Alzheimer's disease *AD) is a devastating neurological disorder characterized by a progressive dementia which affects 5-10% of the elderly over age 65. Genetic factors have clearly been implicated in the early and late-onset familial forms of the linked disease. A form of late-onset AD has been show to be linked to the proximal long arm of chromosome 19 and subsequently associated with Apolipoprotein E (ApoE). Apo E is a plasma apolipoprotein that is involved in lipid transport and metabolism. Apo E is produced in brain and found in three major isoforms in the human population which have been designated E2. E3. E4. These alleles occur at a frequency of approximately 8, 76, and 16 per cent, respectively. Recently, an association between the ApoE4 allele and an increased risk of late-onset AD has been established. Subsequent studies have demonstrated that Apo E2 has a protective effect or delays the age of onset of Ad. The exact mechanism by which the different isoforms exert their effects are as yet unknown. To study the mechanisms by which Apo E exerts its effects and the role which Apo E plays in brain molecular biology, physiology, and metabolism awe are creating Apo E 2. 3. and 4 transgenic mice. Cosmid libraries from human AD patients with the appropriate Apo E genotype were prepared in the cosmid vectors pWE15 and SuperCos 1. Apo E containing cosmid clones were isolated and restriction mapped. Clones of the proper size containing the brain expression control regions for Apo E were produced and purified. Experiments to produce Apo E transgenic mice using microinjection procedures will be carried out using ice which lack a functional Apo E gene (Apo E """"""""knockout"""""""" mice). Mice, lacking a functional murine Apo E, will be produced which are homozygous and heterozygous for the human Apo E2, 3 and 4 alleles. These mice will serve as a model system for the study of the role of Apo E in brain function and metabolism and its potential role in Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
2P50AG005128-12
Application #
3726239
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Duke University
Department
Type
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Petyuk, Vladislav A; Chang, Rui; Ramirez-Restrepo, Manuel et al. (2018) The human brainome: network analysis identifies HSPA2 as a novel Alzheimer’s disease target. Brain 141:2721-2739
Sims, Rebecca (see original citation for additional authors) (2017) Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nat Genet 49:1373-1384
Jun, Gyungah R; Chung, Jaeyoon; Mez, Jesse et al. (2017) Transethnic genome-wide scan identifies novel Alzheimer's disease loci. Alzheimers Dement 13:727-738
Karch, Celeste M; Ezerskiy, Lubov A; Bertelsen, Sarah et al. (2016) Alzheimer's Disease Risk Polymorphisms Regulate Gene Expression in the ZCWPW1 and the CELF1 Loci. PLoS One 11:e0148717
Mez, Jesse; Mukherjee, Shubhabrata; Thornton, Timothy et al. (2016) The executive prominent/memory prominent spectrum in Alzheimer's disease is highly heritable. Neurobiol Aging 41:115-121
Ridge, Perry G; Hoyt, Kaitlyn B; Boehme, Kevin et al. (2016) Assessment of the genetic variance of late-onset Alzheimer's disease. Neurobiol Aging 41:200.e13-200.e20
Hohman, Timothy J; Bush, William S; Jiang, Lan et al. (2016) Discovery of gene-gene interactions across multiple independent data sets of late onset Alzheimer disease from the Alzheimer Disease Genetics Consortium. Neurobiol Aging 38:141-150
Jun, G; Ibrahim-Verbaas, C A; Vronskaya, M et al. (2016) A novel Alzheimer disease locus located near the gene encoding tau protein. Mol Psychiatry 21:108-17
Hohman, Timothy J; Cooke-Bailey, Jessica N; Reitz, Christiane et al. (2016) Global and local ancestry in African-Americans: Implications for Alzheimer's disease risk. Alzheimers Dement 12:233-43
Ghani, Mahdi; Reitz, Christiane; Cheng, Rong et al. (2015) Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals. JAMA Neurol 72:1313-23

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