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

Krishnamurthy, Kamesh, Viviana Cantillana, Haichen Wang, Patrick M. Sullivan, Bradley J. Kolls, Xintong Ge, Yufeng Lin, Brian Mace, and Daniel T. Laskowitz. “ApoE mimetic improves pathology and memory in a model of Alzheimer's disease.” Brain Res 1733 (April 15, 2020): 146685. https://doi.org/10.1016/j.brainres.2020.146685.

PMID
32007397
Full Text

Davis, Albert A., Casey E. Inman, Zachary M. Wargel, Umber Dube, Brittany M. Freeberg, Alexander Galluppi, Jessica N. Haines, et al. “APOE genotype regulates pathology and disease progression in synucleinopathy.” Sci Transl Med 12, no. 529 (February 5, 2020). https://doi.org/10.1126/scitranslmed.aay3069.

PMID
32024799
Full Text

Shi, Yang, Melissa Manis, Justin Long, Kairuo Wang, Patrick M. Sullivan, Javier Remolina Serrano, Rosa Hoyle, and David M. Holtzman. “Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model.” J Exp Med 216, no. 11 (November 4, 2019): 2546–61. https://doi.org/10.1084/jem.20190980.

PMID
31601677
Full Text

Davis, Albert A., Casey E. Inman, Zachary M. Wargel, Alexander Galluppi, Brittany Freeberg, Jason D. Ulrich, Dhruva Dhavale, et al. “APOE Genotype Regulates Pathology and Survival in Mouse Models of Alpha-Synucleinopathy.” In Annals of Neurology, 86:S177–78. WILEY, 2019.

Scholars@Duke

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
Full Text

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
Full Text

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): 864. https://doi.org/10.1038/s41467-017-00910-z.

PMID
29021522
Full Text

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
Full Text

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
Full Text

Pages