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Education
D.V.M., Yangzhou
Univ. (China), 1982
M.S., Yangzhou Univ. (China) (Experimental Pathology), 1986
Ph.D., Iowa State Univ. (Molecular, Cellular, and Developmental
Biology), 1995
Postdoctoral Research Associate, Rockefeller Univ./Mt. Sinai
Medical Center, 1995-1996
Postdoctoral Fellow, Univ. of Alabama at Birmingham, 1997-1999
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-? protein
(A?) in the brain. Overproduction of A? 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 A? induces atherosclerosis
in the heart as well as A? 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. Preliminary data
from our 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. In a preliminary
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. Therefore,
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. Studies are underway
to test this hypothesis.
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.
Recent
Publications
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.
Dimeric
Apolipoprotein A-I in Discoidal High Density Lipoproteins
Forms a “Double Belt” Conformation. Silva GD,
Hilliard GM, Li L, Segrest JP, Davidson
WS. 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 beta-amyloid precursor protein. Int
J Exp Path 2000; 81:231-239.
Segrest
JP, Li L, Anantharamaiah GM, Harvey SC,
Liadaki KN, Zannis V. Structure and function of apolipoprotein
A-I and high-density lipoprotein. Curr Opinion in Lipidol
2000; 11:105-115.
Li
L, Pham D, Ohman T, Fukuchi K. Analysis of mouse
intron 7 DNA sequence of the APP gene: comparison with the
human homologue. DNA Sequence 1999; 10:219-228.
van
Bennekum AM, Li L, Piantedosi R, Shamir
R, Vogel S, Fisher EA, Blaner WS, Harrison, EH. Carboxyl
ester lipase overexpression in rat hepatoma cells and CEL-deficiency
in mice have no impact on hepatic uptake or metabolism of
chylomicron-retinyl ester. Biochemistry 1999; 38:4150-4156.
Li
L, Weng W, van Bennekum AM, Potter SH, Harrison
EH, Blaner WS, Breslow JL, Fisher EA. Intestinal absorption
of dietary cholesteryl ester is decreased but retinyl ester
absorption is normal in carboxyl ester lipase knockout mice.
Biochemistry 1999; 38:4143-4149.
Fukuchi
K, Pham D, Hart M, Li L, Lindsey JR. Beta-Amyloid
protein deposition in skeletal muscle of transgenic mice:
possible model of inclusion body myopathy. Am J Pathol.
1998; 153:1687-1693.
Li
L, Perry R, Wu J, Pham D, Ohman T, Harrell LE,
Go RCP, Fukuchi K. Polymorphic tetranucleotide repeat site
within the intron 7 of the beta-amyloid precursor protein
gene and its lack of association with Alzheimer’s
disease. Human Genetics 1998; 103:86-89.
Hobbies
Outside
of work Dr. Li enjoys activities with her family, playing
table tennis (Ping-Pong), badminton, tennis and volleyball.
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