Ling Li, D.V.M., Ph.D
Associate Professor
Primary Department Affiliation: Medicine
Primary Research Area: Neurodegeneration and Neurodegenerative Disorders
Learning, Memory, and Synaptic Plasticity
Recent Publications
Research Interests
My research interests are focused on the connections between cardiovascular disease and Alzheimer's disease (AD) using molecular, cellular, electrophysiological, and transgenic animal technologies. Other research interests relate to the structure and function of apolipoproteins. Current research activities in my laboratory include:
1. Investigation on the role of dietary and/or genetically induced hypercholesterolemia in the development of AD-type neuropathology and behavior in transgenic mouse models of AD. AD patients develop deposits of amyloid-b protein (Ab) in the brain. Overproduction of Ab is thought to cause AD while heart disease is often caused by atherosclerosis, for which one of the major risk factors is hypercholesterolemia. Using animal models, we have shown that diet-induced hypercholesterolemia induces atherosclerosis and exacerbates AD-type neuropathology and memory deficits. We also have demonstrated for the first time that overproduction of Ab induces atherosclerosis in the heart as well as Ab deposits in the brain. In addition, the degree of atherosclerosis is positively correlated with that of amyloid deposits. Our experimental data suggest that AD and atherosclerosis share causative mechanisms and support the concept that anti-heart disease therapies may be effective in prevention and treatment of AD.
2. Potential application of cholesterol-lowering drugs such as statins in the prevention and treatment of Alzheimer's disease and other age-related dementia. Recent studies from my lab show that statin treatment improves cognitive performance of AD model mice. The induction and maintenance of long-term potentiation (LTP) in the hippocampus is widely considered to be the basis for memory formation and storage. Electrophysiological and biochemical studies are underway to elucidate the cellular and molecular mechanisms by which cholesterol-lowering drugs enhance learning and memory.
3. Role of sugar-induced obesity and insulin resistance in the development of Alzheimer's disease. Obesity resulting from overeating is a major modifiable risk factor for cardiovascular disease and type 2 diabetes, and recently for AD as well. High fat diets have been shown to accelerate the development of AD-type neuropathology and cognitive impairment in transgenic mouse models of AD. Whether excess consumption of simple sugars as in calorically sweetened beverages with an otherwise normal diet affects the development of AD has not been investigated experimentally. We hypothesize that long-term excess intake of simple sugars especially in a liquid form exacerbates AD-type cognitive impairment and neuropathology independent of dietary fat and cholesterol intake. In a recent study, we found that sucrose in drinking water induces insulin resistance, impairs learning and memory, and exacerbates cerebral amyloidosis in a mouse model of AD. Further studies are underway to elucidate the underlying cellular and molecular mechanisms.
4. Structure and function of apolipoprotein A-I. Apolipoprotein (apo) A-I, an integral component of high-density lipoproteins (HDL), is highly elastic in its structure. The unique structural properties of human apoA-I/HDL give rise to a wide range of functions including reverse cholesterol transport, anti-oxidation, anti-inflammation, and immune modulation, resulting in protection against heart disease. Emerging evidence indicates that the role of apoA-I/HDL is not limited to the cardiovascular system. Although apoA-I is produced predominantly in the liver and the intestine, it is generally thought that plasma apoA-I can cross the blood-brain barrier into the brain. We are studying the potential role of apoA-I/HDL in the development of Alzheimer's disease.
Selected Recent Publications
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 Vrièze F, Compton D, Womick M, Arepalli S, Adighibe O, Li L, Pérez-Tur J, Hardy J. ABCA1 polymorphisms and Alzheimer's disease. Neurosci Lett. 2007; 416:180–183.
Li L, Cao D, Kim H, Lester R, Fukuchi K. 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 signaling in Ab uptake and clearance. Brain. 2006; 129:3006-19.
Catte A, Patterson JC, Jones MK, Jerome WG, Bashtovyy D, Su Z, Gu F, Chen J, Aliste MP, Harvey SC, Li L, Weinstein G, Segrest JP. Novel changes in discoidal high density lipoprotein morphology: a molecular dynamics study. Biophys J. 2006; 90:4345-60.
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; 27:1632-1643.
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 CM, Chung BH, Presley JB, Malek G, Zhang X, Dashti N, Li L, Chen J, Bradley K, Kruth HS, Curcio CA. Lipoprotein-like Particles and Cholesteryl Esters in Human Bruch's Membrane: Initial Characterization. Invest Ophthalmol Vis Sci. 2005;46:2576–2586.
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; 343:1293-1311.
Fukuchi K, Hart M, Yan Z, Hassell JR, Li L. Transgenic Mice Overexpressing both amyloid beta-protein and perlecan in pancreatic acinar cells. Histol and Histopathol. 2004; 19:845-52.
Fukuchi1 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:e67.
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. Am J Pathol. 2003;163:2155-64.
Compton D, Wavrant DeVriéze F, Petersen RC, Tangalos E, Li L, Hardy J. Possible Association between Genetic Variability at the Apo(a) Locus and Alzheimer's Disease in ApoE2 carriers, Neuroscience Letters, 2002; 331:60-2.
Hart M, Li L, Tokunaga T, Lindsey JR, Snow AD, Hassell JR, Fukuchi K. Overproduction of perlecan core protein in cultured cells and transgenic mice. J Pathol. 2001; 194:262-269.
Fukuchi K, Li L, Lindsey JR. Amyloid deposition in exocrine glands of transgenic mice overexpressing the C-terminus of human b-amyloid precursor protein. Int J Exp Path 2000; 81:231-239.
Hobbies
Outside of work Dr. Li enjoys activities with her family, playing table tennis (Ping-Pong), badminton, tennis and volleyball.
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