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Principal Investigator: Sarah EV Richards
Organization: BROAD INSTITUTE, INC.
Fiscal Year: 2020
Award: $425,000
Funding agency: National Institute on Aging
Aging-related neurological diseases impact millions people worldwide, and this number is expected to increase
drastically as the global average age continues to increase. While the need to develop new neuroprotective
therapeutics has never been higher, our current efforts rely on only a partial understanding of the molecular,
cellular, and circuit mechanism that drive changes in the aging brain. One such change is increased oxidative
stress arising partially from the brain’s high metabolic needs and exacerbated by brain enrichment of oxidation-catalyzing transition metals and incorporation of peroxidation-sensitive polyunsaturated fatty acid (PUFA)
species into phospholipid membranes. Accumulation of peroxidized lipids results in membrane damage and
ferroptosis, an iron-dependent, non-apoptotic mode of cell death. Our preliminary data suggest that neurons,
astrocytes, and microglia are susceptible to ferroptosis, whereas oligodendrocytes are resistant. However, the
mechanisms regulating differential susceptibility to ferroptosis in these cell types remain unknown.
One possible connection between ferroptosis and neurodegeneration is apolipoprotein E (apoE), the primary
lipid and cholesterol transport protein of the central nervous system (CNS). APOE gene variants modulate the
probability of developing neurodegenerative disease, with each apoE4 allele conferring an approximately 2-fold
increase in risk for late-onset Alzheimer’s disease compared the more common apoE3 allele. In contrast, the
apoE2 variant is enriched in cognitively-intact elders. While many characteristics differentiate apoE4 from the
other isoforms, including decreased protein stability and altered lipid transport, no one mechanism is considered
responsible for increased risk of neurodegeneration in apoE4 carriers. Recent work shows that apoE mediates
transfer of peroxidation-sensitive fatty acids from neurons to astrocytes during periods of enhanced neuronal
activity, suggesting that deficient capacity for lipid transport could lead to accumulation of these potentially toxic
species in neurons. Interestingly, our preliminary data suggest that astrocytes expressing apoE3 may be
protected against some forms of ferroptosis compared to apoE knockout astrocytes, but that this susceptibility
can be rescued by exogenous application of plasma high density lipoproteins (HDL).
We propose to validate our initial findings using primary culture of CNS cells. Because interactions among cell
types in the brain are critical for modeling of brain lipid metabolism, we will use organotypic slice culture to
investigate the impact of apoE isoform on ferroptosis sensitivity. To characterize how isoform-dependent
differences in apoE-lipid interactions impact CNS ferroptosis sensitivity, we will complex apoE to purified plasma
HDL and test how these particles impact ferroptosis sensitivity. Lastly, we will identify the lipid species conferring
resistance to ferroptosis in our preliminary data by constructing apoE lipoprotein nanoparticles containing
individual HDL lipid species and testing their function in cellular assays of ferroptosis sensitivity.
Terms: <APOE e4><APOE-ε4><APOEε4><Acquired brain injury><Age><Aging><Albumins><Alleles><Allelomorphs><Apo-E><ApoE><Apolipoprotein E><Astrocytes><Astrocytus><Astroglia><Automobile Driving><Blood Plasma><Brain><Brain Diseases><Brain Disorders><Brain Injuries><Brain Nervous System><CNS Nervous System><Carrier Proteins><Cell Body><Cell Death><Cell Line><CellLine><Cells><Cellular Assay><Central Nervous System><Cessation of life><Characteristics><Chemicals><Cholesterol><Cognitive><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Complex><Data><Death><Degenerative Neurologic Diseases><Degenerative Neurologic Disorders><Detergents><Development><Disease><Disorder><Disturbance in cognition><Elderly><Encephalon><Encephalon Diseases><Fatty Acid Metabolism Pathway><Fatty Acids><Fe element><Gene variant><Genes><Genetic><Genotype><Glia><Glial Cells><Goals><HDL><HDL Lipoproteins><Heavy Lipoproteins><High Density Lipoproteins><High density lipoprotein><Hortega cell><Human><Impaired cognition><In Vitro><Individual><Intracranial CNS Disorders><Intracranial Central Nervous System Disorders><Iron><Isoforms><Knock-out><Knockout><Kolliker's reticulum><Late Onset Alzheimer Disease><Lead><Link><Lipid Peroxidation><Lipid Trafficking><Lipids><Lipoproteins><Measures><Mediating><Mediator><Mediator of Activation><Mediator of activation protein><Membrane><Metabolic><Methods><Mice><Mice Mammals><Microglia><Modeling><Modern Man><Molecular><Monounsaturated Fatty Acids><Murine><Mus><Nerve Cells><Nerve Degeneration><Nerve Unit><Nervous System Degenerative Diseases><Nervous System Diseases><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neuraxis><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neuroglia><Neuroglial Cells><Neurologic Degenerative Conditions><Neurologic Disorders><Neurological Disorders><Neuron Degeneration><Neurons><Neuroprotectants><Neuroprotective Agents><Neuroprotective Drugs><Non-neuronal cell><Nonneuronal cell><Oligodendrocytes><Oligodendrocytus><Oligodendroglia><Oligodendroglia Cell><Oxidative Stress><Oxygen Consumption><Pb element><Peroxides><Phosphatides><Phospholipids><Plasma><Plasma Serum><Polyunsaturated Fatty Acids><Population><Predisposition><Probability><Process><Protein Isoforms><Proteins><Recombinants><Recovery><Reporting><Research><Resistance><Reticuloendothelial System, Serum, Plasma><Risk><Risk Factors><Role><Series><Slice><Strains Cell Lines><Susceptibility><System><Testing><Therapeutic><Time><Transition Elements><Transport Protein Gene><Transport Proteins><Transporter Protein><Variant><Variation><Work><advanced age><age related neurodegeneration><age-related neurodegenerative disease><age-related neurodegenerative disorder><aged brain><ages><aging brain><allele variant><allelic variant><alpha-Lipoproteins><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><astrocytic glia><brain cell><brain damage><brain health><brain-injured><cardiovascular disease risk><cardiovascular disorder risk><cell assay><cell immortalization><cell type><cholesterol transporters><cognitive dysfunction><cognitive loss><cultured cell line><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><developmental><driving><elders><experiment><experimental research><experimental study><fat metabolism><fatty acid metabolism><fatty acid oxidation><genetic variant><genomic variant><geriatric><gitter cell><heavy metal Pb><heavy metal lead><insight><late life><late onset alzheimer><later life><lipid metabolism><lipid transport><membrane structure><mesoglia><microglial cell><microgliocyte><nano particle><nano-sized particle><nanoparticle><nanosized particle><necrocytosis><nerve cement><nervous system disorder><neural circuit><neural circuitry><neural degeneration><neurocircuitry><neurodegeneration><neurodegenerative><neurodegenerative illness><neurological degeneration><neurological disease><neuronal><neuronal degeneration><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel therapeutics><novel therapy><older adult><older person><oxidation><oxidative damage><oxidative injury><particle><perivascular glial cell><peroxidation><resilience><resistant><senior citizen><small molecule><social role><synaptic circuit><synaptic circuitry><tool><transition metal>