Our research is translational neuroscience based primarily on work with animal models of Alzheimer’s disease. For the last 10 years our group has been working with Alzheimer model mice expressing human APOE3 or APOE4 isoforms. We focus on the role of genes associated with Late Onset Alzheimer’s disease such APOE, TREM2, ABCA7 and others. To evaluate functional and morphological changes on cellular, tissue and organism levels we apply wide array of methods such as behavior testing, immunohistochemistry, transcriptomic and lipidomic analysis. Significant time and effort in those projects have been spent on experiments and analysis of massive high throughput sequencing datasets transcription factor binding, histone modifications, as well as expression profiling in brain following exposure and in response to different dietary patterns and environmental toxicants, as well as the application of promising therapeutic agents.
1979 | Medical Academy Sofia, BULGARIA | MD
1994 | Medical Academy & Bulgarian Academy of Sciences, Sofia, BULGARIA | PhD
Human genetics: Biochemical and Molecular genetics of complex disease
(Epigenetic mechanisms in human pathology)
Fitz NF, Nam KN, Wolfe CM, Letronne F, Playso BE, Iordanova BE, Kozai TDY, Biedrzycki RJ, Kagan VE, Tyurina YY, Han X, Lefterov I,Koldamova R. Phospholipids of APOE lipoproteins activate microglia in an isoform-specific manner in preclinical models of Alzheimer's disease. Nat Commun. 2021 Jun 7;12(1):3416. doi: 10.1038/s41467-021-23762-0. PMID: 34099706; PMCID: PMC8184801.
Fitz NF, Wolfe CM, Playso BE, Biedrzycki RJ, Lu Y, Nam KN, Lefterov I,Koldamova R. Trem2 deficiency differentially affects phenotype and transcriptome of human APOE3 and APOE4 mice. Mol Neurodegener. 2020 Jul 23;15(1):41. doi: 10.1186/s13024-020-00394-4. PMID: 32703241; PMCID: PMC7379780.
Lefterov I, Wolfe CM, Fitz NF, Nam KN, Letronne F, Biedrzycki RJ, Kofler J, Han X, Wang J, Schug J,Koldamova R. APOE2 orchestrated differences in transcriptomic and lipidomic profiles of postmortem AD brain. Alzheimers Res Ther. 2019 Dec 30;11(1):113. doi: 10.1186/s13195-019-0558-0. PMID: 31888770; PMCID: PMC6937981.
Fitz NF, Nam KN,Koldamova R, Lefterov I. Therapeutic targeting of nuclear receptors, liver X and retinoid X receptors, for Alzheimer's disease. Br J Pharmacol. 2019 Sep;176(18):3599-3610. doi: 10.1111/bph.14668. Epub 2019 May 11. PMID: 30924124; PMCID: PMC6715597.
Wolfe CM, Fitz NF, Nam KN, Lefterov I,Koldamova R. The Role of APOE and TREM2 in Alzheimer's Disease-Current Understanding and Perspectives. Int J Mol Sci. 2018 Dec 26;20(1):81. doi: 10.3390/ijms20010081. PMID: 30587772; PMCID: PMC6337314.
Castranio EL, Wolfe CM, Nam KN, Letronne F, Fitz NF, Lefterov I,Koldamova R. ABCA1 haplodeficiency affects the brain transcriptome following traumatic brain injury in mice expressing human APOE isoforms. Acta Neuropathol Commun. 2018 Jul 26;6(1):69. doi: 10.1186/s40478-018-0569-2. PMID: 30049279; PMCID: PMC6062955.
Nam KN, Wolfe CM, Fitz NF, Letronne F, Castranio EL, Mounier A, Schug J, Lefterov I,Koldamova R. Integrated approach reveals diet, APOE genotype and sex affect immune response in APP mice. Biochim Biophys Acta Mol Basis Dis. 2018 Jan;1864(1):152-161. doi: 10.1016/j.bbadis.2017.10.018. Epub 2017 Oct 14. PMID: 29038051; PMCID: PMC5714325.
Nam KN, Mounier A, Wolfe CM, 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(1):4307. doi: 10.1038/s41598-017-04412-2. PMID: 28655926; PMCID: PMC5487356.
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. doi: 10.1016/j.nbd.2017.05.006. Epub 2017 May 11. PMID: 28502803; PMCID: PMC5530876.
Carter AY, Letronne F, Fitz NF, Mounier A, Wolfe CM, Nam KN, Reeves VL, Kamboh H, Lefterov I,Koldamova R. Liver X receptor agonist treatment significantly affects phenotype and transcriptome of APOE3 and APOE4 Abca1 haplo-deficient mice. PLoS One. 2017 Feb 27;12(2):e0172161. doi: 10.1371/journal.pone.0172161. PMID: 28241068; PMCID: PMC5328633.
Fitz NF, Carter AY, Tapias V, Castranio EL, Kodali R, Lefterov I,Koldamova R. ABCA1 Deficiency Affects Basal Cognitive Deficits and Dendritic Density in Mice. J Alzheimers Dis. 2017;56(3):1075-1085. doi: 10.3233/JAD-161056. PMID: 28106559; PMCID: PMC5302049.
Sweet RA, MacDonald ML, Kirkwood CM, Ding Y, Schempf T, Jones-Laughner J, Kofler J, Ikonomovic MD, Lopez OL, Garver ME, Fitz NF,Koldamova R, Yates NA. Apolipoprotein E
4 (APOE 4) Genotype Is Associated with Altered Levels of Glutamate Signaling Proteins and Synaptic Coexpression Networks in the Prefrontal Cortex in Mild to Moderate Alzheimer Disease. Mol Cell Proteomics. 2016 Jul;15(7):2252-62. doi: 10.1074/mcp.M115.056580. Epub 2016 Apr 21. PMID: 27103636; PMCID: PMC4937502.
Nam KN, Mounier A, Fitz NF, Wolfe C, Schug J, Lefterov I,Koldamova R. RXR controlled regulatory networks identified in mouse brain counteract deleterious effects of Aβ oligomers. Sci Rep. 2016 Apr 7;6:24048. doi: 10.1038/srep24048. PMID: 27051978; PMCID: PMC4823697.
Fitz NF, Tapias V, Cronican AA, Castranio EL, Saleem M, Carter AY, Lefterova M, Lefterov I,Koldamova R. 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. doi: 10.1093/brain/awv293. Epub 2015 Oct 28. PMID: 26510953; PMCID: PMC4731410.
Mounier A, Georgiev D, Nam KN, Fitz NF, Castranio EL, Wolfe CM, Cronican AA, Schug J, Lefterov I,Koldamova R. Bexarotene-Activated Retinoid X Receptors Regulate Neuronal Differentiation and Dendritic Complexity. J Neurosci. 2015 Aug 26;35(34):11862-76. doi: 10.1523/JNEUROSCI.1001-15.2015. PMID: 26311769; PMCID: PMC4549399.
Lefterov I, Schug J, Mounier A, Nam KN, Fitz NF,Koldamova R. RNA-sequencing reveals transcriptional up-regulation of Trem2 in response to bexarotene treatment. Neurobiol Dis. 2015 Oct;82:132-140. doi: 10.1016/j.nbd.2015.05.019. Epub 2015 Jun 10. PMID: 26071899; PMCID: PMC4640940.
Lefterov I,Koldamova R. Metabolic Disorders and Neurodegeneration, introduction to the special issue. Neurobiol Dis. 2014 Dec;72 Pt A:1-2. doi: 10.1016/j.nbd.2014.09.018. PMID: 25301714.
Koldamova R, Fitz NF, Lefterov I. ATP-binding cassette transporter A1: from metabolism to neurodegeneration. Neurobiol Dis. 2014 Dec;72 Pt A:13-21. doi: 10.1016/j.nbd.2014.05.007. Epub 2014 May 17. PMID: 24844148; PMCID: PMC4302328.
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. J Alzheimers Dis. 2014;41(2):535-49. doi: 10.3233/JAD-132789. PMID: 24643138; PMCID: PMC4346309.
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. Neurobiol Dis. 2014 Mar;63:107-14. doi: 10.1016/j.nbd.2013.11.005. Epub 2013 Nov 20. PMID: 24269917; PMCID: PMC3939039.
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.1235809. PMID: 23704552; PMCID: PMC4086452.
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. PMID: 23405071; PMCID: PMC3566160.
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 Neurosci. 2012 Sep 19;32(38):13125-36. doi: 10.1523/JNEUROSCI.1937-12.2012. PMID: 22993429; PMCID: PMC3646580.
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/PS1DeltaE9 mice. J Biol Chem. 2010 Nov 19;285(47):36945-57. doi: 10.1074/jbc.M110.127738. Epub 2010 Aug 25. PMID: 20739292; PMCID: PMC2978623.
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. J Neurosci. 2010 May 19;30(20):6862-72. doi: 10.1523/JNEUROSCI.1051-10.2010. PMID: 20484628; PMCID: PMC2883862.
Koldamova R, Fitz NF, Lefterov I. The role of ATP-binding cassette transporter A1 in Alzheimer's disease and neurodegeneration. Biochim Biophys Acta. 2010 Aug;1801(8):824-30. doi: 10.1016/j.bbalip.2010.02.010. Epub 2010 Feb 24. PMID: 20188211; PMCID: PMC3712769.
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 ATP-Binding Agents in PS1/APP Mice. Lett Drug Des Discov. 2009 Sep;6(6):437. doi: 10.2174/157018009789057526. PMID: 20119496; PMCID: PMC2812908.
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. Biochem Pharmacol. 2010 May 1;79(9):1310-6. doi: 10.1016/j.bcp.2009.12.018. Epub 2010 Jan 8. PMID: 20060385; PMCID: PMC2834822.
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 Apr 30;1(2):e00006. doi: 10.1042/AN20090015. PMID: 19570031; PMCID: PMC2695585.
Lefterov I, Bookout A, Wang Z, Staufenbiel M, Mangelsdorf D,Koldamova R. Expression profiling in APP23 mouse brain: inhibition of Abeta amyloidosis and inflammation in response to LXR agonist treatment. Mol Neurodegener. 2007 Oct 22;2:20. doi: 10.1186/1750-1326-2-20. PMID: 17953774; PMCID: PMC2214725.
Koldamova R, Lefterov I. Role of LXR and ABCA1 in the pathogenesis of Alzheimer's disease - implications for a new therapeutic approach. Curr Alzheimer Res. 2007 Apr;4(2):171-8. doi: 10.2174/156720507780362227. PMID: 17430243.
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-beta in Alzheimer's disease brain but not in transgenic mouse brain. J Neurosci. 2005 Nov 16;25(46):10598-606. doi: 10.1523/JNEUROSCI.2990-05.2005. PMID: 16291932; PMCID: PMC6725842.
Koldamova R, Staufenbiel M, Lefterov I. Lack of ABCA1 considerably decreases brain ApoE level and increases amyloid deposition in APP23 mice. J Biol Chem. 2005 Dec 30;280(52):43224-35. doi: 10.1074/jbc.M504513200. Epub 2005 Oct 5. PMID: 16207713.
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 beta production in vitro and in a mouse model of Alzheimer's disease. J Biol Chem. 2005 Feb 11;280(6):4079-88. doi: 10.1074/jbc.M411420200. Epub 2004 Nov 22. PMID: 15557325.
Lazo JS, Ducruet AP,Koldamova RP. Sleuthful pharmacology. Mol Pharmacol. 2003 Aug;64(2):199-201. doi: 10.1124/mol.64.2.199. PMID: 12869623.
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 beta secretion. J Biol Chem. 2003 Apr 11;278(15):13244-56. doi: 10.1074/jbc.M300044200. Epub 2003 Jan 22. PMID: 12547833.
Gadjeva V,Koldamova R. Spin-labeled 1-alkyl-1-nitrosourea synergists of antitumor antibiotics. Anticancer Drug Des. 2001 Aug-Oct;16(4-5):247-53. PMID: 12049483.
Lefterov IM,Koldamova RP, Lefterova MI, Schwartz DR, Lazo JS. Cysteine 73 in bleomycin hydrolase is critical for amyloid precursor protein processing. Biochem Biophys Res Commun. 2001 May 18;283(4):994-9. doi: 10.1006/bbrc.2001.4860. PMID: 11350084.
Koldamova RP, Lefterov IM, Lefterova MI, Lazo JS. Apolipoprotein A-I directly interacts with amyloid precursor protein and inhibits A beta aggregation and toxicity. Biochemistry. 2001 Mar 27;40(12):3553-60. doi: 10.1021/bi002186k. PMID: 11297421.
Lefterov IM,Koldamova RP, Lazo JS. Human bleomycin hydrolase regulates the secretion of amyloid precursor protein. FASEB J. 2000 Sep;14(12):1837-47. doi: 10.1096/fj.99-0938com. PMID: 10973933.
Koldamova RP, Lefterov IM, DiSabella MT, Almonte C, Watkins SC, Lazo JS. Human bleomycin hydrolase binds ribosomal proteins. Biochemistry. 1999 Jun 1;38(22):7111-7. doi: 10.1021/bi990135l. PMID: 10353821.
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. Mol Pharmacol. 1998 Dec;54(6):954-61. doi: 10.1124/mol.54.6.954. PMID: 9855622.
Lefterov IM,Koldamova RP, King J, Lazo JS. The C-terminus of human bleomycin hydrolase is required for protection against bleomycin-induced chromosomal damage. Mutat Res. 1998 Oct 12;421(1):1-7. doi: 10.1016/s0027-5107(98)00148-1. PMID: 9748474.
Koldamova RP, Lefterov IM, Gadjeva VG, Lazo JS. Essential binding and functional domains of human bleomycin hydrolase. Biochemistry. 1998 Feb 24;37(8):2282-90. doi: 10.1021/bi9722204. PMID: 9485374.
Lefterov IM,Koldamova RP. Schedule dependent variation in human lymphocyte sensitivity to bleomycin and repair of chromosomal aberrations in G2. Mutat Res. 1992 Dec 16;284(2):195-204. doi: 10.1016/0027-5107(92)90003-k. PMID: 1281270.
Koldamova RP, Lefterov IM. Synergistic effect of CCNU and bleomycin on human lymphocytes exposed at late G1 and G2 states of the cell cycle. Mutat Res. 1991 Jul;260(3):265-9. doi: 10.1016/0165-1218(91)90035-k. PMID: 1714541.
