Document text
Principal Investigator: Sarah Cohen
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2024
Award: $571,695
Funding agency: National Institute on Aging
ABSTRACT
Alzheimer’s disease (AD) is one of the predominant causes of disability and dependency among older
people, and the sixth leading cause of death in the United States. Late-onset AD is the most common form,
with more than 99% of AD cases occurring after age 65. The strongest genetic risk factor for developing
late-onset AD is carrying the APOE4 allele. Apolipoprotein E (APOE) is primarily expressed by glial cells in
the brain and is the major protein component of lipoprotein particles secreted by astrocytes and microglia.
Lipoprotein particles provide a bidirectional mechanism of lipid transport between glia and neurons. Many
recent studies suggest that a disequilibrium in nervous system lipids is associated with increased risk of
developing AD. However, the mechanisms by which APOE4 affects cellular lipid homeostasis are
incompletely understood. We recently discovered that in glia, APOE can traffic to cytoplasmic lipid droplets
(LDs) rather than undergoing secretion on lipoprotein particles. We hypothesize that APOE plays previously
unrecognized roles in cellular lipid metabolism by acting directly on LDs in astrocytes and microglia.
Astrocytes play important roles in metabolizing peroxidated lipids, while microglia are the primary innate
immune effector cells of the central nervous system. In Aim 1, we will test the effect of modulating APOE in
astrocytes on cellular lipid composition, metabolism, and lipid peroxidation. In Aim 2, we will test the effect
of modulating APOE in microglia on cellular lipid composition, metabolism, and inflammation. In Aim 3, we
will fill a key knowledge gap by developing a community resource visualizing and quantifying LDs in various
brain regions and cell types in mice of different genotypes and ages. Together, these studies will lead to
new insights about the cellular and molecular mechanism by which expression of APOE4 leads to increased
risk of late-onset AD. This work could also lead to the identification of novel drug targets for preventing and
treating AD.
Terms: <65 and older><65 or older><65 years of age and older><65 years of age or more><65 years of age or older><65+ years><65+ years old><> 65 years><AD dementia><AD related dementia><ADRD><APOE e4><APOE-ε4><APOEε4><Affect><Age><Aged 65 and Over><Alleles><Allelomorphs><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer risk factor><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's and related dementias><Alzheimer's disease and related dementia><Alzheimer's disease and related disorders><Alzheimer's disease or a related dementia><Alzheimer's disease or a related disorder><Alzheimer's disease or related dementia><Alzheimer's disease related dementia><Alzheimer's disease risk><Alzheimers Dementia><Amentia><Amyloidosis><Apo-E><ApoE><ApoE protein><Apolipoprotein E><Area><Astrocytes><Astrocytus><Astroglia><Autoregulation><Brain><Brain Nervous System><Brain region><CNS Nervous System><Cause of Death><Cell Death><Cellular biology><Central Nervous System><Code><Coding System><Communities><Cytoplasm><Data><Data Bases><Data Set><Databases><Dementia><Dependence><Deposit><Deposition><Drug Targeting><Educational workshop><Effector Cell><Encephalon><Endoplasmic Reticulum><Ergastoplasm><Fluorescence Activated Cell Sorting Fractionation><Fluorescence-Activated Cell Sorting><Fluorescence-Activated Cell Sortings><Future><Genetic predisposing factor><Genotype><Glia><Glial Cells><Glycolysis><Homeostasis><Hortega cell><Image><Immune><Immunes><Inflammation><Inflammatory><Innate Immunity><Intermediary Metabolism><Investigation><Isoforms><KO mice><Knock-out Mice><Knockout Mice><Knowledge><Kolliker's reticulum><Late Onset Alzheimer Disease><Lipid Peroxidation><Lipid Trafficking><Lipids><Lipoproteins><Metabolic Processes><Metabolism><Mice><Mice Mammals><Microglia><Microscopy><Molecular><Murine><Mus><Native Immunity><Natural Immunity><Nerve Cells><Nerve Degeneration><Nerve Unit><Nervous System><Neural Cell><Neuraxis><Neurocyte><Neuroglia><Neuroglial Cells><Neurologic Body System><Neurologic Organ System><Neuron Degeneration><Neurons><Non-Specific Immunity><Non-neuronal cell><Nonneuronal cell><Nonspecific Immunity><Null Mouse><Older Population><Pathway interactions><Physiological Homeostasis><Play><Primary Senile Degenerative Dementia><Protein Isoforms><Proteins><Research><Research Resources><Resources><Risk><Role><Surface><Testing><Therapeutic><United States><Visualization><Work><Workshop><above age 65><after age 65><age 65 and greater><age 65 and older><age 65 or older><age > 65><age of 65 years onward><aged 65 and greater><aged 65+><aged brain><aged ≥65><ages><aging brain><alzheimer risk><amyloid disease><apo E-4><apo E4><apo epsilon4><apoE epsilon 4><apoE-4><apoE4><apolipoprotein E epsilon 4><apolipoprotein E-4><apolipoprotein E4><astrocytic glia><brain cell><cell biology><cell type><cytokine><data base><disability><fat metabolism><genetic risk factor><gitter cell><human old age (65+)><imaging><in vivo><inherited factor><insight><lab experience><lab training><laboratory experience><laboratory training><late onset alzheimer><lipid metabolism><lipid transport><mesoglia><microglial cell><microgliocyte><mouse model><murine model><natural aging><necrocytosis><nerve cement><neural degeneration><neurodegeneration><neurodegenerative><neurological degeneration><neuronal><neuronal degeneration><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><normal aging><normative aging><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><old age><older groups><older individuals><older person><over 65 years><particle><pathway><perivascular glial cell><prevent><preventing><primary degenerative dementia><senile dementia of the Alzheimer type><social role><trafficking><≥65 years>