Radosveta P. Koldamova, M.D., Ph.D.
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
- 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.
J Biol Chem. 2010 Nov 19;285(47):36945-57. Epub 2010 Aug 25. PMID: 20739292
- 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. PubMed PMID: 20484628
- 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. Epub 2010 Feb 24. PubMed PMID: 20188211
- 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 Jan 7. PubMed PMID: 20060385
- Lefterov I, Fitz NF, Cronican A, Lefterov P, Staufenbiel M, Koldamova R.
Memory deficits in APP23/Abca1+/- mice correlate with the level of Abeta oligomers.
ASN Neuro. 2009 Apr 30;1(2). pii: e00006. doi: 10.1042/AN20090015. PMID: 19570031
- Lefterov, I. Bookout, A.L. Wang, Z. Staufenbiel, M. Mangelsdorf, D. Koldamova, R.
Expression profiling in APP23 mouse brain: inhibition of Aß amyloidosis and inflammation in response to LXR agonist treatment.
(2007) Mol. Neurodegeneration (In press)
- 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. PMID: 17430243
- 1979 MD Medicine, Medical Academy, Sofia, Bulgaria
- 1994 PhD Biology, Experimental Cancer therapy, Bulgarian Academy of Sciences, Sofia, Bulgaria
- NIA grants, AG023662, AG023304, AG028794, AG031956, AG027973
- Alzheimer Disease Association
- Institute for the Study of Aging
- Neuroscience research and Education Foundation