deposited Abeta, there was a wide spectrum of upregulated genes related to lipid metabolism/transport, metabolism of xenobiotics and detoxification. Amongst downregulated genes were those 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 a 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 maintenance 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, which are subject to rapid degradation. Recently we and two other groups have shown independently that ABCA1 deficiency increases amyloid deposition 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 amyloid clearance or facilitate (apoE in particular) amyloid aggregation. To learn more about the ABCA1-ApoE-ApoA-I regulatory axis in brain and its role in amyloid deposition and 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. An important aspect of this research area in our lab is the role of ABCA1 and brain apolipoproteins in amyloid fibril formation and generation of amyloid oligomeric structures.
- Koldamova R, Fitz NF, Lefterov I.
ATP-binding cassette transporter A1: From metabolism to neurodegeneration.
Neurobiology of Disease 2014 [Epub May 17]
- Fitz NF, Castranio EL, Carter AY, Kodali R, Lefterov I, Koldamova R.
Improvement of memory deficits and amyloid-β clearance in aged APP23 mice treated with a combination of anti-amyloid-β antibody and LXR agonist.
Journal of Alzheimer's Disease 2014; 41(2):535-549.
- 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 of Disease 2014; 63:107-114.
- 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; 340(6135):924-c.
- 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.
- 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.
Journal of Neuroscience 2012; 32(38):13125-13136.
- Lefterov I, Fitz NF, Cronican AA, Fogg A, Lefterov P, Kodali R, Wetzel R, Koldamova R.
Apolipoprotein A-I deficiency increases cerebral amyloid angiopathy and cognitive deficits in APP/PS1ΔE9 mice.
Journal of Biological Chemistry 2010; 285(47):36945-36957.
- Koldamova R, Fitz NF, Lefterov I.
The role of ATP-binding cassette transporter A1 in Alzheimer's disease and neurodegeneration.
Biochimica et Biophysica Acta 2010; 1801(8):824-830.
- Fitz NF, Cronican A, Pham T, Fogg A, Fauq AH, Chapman R, Lefterov I, Koldamova R.
Liver X receptor agonist treatment ameliorates amyloid pathology and memory deficits caused by high-fat diet in APP23 mice.
Journal of Neuroscience 2010; 30(20):6862-6872.
- Cronican AA, Fitz NF, Pham T, Fogg A, Kifer B, Koldamova R, Lefterov I.
Proton pump inhibitor lansoprazole is a nuclear liver X receptor agonist.
Biochemical Pharmacology 2010; 79(9):1310-1316.
- Lefterov I, Fitz NF, Cronican A, Lefterov P, Staufenbiel M, Koldamova R.
Memory deficits in APP23/Abca1+/- mice correlate with the level of Aβ oligomers.
ASN Neuro 2009; 1(2):e00006.
- Cohen AD, Ikonomovic MD, Abrahamson EE, Paljug WR, Dekosky ST, Lefterov IM, Koldamova RP, Shao L, Debnath ML, Mason NS, Mathis CA, Klunk WE.
Anti-amyloid effects of small molecule Aβ-binding agents in PS1/APP mice.
Letters in Drug Design and Discovery 2009; 6(6):437-444.
- Lefterov I, Bookout A, Wang Z, Staufenbiel M, Mangelsdorf D, Koldamova R.
Expression profiling in APP23 mouse brain: inhibition of Aβ amyloidosis and inflammation in response to LXR agonist treatment.
Molecular Neurodegeneration 2007; 2:20.
- Koldamova R, Lefterov I.
Role of LXR and ABCA1 in the pathogenesis of Alzheimer's disease - implications for a new therapeutic approach.
Current Alzheimer Research 2007; 4(2):171-178.
- Koldamova RP, Lefterov IM, Staufenbiel M, Wolfe D, Huang S, Glorioso JC, Walter M, Roth MG, Lazo JS.
The liver X receptor ligand T0901317 decreases amyloid β production in vitro and in a mouse model of Alzheimer's disease.
Journal of Biological Chemistry 2005; 280(6):4079-4088.
- Koldamova R, Staufenbiel M, Lefterov I.
Lack of ABCA1 considerably decreases brain ApoE level and increases amyloid deposition in APP23 mice.
Journal of Biological Chemistry 2005; 280(52):43224-43235.
- Klunk WE, Lopresti BJ, Ikonomovic MD, Lefterov IM, Koldamova RP, Abrahamson EE, Debnath ML, Holt DP, Huang GF, Shao L, DeKosky ST, Price JC, Mathis CA.
Binding of the positron emission tomography tracer Pittsburgh compound-B reflects the amount of amyloid-β in Alzheimer's disease brain but not in transgenic mouse brain.
Journal of Neuroscience 2005; 25(46):10598-10606.
- Koldamova RP, Lefterov IM, Ikonomovic MD, Skoko J, Lefterov PI, Isanski BA, DeKosky ST, Lazo JS.
22R-hydroxycholesterol and 9-cis-retinoic acid induce ATP-binding cassette transporter A1 expression and cholesterol efflux in brain cells and decrease amyloid β secretion.
Journal of Biological Chemistry 2003; 278(15):13244-13256.
- Lazo JS, Ducruet AP, Koldamova RP.
Molecular Pharmacology 2003; 64(2):199-201.
- Lefterov IM, Koldamova RP, Lefterova MI, Schwartz DR, Lazo JS.
Cysteine 73 in bleomycin hydrolase is critical for amyloid precursor protein processing.
Biochemical and Biophysical Research Communications 2001; 283(4):994-999.
- Koldamova RP, Lefterov IM, Lefterova MI, Lazo JS.
Apolipoprotein A-I directly interacts with amyloid precursor protein and inhibits Aβ aggregation and toxicity.
Biochemistry 2001; 40(12):3553-3560.
- Gadjeva V, Koldamova R.
Spin-labeled 1-alkyl-1-nitrosourea synergists of antitumor antibiotics.
Anti-Cancer Drug Design 2001; 16(4-5):247-253.
- Lefterov IM, Koldamova RP, Lazo JS.
Human bleomycin hydrolase regulates the secretion of amyloid precursor protein.
FASEB Journal 2000; 14(12):1837-1847.
- Koldamova RP, Lefterov IM, DiSabella MT, Almonte C, Watkins SC, Lazo JS.
Human bleomycin hydrolase binds ribosomal proteins.
Biochemistry 1999; 38(22):7111-7117.
- Lefterov IM, Koldamova RP, King J, Lazo JS.
The C-terminus of human bleomycin hydrolase is required for protection against bleomycin-induced chromosomal damage.
Mutation Research 1998; 421(1):1-7.
- Koldamova RP, Lefterov IM, Gadjeva VG, Lazo JS.
Essential binding and functional domains of human bleomycin hydrolase.
Biochemistry 1998; 37(8):2282-2290.
- Koldamova RP, Lefterov IM, DiSabella MT, Lazo JS.
An evolutionarily conserved cysteine protease, human bleomycin hydrolase, binds to the human homologue of ubiquitin-conjugating enzyme 9.
Molecular Pharmacology 1998; 54(6):954-961.
- Lefterov IM, Koldamova RP.
Schedule dependent variation in human lymphocyte sensitivity to bleomycin and repair of chromosomal aberrations in G2.
Mutation Research 1992; 284(2):195-204.
- Koldamova RP, Lefterov IM.
Synergistic effect of CCNU and bleomycin on human lymphocytes exposed at late G1 and G2 states of the cell cycle.
Mutation Research 1991; 260(3):265-269.
- NIA grants, AG023662, AG023304, AG028794, AG031956, AG027973
- Alzheimer Disease Association
- Institute for the Study of Aging
- Neuroscience research and Education Foundation