Patrick Sullivan, PhD

Associate Professor Emeritus of Medicine
Senior Fellow of the Center for the Study of Aging and Human Development
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 - Chapel Hill, 1993

Publications

Williams, Tristan, Alejandra Jolie Ruiz, Angelica Maria Ruiz, Quan Vo, Wangchen Tsering, Guilian Xu, Karen McFarland, et al. “Impact of APOE genotype on prion-type propagation of tauopathy.” Acta Neuropathol Commun 10, no. 1 (April 19, 2022): 57. https://doi.org/10.1186/s40478-022-01359-y.

PMID
35440098
Full Text

Wang, Shaowei, Boyang Li, Victoria Solomon, Alfred Fonteh, Stanley I. Rapoport, David A. Bennett, Zoe Arvanitakis, et al. “Calcium-dependent cytosolic phospholipase A2 activation is implicated in neuroinflammation and oxidative stress associated with ApoE4.” Mol Neurodegener 16, no. 1 (April 16, 2021): 26. https://doi.org/10.1186/s13024-021-00438-3.

PMID
33863362
Full Text

Shinohara, Mitsuru, Takahisa Kanekiyo, Masaya Tachibana, Aishe Kurti, Motoko Shinohara, Yuan Fu, Jing Zhao, et al. “APOE2 is associated with longevity independent of Alzheimer's disease.” Elife 9 (October 19, 2020). https://doi.org/10.7554/eLife.62199.

PMID
33074098
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.” In Annals of Neurology, 88:S171–S171, 2020.

Scholars@Duke

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.” In Annals of Neurology, 88:S197–S197, 2020.

Scholars@Duke

Wong, Man Ying, Michael Lewis, James J. Doherty, Yang Shi, Anil G. Cashikar, Anna Amelianchik, Svitlana Tymchuk, et al. “25-Hydroxycholesterol amplifies microglial IL-1β production in an apoE isoform-dependent manner.” J Neuroinflammation 17, no. 1 (June 17, 2020): 192. https://doi.org/10.1186/s12974-020-01869-3.

PMID
32552741
Full Text

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

Koller, Emily J., Elsa Gonzalez De La Cruz, Mary Weinrich, Tosha Williams, Pedro E. Cruz, Daniel Ryu, Todd E. Golde, et al. “Intracerebral Expression of AAV-APOE4 Is Not Sufficient to Alter Tau Burden in Two Distinct Models of Tauopathy.” Mol Neurobiol 57, no. 4 (April 2020): 1986–2001. https://doi.org/10.1007/s12035-019-01859-4.

PMID
31903524
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

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