University of Pittsburgh

The Koldamova/ Lefterov Lab

 

Content on this page requires a newer version of Adobe Flash Player.

Get Adobe Flash player

Research in Koldamova & Lefterov Laboratory

The research in our laboratory is focused on major themes, interconnected by the common goal to better understand the molecular pathogenesis of Alzheimer's disease in the early stages, when therapeutic intervention could slow the progression of the disease.

Transcriptional control by Nuclear Receptors LXR and RXR in brain and their role in Alzheimer's disease.

The role of LXR/RXR heterodimers and their major target gene ABCA1 in Alzheimer's disease was established with seminal contributions of Koldamova & Lefterov Lab[1-3]. Subsequently the research in this field had a significant impact on many aspects of AD research, including a rationalized therapeutic approach that considers physiological regulatory mechanisms. For quite a long time it has been generally accepted that the therapeutic effects of synthetic small molecule LXR and RXR ligands on cognitive performance and clearance of soluble Aβ were primarily mediated by improved APOE lipidation – a definitive and major function of ABCA1. The results of our most recent studies clearly indicate, however, that ligand activated RXR homodimers and possibly LXR/RXR heterodimers, initiate transcription programs with short and long term beneficial effects mediated by up-regulation of genes/proteins involved in phagocytosis, signalling pathways important for Aβ clearance by microglia and stimulated adult neurogenesis[4-7]. The biology of LXR and RXR transcription factors and their major targets – ABCA1 and APOE, ever since, remains a major part of the research in the laboratory.

The role of APOE isoforms in Alzheimer's disease pathogenesis.

While an increased risk for developing AD in APOEε4 carriers has been known for almost 25 years now, we have a limited knowledge of what exactly makes APOEε4 a risk factor, why the risk is increased and what are the underlying molecular mechanisms. Using in vitro and animal models of AD, we have been able to demonstrate that the lipidation status of APOE, at least in mice with AD-like phenotype, is critical for its major function in brain, which is cholesterol and phospholipids transport[8]. Apparently, the lipidation status of APOE influences also its ability to bind Aβ, and to deliver soluble Aβ species to microglia for phagocytosis and clearance. Molecular mechanisms underlying the efficient clearance of Aβ obviously include the lipid composition of HDL-like particles in brain. With the results of our most recent research we are suggesting that the molecular lipid speciation of APOE/Aβ complexes is critical for the delivery of Aβ to microglia, for activation of downstream SYK signaling cascades triggered by microglial immune-receptors and their adapters and ultimately clearance of Aβ. To address further those issues, we are using complex AD animal models on human APOE genetic background with controlled expression of mouse Abca1 or deletion of nuclear LXR or RXR receptors.

Gene-environmental interactions, neuroinflammation and memory impairment.

Gene-environmental interactions, neuroinflammation and memory impairment. It has been increasingly recognized that the transport of brain lipids and epigenetic changes in brain have a substantial role in memory formation, cognitive performance and clearance of Aβ. The identification of environmental factors with a known role in memory and cognitive performance, in neuroinflammation and AD pathogenesis that might exert their effects through the above mechanisms is extremely important. Traumatic Brain Injury with its short and long term consequences is highly relevant in this regard: inflammatory response and cognitive decline, not necessarily part of a developing AD, are important part of the clinical picture and long term consequences of the disease. In a model of TBI we are exploring the effect of age and expression of human APOE isoforms, emphasizing changes in gene-gene interactions, changes in existing gene networks and identification of newly established networks that can direct future translational research. High Fat Diet is an environmental factor easy to overlook, and constantly underestimated when it comes to AD risk and pathogenesis – not least it is difficult to investigate. HFD and its effects on AD-like phenotype of AD model mice has been and remains a major theme in our research. Currently we are addressing relevant questions using complex animal models, Next Generations Sequencing, Multidimensional Lipidomics Approaches and state of the art statistical and bioinformatics tools for data analysis. Exposure to environmental toxicants, like Arsenic, at human relevant doses, is an example where changes in transcriptional regulation in brain and epigenetic modifications play an important role in memory impairment and cognitive decline, particularly in association with prenatal exposure, and we are investing substantial effort to answer questions relevant to the underlying molecular mechanisms of their effects on age dependent transgenerational development of dementia.

The research in Koldamova & Lefterov Laboratory is supported by NIH/NIA, NIH/NIEHS, DoD and private sources.

  1. 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.
    DOI:10.1074/jbc.M411420200 PMID:15557325
  2. 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.
    DOI:10.1074/jbc.M504513200 PMID:16207713
  3. Koldamova, R. P., Lefterov, I. M., Ikonomovic, M. D., Skoko, J., Lefterov, P. I., Isanski, B. A., DeKosky, S. T. & Lazo, J. S.
    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.
    The Journal of biological chemistry 2003; 278, 13244-13256
    DOI: 10.1074/jbc.M300044200 PMID: M300044200
  4. 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.
    DOI:10.1126/science.1235809 PMID:23704552
  5. 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.
    Scientific Reports. 2016 Apr 7; 6:24048.
    DOI:10.1038/srep24048 PMID:27051978
  6. 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.
    Journal of Neuroscience. 2015 Aug 26; 35(34):11862-76.
    DOI:10.1523/JNEUROSCI.1001-15.2015 PMID:26311769
  7. Lefterov, I., Schug, J., Mounier, A., Nam, K. N., Fitz, N. F. & Koldamova, R.
    RNA-sequencing reveals transcriptional up-regulation of Trem2 in response to bexarotene treatment..
    Neurobiology of disease 2015; 82, 132-140
    DOI:0.1016/j.nbd.2015.05.019 PMID:26071899
  8. Fitz, N. F., Tapias, V., Cronican, A. A., Castranio, E. L., Saleem, M., Carter, A. Y., Lefterova, M., Lefterov, I. & Koldamova, R.
    Opposing effects of Apoe/Apoa1 double deletion on amyloid-beta pathology and cognitive performance in APP mice..
    Brain : a journal of neurology 2015; 138, 3699-3715
    DOI:10.1093/brain/awv293 PMID:26510953