Ling Li, PhD

Bio

Dr. Li was trained as a pathologist and a molecular, cellular, and developmental biologist with emphasis on pathogenesis of lipid disorders and Alzheimer’s disease. Since 2000, Dr. Li has developed multiple research programs investigating the pathogenic and therapeutic connections between lipid metabolism and Alzheimer’s disease using transgenic and knockout mouse models. A combination of genetic, pharmacological, behavioral, electrophysiological, proteomic/prenylomic, and other biochemical approaches are employed to conduct translational research in Dr. Li’s laboratory.

Expertise

• Alzheimer's disease
• lipid/lipoprotein metabolism
• cardiovascular/cerebrovascular disease
• genetically modified mouse models for biomedical research

Awards & Recognition

• Fesler-Lampert Chair in Aging Studies, 2015-2016
• VFW Endowed Chair in Pharmacotherapy for the Elderly, 2010-present
• Best Paper Award on obesity/nutrition research from the Science Unbound Foundation, 2008
• Philanthropic Research Award – Lowder Foundation, 2006-2011
• Chunhui Project Delegate, Ministry of Education, China, 2007
• Outstanding Faculty Oral Presentation Award – UAB Center for Aging Annual Meeting, 2006
• Outstanding Young Investigator Presentation Recognition – Gordon Research Conference on Lipoprotein Metabolism, 2006
• NIH DVM Postdoctoral Training Fellowship, 1997-1999
• Minority Student Award for Academic Excellence at Iowa State Univ., 1995
• David R. Griffith Research Excellence Award at Iowa State Univ., 1995
• The Holco Award for Graduate Research Excellence at Iowa State Univ., 1995
• NIH Postdoctoral Training Fellowship, 1995-1996
• Outstanding Oral Presentation Award at the annual meeting of AOCS, 1993
• Honored Student Award from American Oil Chemists’ Society (AOCS), 1993
• Sigma Xi Grants-in-Aid of Research Award, 1993
• Honor Societies of Gamma Sigma Delta and Phi Kappa Phi, 1992
• Study Abroad Scholarship, Education and Science Commission of China, 1989-1990

Professional Associations

1991- American Association for the Advancement of Science (AAAS)
1997- Society for Neuroscience (SfN)
2008- American Society of Biochemistry and Molecular Biology (ASBMB)
2011- International Prenylation Society (IPS) – Founding member
2012- ResearchersAgainstAlzheimer's

Research Summary

The research in Dr. Ling Li’s laboratory focuses on the connections between Alzheimer’s disease (AD) and cardiovascular/cerebrovascular disease, in particular on the role of cholesterol/lipoprotein-related pathways in these disorders. The research team employs a combination of genetic, pharmacological, behavioral, pathological, electrophysiological, and transcriptomic/proteomic/prenylomic approaches to address basic and clinical questions. Current research projects in Dr. Li's laboratory include: the role of cholesterol, isoprenoids, protein prenylation and related small GTPases in regulating synaptic plasticity and cognitive function in Alzheimer’s disease; structure and function of high-density lipoproteins (HDL) and associated apolipoproteins including APOA-I, APOE, and APOJ (clusterin); the therapeutic potential of HDL-mimetic peptides to rescue lipidation deficiency associated with APOE4 and to enhance cerebrovascular function and cognitive performance in aging and in Alzheimer’s disease; and modeling and reversing Alzheimer’s pathology in human iPSC-derived brain organoids. Other research projects in Dr. Li's laboratory investigate the role of systemic and neuro-inflammation in aging and in Alzheimer’s disease and the therapeutic potential of natural and synthetic anti-inflammatory compounds for Alzheimer’s disease. The long-term goal of the Li lab research is to unravel the complexity of the pathogenic process of dementia and develop effective approaches to prevent/mitigate cognitive decline and other comorbidities associated with aging and Alzheimer’s disease.

Research Interests

• Alzheimer’s disease
• Atherosclerosis
• Insulin resistance and diabetes
• Isoprenoids and protein prenylation
• Cholesterol and lipoproteins
• Inflammation
• Learning and memory
• Synaptic plasticity

Research Projects

• Cholesterol, isoprenoids, and related pharmacological interventions in Alzheimer’s disease
• Role of obesity, insulin resistance, and diabetes in the development of AD and therapeutic potential of anti-diabetic drugs for AD.
• Structure and function of HDL and its associated proteins and therapeutic potential of HDL-mimetic peptides in atherosclerosis and AD.
• Role of systemic and neuro-inflammation in the development of Alzheimer’s disease

Research Funding Grants

Current Research Funding Grants

• NIH/NIA RO1 AGO58081 Grant Award (PI), 2018-2023

• NIH/NIA RF1 AG05697601 Grant Award (PI), 2017-2022

• NIH/NIA R21 AG056025 Grant Award (PI), 2017-2019

• Grant-in-Aid, Office of the Vice President for Research (Co-PI), UMN, 2016-2018

Past Research Funding Grants
• Translational Tech and Resources (TTR) Grant (PI), UMN, 2016-2017
• GAP Grant Program (PI), College of Pharmacy, UMN, 2015-2017
• Alzheimer’s Drug Discovery Foundation (ADDF) Research Grant (PI), 2013-2016
• Faculty Research Development Grant Award (PI), AHC, UMN, 2014-2016
• Wallin Neurosci Discovery Program Grant (Co-I), 2015-2016
• Fesler-Lampert Chair in Aging Studies Grant (PI), 2015-2016
• Engebretson/Bighley Drug Design & Dev Grant (PI), College of Pharmacy, UMN, 2013-2015
• Grant-in-Aid, Office of the Vice President for Research (PI), UMN, 2013-2015
• Faculty Research Development Grant Award (PI), AHC, UMN, 2011-2012
• Alzheimer’s Disease Research Award (PI) – American Health Assistance Foundation, 2010-2012
• Investigator Initiated Research Award (PI) – Alzheimer’s Association, 2009-2012
• NIH/NHLBI P01 HL34343 Grant Award (Co-PI of Project 1), 2008-2010
• NIH/NIA R01 AG031846 Grant Award (PI), 2008-2013
• Philanthropic Research Award (PI) – Lowder Foundation, 2006-2011
• Investigator Initiated Research Award (PI) – Alzheimer’s Association, 2005-2008
• NIH/NIA R21 AG025949 Grant Award (PI), 2005-2008
• Career Development Research Award (PI) – American Fed for Aging Research, 2004-2007
• Grant-in-Aid Research Award (PI) – American Heart Association, 2004-2007
• NIH/NHLBI P01 HL34343 Grant Award (Core Director and Co-PI of Proj. 1), 2002-2007
• New Investigator Research Award (PI) – Alzheimer’s Association, 2000-2002

Qu W, Suazo KF, Liu W, Cheng S, Jeong A, Hottman D, Yuan LL, Distefano MD, Li L. Neuronal Protein Farnesylation Regulates Hippocampal Synaptic Plasticity and Cognitive Function. Mol Neurobiol. 2021 Mar;58(3):1128-1144. PMID: 33098528 PMCID: PMC7880878.

Suazo KF, Jeong A, Ahmadi M, Brown C, Qu W, Li L, Distefano M. Metabolic labeling with an alkyne probe reveals similarities and differences in the prenylomes of multiple brain-derived cell lines. Sci Rep. 2021 Feb 23;11(1):4367. PMID: 33623102 PMCID: PMC7902609.

Qu W, Li L. Loss of TREM2 confers resilience to age-related synaptic and cognitive decline. J Neurosci. 2020 Dec 9;40(50):9552-9563. PMID: 33139402 PMCID: PMC7726534.

Chernick D, Zhong R, Li L. The role of HDL and HDL mimetic peptides as potential therapeutics for Alzheimer’s disease. Invited review/feature paper. Biomolecules. 2020 Sep 4;10(9):E1276. PMID: 32899606 PMCID: PMC7563116.

Swaminathan SK, Zhou AL, Ahlschwede KM, Curran GL, Lowe VJ, Li L, Kandimalla KK. HDL mimetic peptide 4F efficiently crosses the blood-brain barrier and modulates amyloid beta distribution between brain and plasma. J Pharmacol Exp Ther. 2020 Nov;375(2):308-316. PMID: 32778535 PMCID: PMC7589947.

Chernick D, Ortiz-Valle S, Jeong A, Qu W, Li L. Peripheral versus central nervous system APOE in Alzheimer's disease: Interplay across the blood-brain barrier. Neurosci Lett 2019 Aug 24;708:134306. Epub 2019 Jun 7. PMID:31181302 PMCID: PMC6693948.

Crane A, Aravalli RN, Asakura A, Krishnan VD, Carlson DF, Cheeran MCJ, Danczyk G, Dutton JR, Hackett PB, Hu WS, Li L, Lu WC, Miller ZD, O’Brien TD, Panoskaltsis-Mortari A, Parr AM, Pearce C, Ruiz-Estevez M, Shiao M, Sipe C, Toman NG, Voth J, Xie H, Steer CJ, Low WC. Interspecies Organogenesis for Human Transplantation. Cell Transplantation. 2019 Sep-Oct;28(9-10):1091-1105. PMID: 31426664 PMCID: PMC6767879.

Zhou AL, Swaminathan SK, Curran GL, Poduslo JF, Lowe VJ, Li L, Kandimalla KK. Apolipoprotein A-I crosses the blood-brain barrier through clathrin-independent and cholesterol-mediated endocytosis. J Pharmacol Exp Ther. 2019 Jun;369(3):481-488. PMID: 30971477 PMCID: PMC6538888.

Wu J, Li Y, Schuller RM, Li L, Litmeyer A, Bein G, Sachs UJ, Bayat B. The nonconservative CD177 single‐nucleotide polymorphism c.1291G>A is a genetic determinant for human neutrophil antigen‐2 atypical/low expression and deficiency. Transfusion. 2019 May;59(5):1836-1842. PMID: 30828823 PMCID: PMC6499709.

Li D, Huang F, Zhao Y, Villata PW, Griffin TJ, Zhang L, Li L, Yu F. Plasma lipoproteome in Alzheimer's disease: A proof-of-concept study. Clin Proteomics. 2018 Sep 20;15:31. PMID: 30250409 PMCID: PMC6147047

Chernick D, Ortiz-Valle S, Jeong A, Swaminathan SK, Kandimalla KK, Rebeck GW, Li L. High-density lipoprotein mimetic peptide 4F mitigates amyloid-β-induced inhibition of apolipoprotein E secretion and lipidation in primary astrocytes and microglia. J Neurochem. 2018 Dec;147(5):647-662. doi: 10.1111/jnc.14554.

Heuss ND, Pierson MJ, Roehrich H, McPherson SW, Gram, AL, Li L, Gregerson DS. Optic nerve as a source of activated retinal microglia post-injury. Acta Neuropathol Commun. 2018 Jul 23;6(1):66. PMID: 30037353 PMCID: PMC6055350.

Suazo KF, Hurben AK, Liu K, Xu F, Thao P, Sudheer C, Li L, Distefano M. Metabolic Labeling of Prenylated Proteins Using Alkyne-Modified Isoprenoid Analogues. Curr Protoc Chem Biol. 2018 Sep;10(3):e46. PMID: 30058775 PMCID: PMC6158066.

Jeong A, Suazo KF, Wood G, Distefano M, Li L.Isoprenoids and Protein Prenylation: Implications in the Pathogenesis and Therapeutic Intervention of Alzheimer’s Disease. Crit Rev Biochem Mol Biol. 2018 Jun;53(3):279-310. PubMed PMID: 29718780

Hottman D, Cheng S, Gram A, LeBlanc K, Yuan L, Li L.Systemic or Forebrain Neuron Specific Deficiency of Geranylgeranyltransferase-1 Impairs Synaptic Plasticity and Reduces Dendritic Spine Density. Neuroscience. 2018 Mar 1;373:207-217.PMID: 29406266 PMCID: PMC5816690

Cheng S, Wani WY, Hottman DA, Jeong A, Cao D, LeBlanc KJ, Saftig P, Zhang J, Li L. Haplodeficiency of Cathepsin D does not affect cerebral amyloidosis and autophagy in APP/PS1 transgenic mice. J Neurochem. 2017 Jul;142(2):297-304.

Li D, Thomas R, Tsai MY, Li L, Vock DM, Greimel S, Yu F. Vascular biomarkers to predict response to exercise in Alzheimer's disease: the study protocol. BMJ Open. 2016 Dec 30;6(12):e011054. PMID: 28039287 PMCID: PMC5223628

Palsuledesai CC, Ochocki JD, Kuhns MM, Wang YC, Warmka JK, Chernick DS, Wattenberg EV, Li L, Arriaga EA, Distefano MD. Metabolic Labeling with an Alkyne-modified Isoprenoid Analog Facilitates Imaging and Quantification of the Prenylome in Cells. ACS Chem Biol. 2016 Oct 21;11(10):2820-2828; PMID: 27525511 PMCID: PMC5074897

Wu J, Li L. Autoantibodies in Alzheimer's disease: potential biomarkers, pathogenic roles, and therapeutic implications. J Biomed Res. 2016 Sep;30(5):361-372. PMID: 27476881 PMCID: PMC5044708

Segrest JP, Jones MK, Catte A, Manchekar M, Datta G, Zhang L, Zhang R, Li L, Patterson JC, Palgunachari MN, Oram JF, Ren G. Surface density-induced pleating of a lipid monolayer drives nascent high density lipoprotein assembly. Structure 2015 Jul 7; 23(7):1214-26. PMID: 26095027 PMCID: PMC4496276

Li Y, Mair DC, Schuller RM, Li L, Wu J. Genetic mechanism of human neutrophil antigen 2 deficiency and expression variations. PLOS Genetics. 2015; 11(5):e1005255. PMID: 26024230 PMCID: PMC4449163

Wood WG, Li L, Muller WE, Eckert GP. Cholesterol as a Causative Factor in Alzheimer Disease: A Debatable Hypothesis. J Neurochem. 2014; 129(4):559-72. PMID: 24329875 PMCID: PMC3999290

Parent M, Hottman DA, Cheng S, Zhang W, McMahon LL, Yuan L, Li L. Simvastatin Treatment Enhances NMDAR-Mediated Synaptic Transmission by Upregulating the Surface Distribution of the GluN2B Subunit. Cell Mol Neurobiol. 2014; 34(5):693-705. PMID: 24687455 PMCID: PMC4142643

Hottman DA, Li L. Protein Prenylation and Synaptic Plasticity: Implications for Alzheimer’s Disease. Mol Neurobiol. 2014 Aug; 50(1):177-85. PMID: 24390573 PMCID: PMC4082763

Hottman DA, Chernick D, Cheng S, Wang Z, Li L. HDL and Cognition in Neurodegenerative Disorders. Neurobiol Dis. 2014; 72:22-36. PMID: 25131449 PMCID: PMC4252583

Cheng S, LeBlanc K, Li L. Triptolide preserves cognitive function and reduces neuropathology in a mouse model of Alzheimer’s disease. PLOS One. 2014; 9(10): e108845. PMID: 25275487 PMCID: PMC4183525

Chen Y, Peng Y, Che, P, Gannon M, Liu Y, Li L, Bu G, van Groen T, Jiao, K, Wang Q. 2A adrenergic receptor promotes amyloidogenesis through disrupting APP-SorLA interaction. Proc Nat Acad Sci USA. 2014 Dec 2;111(48):17296-301. PMID: 25404298 PMCID: PMC4260556

Cheng S, Cao D, Hottman DA, Yuan L, Bergo MO, Li L. Farnesyltransferase Haplodeficiency Reduces Neuropathology and Rescues Cognitive Function in a Mouse Model of Alzheimer's Disease. J Biol Chem 2013; 288(50):35952–35960. PMCID: PMC3861644

Li L, Zhang W, Cheng S, Cao D, Parent M. Isoprenoids and Related Pharmacological Interventions: Potential Application in Alzheimer's Disease. Mol Neurobiol. 2012; 46:64–77.

Kou J, Song M, Pattanayak A, Lim JE, Yang J, Cao D, Li L, Fukuchi K. Combined treatment of A immunization with statin in a mouse model of Alzheimer’s disease. J Neuroimmunol. 2012;244(1-2):70-83.

Mans RA, McMahon L, Li L. Simvastatin-mediated enhancement of long-term potentiation is driven by farnesyl-pyrophosphate depletion and inhibition of farnesylation. Neuroscience 2012; 202:1-9.

Li L, Li S, Jones MK, Segrest JP. Rotational and hinge dynamics of discoidal high density lipoproteins probed by interchain disulfide bond formation. 2011. Biochimica Biophysica Acta 2012; 1821(3):481-9.

Akhter H, Katre A, Li L, Liu X, Liu RM. Therapeutic potential and anti-amyloidosis mechanisms of tert-butylhydroquinone for Alzheimer’s disease. J Alzheimers Dis 2011; 26(4):767-78.

Jones MK, Gu F, Catte A, Li L, Segrest JP. ""Sticky"" and “Promiscuous”—the Yin and Yang of Apolipoprotein A-I Termini in Discoidal High Density Lipoproteins: A Combined Computational-Experimental Approach. Biochemistry 2011; 50(12):2249-63. PMCID: PMC3119339

Liu RM, van Groen T, Katre A, Cao D, Kadisha I, Ballinger C, Carroll, SL, Wang L, Li L. Knockout of plasminogen activator inhibitor 1 gene reduces amyloid beta peptide burden in a mouse model of Alzheimer's disease. Neurobiol Aging 2011, 32(6):1079-89. PMCID: PMC2888674

Lewis T, Cao D, Lu H, Mans RA, Su YR, Jungbauer L, Linton MF, Fazio S, LaDu MJ, Li L. Overexpression of human apolipoprotein A-I preserves cognitive function and attenuates neuroinflammation and cerebral amyloid angiopathy in a mouse model of Alzheimer's disease. J Biol Chem 2010; 285(47):36958-68. PMCID: PMC2978624

Jones MK, Zhang L, Catte A, Li L, Oda M, Ren G, Segrest JP. Assessment of the Validity of the Double Super Helix Model for Reconstituted High Density Lipoproteins: A combined computational-experimental approach. J Biol Chem 2010; 285(52):41161-71. PMCID: PMC3003414

Kou J, Kim HD, Jin J, Cao D, Li L, Lalonde R, Fukuchi KI. Simvastatin enhances immune responses to Abeta vaccination and attenuates vaccination-induced behavioral alterations. Brain Res. 2010;1356:102-11. PMCID: PMC2943023

Mans RA, Chowdhury N, Cao D, McMahon L, Li L. Simvastatin enhances hippocampal long-term potentiation in C57BL/6 mice. Neuroscience 2010; 166:435-44. PMCID: PMC2824052

Gu F, Jones MK, Chen J, Catte A, Patterson JC, Jerome WG, Li L, Segrest JP. Structures of discoidal high density lipoproteins: a combined computational-experimental approach. J Biol Chem. 2010;285(7):4652-65. PMCID: PMC2836071

Jones MK, Catte A, Li L, Segrest JP. Dynamics of Activation of Lecithin:Cholesterol Acyltransferase by Apolipoprotein A-I. Biochemistry 2009; 48:11196-210. PMCID: PMC2814595

Handattu SP, Garber DW, Monroe CC, van Groen T, Kadish I, Nayyar G, Cao D, Palgunachari MN, Li L, Anantharamaiah GM. Oral apolipoprotein A-I mimetic peptide improves cognitive function and reduces amyloid burden in a mouse model of Alzheimer's disease. Neurobiol Dis. 2009; 34:525-534.

Jones MK, Catte A, Patterson JC, Gu F, Chen J, Li L, Segrest JP. Thermal Stability of Apolipoprotein A-I in High Density Lipoproteins by Molecular Dynamics. Biophys J. 2009; 96:354-71. PMCID: PMC2716522

Li L, Cao D, Desmond R, Rahman A, Lah JJ, Levey AI, Zamrini E. Cognitive performance and plasma levels of homocysteine, vitamin B12, folate, and lipids in patients with Alzheimer’s disease. Dement Geriatr Cogn Disord. 2008; 26:384-390. PMCID: PMC2679366

Li L, Weng W, Fisher EA. Plasma carboxyl ester lipase activity modifies apoB-lipoprotein composition and turnover but has no effect on atherosclerosis in a transgenic mouse model. Metabolism. 2008; 57:1361-68. PMCID: PMC2587065

Jin J, Kim H, Maxwell JA, Li L, Fukuchi K. Toll-like receptor 4-dependent upregulation of cytokines in a transgenic mouse model of Alzheimer's disease. J Neuroinflammation 2008; 5:23. PMCID: PMC2430555

Cao D, Lu H, Lewis TL, Li L. Intake of Sucrose-Sweetened Water Induces Insulin Resistance and Exacerbates Memory Deficits and Amyloidosis in a Transgenic Mouse Model of Alzheimer’s Disease. J Biol Chem. 2007; 282: 36275-36282.

Wavrant-De Vrieze F, Compton D, Womick M, Arepalli S, Adighibe O, Li L, Perez-Tur J, Hardy J. ABCA1 polymorphisms and Alzheimer's disease. Neurosci Lett. 2007; 416:180-3. PMCID: PMC1945126

Li L, Cao D, Kim H, Fukuchi K, Lester R. Simvastatin enhances learning and memory independent of amyloid load in mice. Annals Neurol. 2006; 60:729-39.

Tahara K, Kim HD, Jin J, Maxwell JA, Li L, Fukuchi K. Role of toll-like receptor signalling in Abeta uptake and clearance. Brain. 2006; 129:3006-19. PMCID: PMC2445613

Cao D, Fukuchi K, Wan H, Kim H, Li L. Lack of LDL receptor aggravates learning deficits and amyloid deposits in Alzheimer transgenic mice. Neurobiol Aging. 2006;27(11):1632-43.

Silva GD, Hilliard GM, Li L, Segrest JP, Davidson WS. Dimeric Apolipoprotein A-I in Discoidal High Density Lipoproteins Forms a “Double Belt” Conformation. Biochemistry. 2005; 44:8600-8607.

Li L, Chen J, Mishra V, Kurtz J, Cao D, Klon AE, Harvey SC, Anantharamaiah GM, Segrest JP. Double Belt Structure of Discoidal High Density Lipoproteins: Molecular Basis for Size Heterogeneity. J Mol Biol. 2004; 343(5):1293-1311.

Fukuchi K, Katsuya T, Sugimoto K, Kuremura M, Kim H, Li L, Ogihara T. LMNA Mutation in a 45-Year Old Japanese with Hutchinson-Gilford Progeria Syndrome. J Med Genet. 2004;41(5):e67.

Fukuchi K, Hart M, Yan Z, Hassell JR, Li L. Transgenic Mice Overexpressing both Amyloid beta-Protein and Perlecan in Pancreatic Acinar Cells. Histol Histopathol. 2004;19(3):845-52.

Li L, Cao D, Garber DW, Kim H, Fukuchi K. Association of Aortic Atherosclerosis with Cerebral beta-Amyloidosis and Learning Deficits in a Mouse Model of Alzheimer’s Disease. Amer J Pathol. 2003; 163:2155-64. PMCID: PMC1892402