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Principal Investigator: Ta Yuan CHANG
Organization: DARTMOUTH COLLEGE
Fiscal Year: 2020
Award: $408,373
Funding agency: National Institute on Aging
ABSTRACT of the administrative supplement proposal for the parent grant
“Alleviating lysosomal lipid defects in ADRD by blocking cholesterol storage”
The long-term goal of this laboratory is to produce cholesterol metabolism-based therapeutics to
treat AD and ADRDs. Vascular dementia (VaD), an ADRD, is the second most common form of
dementia after AD in the US. The etiology of VaD is complex, but is closely associated with
dyslipidemia, atherosclerosis, stroke, and diabetes. Atherosclerosis is characterized by
accumulation of cholesterol, cholesteryl esters and other lipids in macrophages and smooth muscle
cells within the arterial walls. Acyl coenzyme A: cholesterol acyltransferase 1 (ACAT1) is an enzyme
that converts cholesterol to cholesterol esters for storage in all cells, including macrophages, smooth
muscle cells, as well as microglia and neurons in the brain. Our laboratory has been working on
ACAT1 for several decades. We and others demonstrated that in mouse models, inhibiting ACAT1
benefit several diseases, including atherosclerosis, diet induced obesity, and AD.
ApoE is a lipoprotein that transports cholesterol and other lipids in the body and in the brain. Apoe3
is the major allele. Apoe4, a minor allele, is a major genetic risk factor for AD; it is also a genetic risk
factor for stroke associated VaD. It is desirable to produce animal models that partially recapitulate
the essential features of VaD, such that candidate drug(s) can be tested at the preclinical level.
However, at present, no mouse model for atherosclerosis associated VaD in ApoE isoform
specific manner is available. To begin to fill this void, in the supplement request, we propose to
produce such a model, and we refer it as the Athero/E3 and Athero/E4 mice.
Compound F is a clinically approved small molecule ACAT1 inhibitor, originally intended to treat
atherosclerosis, but was abandoned because compound F was not as efficient as statin in reducing
serum cholesterol levels in men. Whether F was permeable to blood brain barrier was unknown. We
have developed a nanoparticle platform and showed that F present in this nanoparticle is permeable
to blood brain barrier. We have also shown that after IP injections to mice, nanoparticle F efficiently
inhibited ACAT1 in body cells and in brain cells. In the supplement request, we propose to use
nanoparticle F to treat the Athero/E3 and Athero/E4 mice under Western diet.
Terms: <3-D><3-Dimensional><3D><ACAT><ACAT enzyme><AD related dementia><ADRD><APOE e4><APOE-ε4><APOEε4><Acyl CoA><Acyl Coenzyme A><Acyl-CoA-Cholesterol Acyltransferase><Administrative Supplement><Alleles><Allelomorphs><Alzheimer related dementia><Alzheimer's disease related dementia><Amentia><Animal Model><Animal Models and Related Studies><Apo-E><ApoE><Apolipoprotein E><Apoplexy><Arteriosclerotic Dementia><Atheroscleroses><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Blood - brain barrier anatomy><Blood Serum><Blood-Brain Barrier><Brain><Brain Nervous System><Brain Vascular Accident><Causality><Cell Body><Cells><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Cholesterol><Cholesterol Acyltransferase><Cholesterol Esterifying Enzyme><Cholesterol Esters><Cholesterol Homeostasis><Cholesteryl Esters><Clinical><Complex><Defect><Degenerative Neurologic Diseases><Degenerative Neurologic Disorders><Dementia><Diabetes Mellitus><Diet><Disease><Disorder><Dyslipidemias><Encephalon><Enzyme Gene><Enzymes><Etiology><Fatty Acyl CoA><Goals><Hemato-Encephalic Barrier><Hortega cell><IP injection><Intraperitoneal Injections><Isoforms><Laboratories><Leiomyocyte><Lipids><Lipoprotein (a)><Lipoprotein Lp(a)><Long-Chain Acyl CoA><Lp(a)><Mice><Mice Mammals><Microglia><Minor><Modeling><Murine><Mus><Nerve Cells><Nerve Unit><Nervous System Degenerative Diseases><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neurons><Obesity><Outcome><Permeability><Protein Isoforms><Serum><Smooth Muscle Cells><Smooth Muscle Myocytes><Smooth Muscle Tissue Cell><Sterol O-Acyltransferase><Stroke><Testing><Therapeutic><Vascular Dementia><acyl-CoA cholesterol acyltransferase><adiposity><apo E-3><apo E-4><apo E3><apo E4><apo epsilon4><apoE epsilon 4><apoE-3><apoE-4><apoE3><apoE4><apolipoprotein E epsilon 4><apolipoprotein E-3><apolipoprotein E-4><apolipoprotein E3><apolipoprotein E4><atheromatosis><atherosclerotic disease><atherosclerotic vascular disease><base><bloodbrain barrier><brain attack><brain cell><causation><cerebral vascular accident><cerebrovascular accident><cholesterol metabolism><corpulence><corpulency><corpulentia><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><diabetes><dietary><disease causation><drug candidate><drug detection><drug testing><efficacy testing><genetic risk factor><gitter cell><inherited factor><inhibitor><inhibitor/antagonist><macrophage><men><men's><mesoglia><microglial cell><microgliocyte><model of animal><model organism><mouse model><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><neurodegenerative illness><neuronal><obese><obese people><obese person><obese population><parent grant><perivascular glial cell><pre-clinical><preclinical><small molecule><three dimensional><vascular contributions to dementia><western diet>