MAR 19, 2014 1:00 PM PDT

ABCA1 and APOE: Intertwined roles in Alzheimers disease

Presented at: Neuroscience
Speaker
  • Associate Professor at the Department of Environmental & Occupational Health, University of Pittsburgh
    Biography
      Radosveta (Rada) Koldamova, MD, PhD is Associate Professor at the Department of Environmental & Occupational Health, University of Pittsburgh, Pittsburgh, PA. Dr. Koldamova research has been distinguished by groundbreaking findings in the area of Nuclear Receptor biology in brain and their targets, relevant to AD pathogenesis and therapy. Prior to her appointment at Pitt in 1995, Dr. Koldamova served as a General Practitioner and an Instructor and Lecturer in Biochemistry at the School of Medicine, Stara Zagora, Bulgaria. She defended her PhD thesis in Biochemistry and Molecular Biology at the Bulgarian Academy of Sciences. From 1995 to 2005, she was a postdoctoral fellow and then Assistant Professor at the Department of Pharmacology, School of Medicine University of Pittsburgh. While at Pharmacology, Dr. Koldamova discovered the role of cholesterol transporter ABCA1 and its transcriptional regulators LXR/RXR in AD using in vitro and in vivo model systems. The original reports published by Dr. Koldamova on biology of brain LXR, ABCA1 and therapeutic approaches for AD based on ligand activated NR established a new and fruitful area of AD research. Dr. Koldamova has served on numerous academic, scientific, and professional committees. She is a member of the Society for Neuroscience, International Society to Advance Alzheimer Research and Treatment, and American Society for Biochemistry and Molecular Biology, and is a Principal Investigator on Federal Agencies and Private foundations funded grant awards.

    Abstract

    ATP-binding cassette transporter A1 (ABCA1) mediates cholesterol efflux to lipid-free apolipoproteins such as apolipoprotein A-I (apoA-I) and apolipoprotein E (apoE). ABCA1 is essential regulator of high density lipoprotein generation (HDL) a role that defines its significance for cardiovascular disease. ABCA1 and APOE are transcriptionally regulated by Liver X Receptors (LXR) and Retinoic X Receptors (RXR).
    The inheritance of 4 allele of APOE is the major genetic risk factor for late-onset Alzheimers disease (AD). Patients carrying APOE4 allele, compared to those with the other two isoforms, have more amyloid plaques a finding replicated in human Amyloid precursor protein (APP) transgenic mice. Recent data suggest that ABCA1 via its control over apoE lipidation may have a role in AD. Studies from our and other groups have demonstrated that lack of ABCA1 increases amyloid deposition and cognitive decline in different AD model mice accompanied by significant decrease in the levels of apoE and apoA-I. In contrast, treatment with LXR or RXR ligands increases ABCA1 and apoE levels and significantly ameliorates amyloid pathology. In a recent study using APP mice we demonstrated that ABCA1 haplo deficiency had a differential effect on the phenotype of APOE3 or APOE4 expressing mice. The lack of one copy of Abca1 significantly aggravated memory deficits, Aβ plaques and Aβ clearance in APP/APOE4 but not in APP/APOE3 mice. Interestingly, we found a correlation between HDL in plasma and amyloid load in brain, suggesting a causative connection between peripheral lipoproteins and Aβ load in the CNS.
    In conclusion, these studies demonstrate that future therapies targeting ABCA1 and APOE expression such as LXR/RXR agonists could have a favorable effect on the outcome in AD patients including APO4 carriers.
     


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