Renee C. LeBoeuf, Ph.D.
Biosketch Information
Email: leboeuf@u.washington.edu
A. Research Program
The long-term goal of Dr. LeBouef’s research is to understand the molecular mechanisms causing Alzheimer's Disease (AD). Animal models overexpressing selected genes thought to participate in AD and aging processes have or will be generated. Prevention and treatment schemes for AD and other factors contributing to aberrant aging processes can then be designed.
B. Current Status
Three sets of genetically engineered mice are currently being generated and studied to examine the role of amyloid precursor protein, apoE, presenilin molecules, and inflammation in AD and aging. Most of these animals have been and are being constructed in conjuction with GAATG faculty. Trainees will participate in the phenotypic characterization of these mice, and in the design of new genetically engineered animals. This involves technical training in molecular biology, mouse husbandry and genetics, immunocytochemistry, in situ procedures, and protein quantification. Scientific training will include understanding how to use animal models to study human pathology.
1) The first focus is to produce mice exhibiting AD-like pathology in the brain using DNA constructs coding for amyloid precursor protein (APP). Dr. LeBoeuf and her collaborators have initially generated mice overexpressing full length and C-terminal regions of APP. Amyloid plaques are absent in mice expressing the C-terminal regions of APP, and mice with full length constructs are just being examined. Interestingly, for APP C-terminal transgenic mice, muscle tissue shows signs of early degeneration resembling features of inclusion body myositis, a pathological condition in muscle due to Ab aggregation. Although Ab fragments are not seen in the muscles, this degeneration is distinct for transgenic as compared to littermate control mice not expressing the construct.
2) Mice overexpressing apoE3 and apoE4 alleles are now available. Dr. LeBoeuf and her colleagues have found no induction of plaque formation in C-terminal APP mice crossed to animals overexpressing apoE3 or with animals which lack the expression of apoE (apoE-null). Crosses with apoE4 animals are underway. Also, strategies to elevate the expression of apoE alleles in the brain are being conducted.
3) Mice overexpressing presenilin 1 are currently being generated.
4) Dr. LeBoeuf and her research group are testing the hypothesis that inflammatory factors contribute to aging in animals. Using mice deficient in TNF-a and IL-1 receptors, they are examining the response to brain injection of Ab, and will examine brain biology in their transgenic mice crossed to receptor-null animals.
C. Investigator
Dr. LeBoeuf is Research Associate Professor of Medicine, a Core Faculty member of the Nutritional Sciences Program, and head of the Nutrient-Gene Subcore of the Clinical Nutrition Research Unit (NIH/NIDDK P30 DK35816).
D. Selected Relevant Publications
Lusis AJ, LeBoeuf RC. Genetic control of mammalian lipoproteins: Mouse model. Methods Enzymol 128:877-894, 1986.
Lusis AJ, Taylor BA, Quon D, Zollman S, LeBoeuf RC. Genetic factors controlling structure and expression of apolipoproteins B and E in mice. J Biol Chem 262:7594-7604, 1987.
LeBoeuf RC, Caldwell M, Kirk E. Regulation by nutritional status of lipids and apolipoproteins A-I, A-II, and A-IV in inbred mice. J Lipid Res 35:121-133, 1994.
LeBoeuf RC, Zia Y-R, Oram JF, Lusis AJ. Mapping of the gene for high-density lipoprotein binding protein (Hdlbp) to proximal mouse chromosome 1. Genomics 23:296-298, 1994.
LeBoeuf RC, Tolson D, Heinecke JW. Dissociation between tissue iron concentrations and transferrin saturation among inbred mice. J Lab Clin Med 126:128-136, 1995.
Kirk EA, Moe GL, Caldwell MT, Lernmark JA, Wilson DL, LeBoeuf RC. Hyper- and hypo-responsiveness to dietary fat and cholesterol among inbred mice: Searching for level and variability genes. J Lipid Res 36:1522-1532, 1995.
Kunjathoor VV, Wilson DL, LeBoeuf RC. Increased atherosclerosis in streptozotocin-induced diabetic mice. J Clin Invest 97:1767-1773, 1996.
LeBoeuf RC, Caldwell M, Tu A-Y, Albers JJ. Phospholipid transfer protein maps to distal mouse chromosome 2. Genomics 34:259-260, 1996.
Fukuchi K, Ho L, Younkin SG, Kunkel DD, Ogburn CE, LeBoeuf RC, Furlong CE, Deeb SS, Nochlin D, Wegiel J, Wisniewski HM, Martin GM. High levels of circulating b-amyloid peptide do not cause cerebral b-amyloidosis in transgenic mice. Am J Path 149:219-227, 1996.
Ohman R, Dang N, LeBoeuf RC, Furlong CE, Fukuchi K. Expression of apolipoprotein E inhibits aggregation of the C-terminal fragments of b-amyloid precursor protein. Neurosci Lett 210:65-68, 1996.
Schreyer SA, Peschon JJ, LeBoeuf RC. Accelerated atherosclerosis in mice lacking tumor necrosis factor receptor p55. J Biol Chem 271:26174-26178, 1996.
LeBoeuf RC, Uelmen PJ, Choe O, Chan L. Acyl-coenzyme A:cholesterol acyltransferase (Acact) and apolipoprotein A-II (Apoa2) do not account for phenotypic differences in atherosclerosis susceptibility (Ath1) as assessed by recombinant inbred strain analysis. Mouse Genome 94:874-876, 1996.