Patrick Sullivan, PhD

Associate Professor in Medicine, Geriatrics
Campus mail 508 Fulton St., Grecc 182, Durham, NC 27705
Phone (919) 286-0411
Email address p.sullivan@duke.edu

The primary focus of my lab is to investigate the relationship between APOE genotype and late onset Alzheimer’s disease (AD).  The single most common and influential gene in AD is the APOE gene.  The APOE gene is polymorphic; encoding three different alleles designated APOE2, E3 or E4.  APOE4 carriers have the highest risk for AD while APOE3 carriers have an essentially neutral risk and APOE2 carriers may be protected against AD.  The APOE4 gene is also linked to increased risk for atherosclerosis, cerebral amyloid angiopathy, peripheral neuropathy, multiple sclerosis, stroke and type II diabetes; as well as an increased susceptibility to HIV and Chlamydia infections, head injury and cognitive decline following coronary bypass surgery.  The fact that 28% of the US population are carriers of the APOE4 gene, underscores the need for a better understanding of APOE’s relationship to disease.  The major challenge facing researchers today is determining why some APOE4 carriers succumb to disease while others do not.  Genetic modifiers and environmental risk factors likely explain different individual outcomes. The primary environmental risk factors are thought to be; a Westernized diet, low physical activity, chronic stress, poor sleep habits, andro/menopause and most importantly, age.

We are currently working to test novel drug formulations that specifically target putative apoE dependent mechanisms involved in neurodegeneration.  Our initial screens involve neuronal-glial cell culture models that eventually will lead to testing in animals.  We currently use the best available animal model of apoE-linked AD, the human apoE targeted replacement (TR) or “knock in” mice.  I created three lines of human apoE TR mice, each expressing one the three human apoE isoforms and have since made multiple crosses to other AD related genes (e.g. APP, PS1 and tau).  I have given the apoE TR mice and made the crosses available to over 70 labs worldwide.

We are also working to build a better model of late onset AD by combining the apoE TR mice with non-mutated human APP and tau KI mice.  We think this is important because over 98% of all AD cases contain no mutations in the APP or tau genes.  Our hope is to better understand the true etiology and progression of late onset AD.  If successful this new model should aid in both novel target identification and new drug testing to produce therapeutics with greater efficacy in treating AD.

Education and Training

  • Ph.D., University of North Carolina at Chapel Hill, 1993

Publications

Brown, CM, Wright, E, Colton, CA, Sullivan, PM, Laskowitz, DT, and Vitek, MP. "Apolipoprotein E isoform mediated regulation of nitric oxide release." Free Radical Biology & Medicine 32, no. 11 (June 2002): 1071-1075.

PMID
12031891
Full Text

Rickman, CB, Sullivan, PM, Mace, BE, and Rickman, DW. "Targeted replacement of human ApoE Isoforms in aged mice: Risk factors for retinal degeneration?." May 2002.

Scholars@Duke

Brown, CM, Colton, CA, Sullivan, PM, and Vitek, MP. "Sexual dimorphism in apolipoprotein E isoform specific regulation of nitric oxide release in targeted replacement mice." NEUROBIOLOGY OF AGING 23, no. 1 (2002): S404-S404.

Scholars@Duke

DeMattos, RB, Brendza, RP, Heuser, JE, Kierson, M, Cirrito, JR, Fryer, J, Sullivan, PM, Fagan, AM, Han, X, and Holtzman, DM. "Purification and characterization of astrocyte-secreted apolipoprotein E and J-containing lipoproteins from wild-type and human apoE transgenic mice." Neurochemistry International 39, no. 5-6 (November 2001): 415-425.

PMID
11578777
Full Text

Knouff, C, Hinsdale, ME, Mezdour, H, Altenburg, MK, Watanabe, M, Quarfordt, SH, Sullivan, PM, and Maeda, N. "Apo E structure determines VLDL clearance and atherosclerosis risk in mice." The Journal of Clinical Investigation 103, no. 11 (June 1999): 1579-1586.

PMID
10359567
Full Text

Sullivan, PM, Mezdour, H, Quarfordt, SH, and Maeda, N. "Type III hyperlipoproteinemia and spontaneous atherosclerosis in mice resulting from gene replacement of mouse Apoe with human Apoe*2." The Journal of Clinical Investigation 102, no. 1 (July 1998): 130-135.

PMID
9649566
Full Text

Roses, AD, Gilbert, J, Xu, PT, Sullivan, P, Popko, B, Burkhart, DS, Christian-Rothrock, T, Saunders, AM, Maeda, N, and Schmechel, DE. "Cis-acting human ApoE tissue expression element is associated with human pattern of intraneuronal ApoE in transgenic mice." Neurobiology of Aging 19, no. SUPPL. 1 (January 1, 1998).

Full Text

Roses, AD, Gilbert, J, Xu, PT, Sullivan, P, Popko, B, Burkhart, DS, Rothrook, TC, Saunders, AM, Maeda, N, and Schmechel, DF. "APOE and Alzheimer disease: Human susceptibility genes and appropriate transgenic models." Brain Pathology 7, no. 4 (December 1, 1997): 1033-1036.

Scholars@Duke

Sullivan, PM, Mezdour, H, Aratani, Y, Knouff, C, Najib, J, Reddick, RL, Quarfordt, SH, and Maeda, N. "Targeted replacement of the mouse apolipoprotein E gene with the common human APOE3 allele enhances diet-induced hypercholesterolemia and atherosclerosis." The Journal of Biological Chemistry 272, no. 29 (July 1997): 17972-17980.

PMID
9218423
Full Text

Joseph, DR, O'Brien, DA, Sullivan, PM, Becchis, M, Tsuruta, JK, and Petrusz, P. "Overexpression of androgen-binding protein/sex hormone-binding globulin in male transgenic mice: tissue distribution and phenotypic disorders." Biology of Reproduction 56, no. 1 (January 1997): 21-32.

PMID
9002629
Full Text

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