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

Yun, SH, Gamkrelidze, G, Stine, WB, Sullivan, PM, Pasternak, JF, Ladu, MJ, and Trommer, BL. "Amyloid-beta1-42 reduces neuronal excitability in mouse dentate gyrus." Neuroscience Letters 403, no. 1-2 (July 2006): 162-165.

PMID
16765515
Full Text

Blain, J-F, Sullivan, PM, and Poirier, J. "A deficit in astroglial organization causes the impaired reactive sprouting in human apolipoprotein E4 targeted replacement mice." Neurobiology of Disease 21, no. 3 (March 2006): 505-514.

PMID
16171999
Full Text

Malek, G, Mace, B, Saloupis, P, Schmechel, D, Rickman, D, Sullivan, P, and Rickman, CB. "Initial observations of key features of age-related macular degeneration in APOE targeted replacement mice.", 109-117. January 2006.

PMID
17249563
Scholars@Duke

Yun, SH, Park, KA, Sullivan, P, Pasternak, JF, Ladu, MJ, and Trommer, BL. "Blockade of nicotinic acetylcholine receptors suppresses hippocampal long-term potentiation in wild-type but not ApoE4 targeted replacement mice." Journal of Neuroscience Research 82, no. 6 (December 2005): 771-777.

PMID
16273551
Full Text

Malek, G, Johnson, LV, Mace, BE, Saloupis, P, Schmechel, DE, Rickman, DW, Toth, CA, Sullivan, PM, and Bowes Rickman, C. "Apolipoprotein E allele-dependent pathogenesis: a model for age-related retinal degeneration." Proceedings of the National Academy of Sciences of the United States of America 102, no. 33 (August 3, 2005): 11900-11905.

PMID
16079201
Full Text

Fryer, JD, Demattos, RB, McCormick, LM, O'Dell, MA, Spinner, ML, Bales, KR, Paul, SM, Sullivan, PM, Parsadanian, M, Bu, G, and Holtzman, DM. "The low density lipoprotein receptor regulates the level of central nervous system human and murine apolipoprotein E but does not modify amyloid plaque pathology in PDAPP mice." The Journal of Biological Chemistry 280, no. 27 (July 2005): 25754-25759.

PMID
15888448
Full Text

Morikawa, M, Fryer, JD, Sullivan, PM, Christopher, EA, Wahrle, SE, DeMattos, RB, O'Dell, MA, Fagan, AM, Lashuel, HA, Walz, T, Asai, K, and Holtzman, DM. "Production and characterization of astrocyte-derived human apolipoprotein E isoforms from immortalized astrocytes and their interactions with amyloid-beta." Neurobiology of Disease 19, no. 1-2 (June 2005): 66-76.

PMID
15837562
Full Text

Grootendorst, J, Bour, A, Vogel, E, Kelche, C, Sullivan, PM, Dodart, J-C, Bales, K, and Mathis, C. "Human apoE targeted replacement mouse lines: h-apoE4 and h-apoE3 mice differ on spatial memory performance and avoidance behavior." Behavioural Brain Research 159, no. 1 (April 2005): 1-14.

PMID
15794991
Full Text

Fryer, JD, Simmons, K, Parsadanian, M, Bales, KR, Paul, SM, Sullivan, PM, and Holtzman, DM. "Human apolipoprotein E4 alters the amyloid-beta 40:42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience 25, no. 11 (March 2005): 2803-2810.

PMID
15772340
Full Text

Wang, C, Wilson, WA, Moore, SD, Mace, BE, Maeda, N, Schmechel, DE, and Sullivan, PM. "Human apoE4-targeted replacement mice display synaptic deficits in the absence of neuropathology." Neurobiol Dis 18, no. 2 (March 2005): 390-398.

PMID
15686968
Full Text

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