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

Kuszczyk, MA, Sanchez, S, Pankiewicz, J, Kim, J, Duszczyk, M, Guridi, M, Asuni, AA, Sullivan, PM, Holtzman, DM, and Sadowski, MJ. "Blocking the interaction between apolipoprotein E and Aβ reduces intraneuronal accumulation of Aβ and inhibits synaptic degeneration." The American Journal of Pathology 182, no. 5 (May 2013): 1750-1768.

PMID
23499462
Full Text

Peng, J, Xu, X, Mace, BE, Vanderveer, LA, Workman, LR, Slifker, MJ, Sullivan, PM, Veenstra, TD, and Clapper, ML. "Estrogen metabolism within the lung and its modulation by tobacco smoke." Carcinogenesis 34, no. 4 (April 2013): 909-915.

PMID
23276798
Full Text

Dhungana, H, Rolova, T, Savchenko, E, Wojciechowski, S, Savolainen, K, Ruotsalainen, A-K, Sullivan, PM, Koistinaho, J, and Malm, T. "Western-type diet modulates inflammatory responses and impairs functional outcome following permanent middle cerebral artery occlusion in aged mice expressing the human apolipoprotein E4 allele." Journal of Neuroinflammation 10 (January 2013): 102-null.

PMID
23957944
Full Text

Hunter, JM, Cirrito, JR, Restivo, JL, Kinley, RD, Sullivan, PM, Holtzman, DM, Koger, D, Delong, C, Lin, S, Zhao, L, Liu, F, Bales, K, and Paul, SM. "Emergence of a seizure phenotype in aged apolipoprotein epsilon 4 targeted replacement mice." Brain Research 1467 (July 2012): 120-132.

PMID
22682924
Full Text

Lei, B, Mace, B, Bellows, ST, Sullivan, PM, Vitek, MP, Laskowitz, DT, and James, ML. "Interaction Between Sex and Apolipoprotein E Genetic Background in a Murine Model of Intracerebral Hemorrhage." TRANSLATIONAL STROKE RESEARCH 3 (July 2012): S94-S101.

PMID
23935764
Full Text

Hawkes, CA, Sullivan, PM, Hands, S, Weller, RO, Nicoll, JAR, and Carare, RO. "Disruption of arterial perivascular drainage of amyloid-β from the brains of mice expressing the human APOE ε4 allele." Plos One 7, no. 7 (January 2012): e41636-null.

PMID
22848551
Full Text

Arold, S, Sullivan, P, Bilousova, T, Teng, E, Miller, CA, Poon, WW, Vinters, HV, Cornwell, LB, Saing, T, Cole, GM, and Gylys, KH. "Apolipoprotein E level and cholesterol are associated with reduced synaptic amyloid beta in Alzheimer's disease and apoE TR mouse cortex." Acta Neuropathologica 123, no. 1 (January 2012): 39-52.

PMID
22020632
Full Text

Ding, J-D, Johnson, LV, Herrmann, R, Farsiu, S, Smith, SG, Groelle, M, Mace, BE, Sullivan, P, Jamison, JA, Kelly, U, Harrabi, O, Bollini, SS, Dilley, J, Kobayashi, D, Kuang, B, Li, W, Pons, J, Lin, JC, and Bowes Rickman, C. "Anti-amyloid therapy protects against retinal pigmented epithelium damage and vision loss in a model of age-related macular degeneration." Proc Natl Acad Sci U S A 108, no. 28 (July 12, 2011): E279-E287.

PMID
21690377
Full Text

Sullivan, PM, Han, B, Liu, F, Mace, BE, Ervin, JF, Wu, S, Koger, D, Paul, S, and Bales, KR. "Reduced levels of human apoE4 protein in an animal model of cognitive impairment." Neurobiology of Aging 32, no. 5 (May 2011): 791-801.

PMID
19577821
Full Text

Sullivan, PM. "APOE-based models of "pre-dementia"." Neuromethods 48 (January 11, 2011): 439-447.

Full Text

Pages