Patrick Sullivan, PhD

Associate Professor of Medicine
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

Tachibana, Masaya, Marie-Louise Holm, Chia-Chen Liu, Mitsuru Shinohara, Tomonori Aikawa, Hiroshi Oue, Yu Yamazaki, et al. “APOE4-mediated amyloid-β pathology depends on its neuronal receptor LRP1..” J Clin Invest 129, no. 3 (March 1, 2019): 1272–77. https://doi.org/10.1172/JCI124853.

PMID
30741718
Full Text

Liao, Fan, Aimin Li, Monica Xiong, Nga Bien-Ly, Hong Jiang, Yin Zhang, Mary Beth Finn, et al. “Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation..” J Clin Invest 128, no. 5 (May 1, 2018): 2144–55. https://doi.org/10.1172/JCI96429.

PMID
29600961
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Huynh, Tien-Phat V., Fan Liao, Caroline M. Francis, Grace O. Robinson, Javier Remolina Serrano, Hong Jiang, Joseph Roh, et al. “Age-Dependent Effects of apoE Reduction Using Antisense Oligonucleotides in a Model of β-amyloidosis..” Neuron 96, no. 5 (December 6, 2017): 1013-1023.e4. https://doi.org/10.1016/j.neuron.2017.11.014.

PMID
29216448
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Baek, Amy E., Yen-Rei A. Yu, Sisi He, Suzanne E. Wardell, Ching-Yi Chang, Sanghoon Kwon, Ruchita V. Pillai, et al. “The cholesterol metabolite 27 hydroxycholesterol facilitates breast cancer metastasis through its actions on immune cells..” Nat Commun 8, no. 1 (October 11, 2017). https://doi.org/10.1038/s41467-017-00910-z.

PMID
29021522
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Shi, Yang, Kaoru Yamada, Shane Antony Liddelow, Scott T. Smith, Lingzhi Zhao, Wenjie Luo, Richard M. Tsai, et al. “ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy..” Nature 549, no. 7673 (September 28, 2017): 523–27. https://doi.org/10.1038/nature24016.

PMID
28959956
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Zhao, Na, Chia-Chen Liu, Alexandra J. Van Ingelgom, Yuka A. Martens, Cynthia Linares, Joshua A. Knight, Meghan M. Painter, Patrick M. Sullivan, and Guojun Bu. “Apolipoprotein E4 Impairs Neuronal Insulin Signaling by Trapping Insulin Receptor in the Endosomes..” Neuron 96, no. 1 (September 27, 2017): 115-129.e5. https://doi.org/10.1016/j.neuron.2017.09.003.

PMID
28957663
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Calippe, Bertrand, Sebastien Augustin, Fanny Beguier, Hugo Charles-Messance, Lucie Poupel, Jean-Baptiste Conart, Shulong J. Hu, et al. “Complement Factor H Inhibits CD47-Mediated Resolution of Inflammation..” Immunity 46, no. 2 (February 21, 2017): 261–72. https://doi.org/10.1016/j.immuni.2017.01.006.

PMID
28228282
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Pankiewicz, Joanna E., Jairo Baquero-Buitrago, Sandrine Sanchez, Jennifer Lopez-Contreras, Jungsu Kim, Patrick M. Sullivan, David M. Holtzman, and Martin J. Sadowski. “APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice..” Molecular Neurodegeneration 12, no. 1 (January 31, 2017). https://doi.org/10.1186/s13024-017-0156-1.

PMID
28143566
Full Text

Teter, Bruce, Mary Jo LaDu, Patrick M. Sullivan, Sally A. Frautschy, and Greg M. Cole. “Apolipoprotein E isotype-dependent modulation of microRNA-146a in plasma and brain..” Neuroreport 27, no. 11 (August 3, 2016): 791–95. https://doi.org/10.1097/WNR.0000000000000608.

PMID
27281274
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Zhao, Lingzhi, Andrew J. Gottesdiener, Mayur Parmar, Mingjie Li, Stephen M. Kaminsky, Maria J. Chiuchiolo, Dolan Sondhi, et al. “Intracerebral adeno-associated virus gene delivery of apolipoprotein E2 markedly reduces brain amyloid pathology in Alzheimer's disease mouse models..” Neurobiol Aging 44 (August 2016): 159–72. https://doi.org/10.1016/j.neurobiolaging.2016.04.020.

PMID
27318144
Full Text

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