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Principal Investigator: Marissa Sobolewski Terry
Organization: UNIVERSITY OF ROCHESTER
Fiscal Year: 2024
Award: $1,625,947
Funding agency: National Institute of Neurological Disorders and Stroke
A hallmark of Alzheimer’s Disease (AD) is regional brain “iron (Fe) overload”. We hypothesize that life-
long exposure to inhaled Fe via air pollution (AP) is a contributor to elevated brain Fe and AD risk. In support of
this hypothesis, AP has been linked to increased risk for AD with fine particulate matter (PM2.5) associated with
increased risk for dementia, reduced memory, processing speed and increased cognitive impairment, PM2.5
exposures include ultrafine particles and metal contaminants. Of the many redox active metals/trace element
pollutants in AP, Fe is often found at the highest concentrations. Studies examining Fe in frontal cortex of AD
brains reported an abundant presence of magnetite (Fe2+/Fe3+ iron oxide) nanoparticles, consistent with an
exogenous exposure rather than endogenous Fe source. It is critical to note that metal contaminants in AP are
not borne equally by everyone. Low socioeconomic status (SES) communities show the highest AP and metal
contamination levels (Fe - top percentiles ~0.135 µg/m3). In fact, neighborhood-level SES measures associate
with memory and dementia risk. Further support for differential risk and the need to investigate inhaled Fe toxicity comes from the subway systems where Fe levels range 1000 x higher, from 141±81 to 329±116 µg/m3. These
“ambient” and “subway” level concentrations provide the rationale for our experiments evaluating the link
between inhaled Fe and neurodegenerative risk. Our preliminary data in mice demonstrates that inhaled Fe at
“Subway” concentrations (~135 µg/m3) increases brain corpora amylacea, elevates phosphorylated tau protein
levels, and results in female-specific hippocampal reductions and memory deficits. (AIM 1). We will evaluate
whether AD-associated phenotypes arise at lower, closer to ambient Fe level exposures (1.35 µg/m3) and
evaluate a time course of prodromal progression seen in AD studies, while differentiating between exogenous
inhaled Fe from endogenous Fe. (AIM 2) Further escalating risk in these communities, poverty-related stress is
characterized by a largely uncontrollable set of conditions, comprising a major risk factor for cognitive decline.
Higher perceived stress is associated with increased risk for mild cognitive impairment, and two or more stressful
life events increases risk for all-cause dementia. We predict that “ambient” Fe and deprived environments with
uncontrollable stress exposures will result in AD neuropathology and memory loss, similar to higher “Subway”
exposures. (AIM 3) We additionally predict that, conversely, enrichment with controllable stress will improve
memory and ameliorate deficits associated with “Subway’ level Fe inhalation. These outcomes will derive from
shared biological effects on oxidative stress and ferroptosis, with consequently increased neuroinflammation,
reactive astrogliosis with white matter damage and neuronal loss. This research will inform public health policy
and prevention to improve quality of life by mitigating cognitive and memory loss. Moreover, these studies
advance our mechanistic understanding of how co-occurring environmental stressors, with shared biological
consequences, can converge to enhance risk.
Terms: <21+ years old><AD dementia><Acceleration><Adult><Adult Human><Air Pollution><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer risk factor><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's brain><Alzheimer's disease brain><Alzheimer's disease risk><Alzheimers Dementia><Amentia><Ammon Horn><Amyloid (Aβ) plaques><Amyloid Plaques><Astrocytes><Astrocytus><Astroglia><Autoregulation><Behavior Conditioning Therapy><Behavior Modification><Behavior Therapy><Behavior Treatment><Behavioral><Behavioral Conditioning Therapy><Behavioral Modification><Behavioral Therapy><Behavioral Treatment><Biological><Biometals><Blood - brain barrier anatomy><Blood-Brain Barrier><Blue Body><Brain><Brain Nervous System><Brain region><Caring><Characteristics><Cognitive Discrimination><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Communities><Complex Mixtures><Conditioning Therapy><Cornu Ammonis><Corpora amylacea><Data><Dementia><Deposit><Deposition><Development><Diameter><Discrimination><Disproportionate number of females><Disproportionate number of women><Disproportionately affects females><Disproportionately affects women><Disproportionately impacts females><Disproportionately impacts women><Disproportionately in females><Disproportionately in women><Disturbance in cognition><Economic Income><Economical Income><Elderly><Elements><Encephalon><Environment><Epidemiology><Exposure to><Fe element><Fe metabolism><Fe overload><Fe oxide><Female><Food><Gases><Gender Bias><Glutamates><Grant><Health Policy><Hemato-Encephalic Barrier><Hippocampus><Homeostasis><Hortega cell><Housing><Impaired cognition><Impoverished><Income><Inhalation><Inhaling><Iron><Iron Overload><L-Glutamate><Lead><Link><Lipid Peroxidation><MT-bound tau><Measures><Mediating><Medical><Memory><Memory Deficit><Memory Loss><Memory impairment><Metals><Mice><Mice Mammals><Microglia><Murine><Mus><Neighborhoods><Nerve Cells><Nerve Degeneration><Nerve Unit><Neural Cell><Neuritic Plaques><Neurocyte><Neuron Degeneration><Neurons><Outcome><Oxidation-Reduction><Oxidative Stress><PM0.1><PM2.5><Particulate><Pb element><Peripheral><Phenotype><Physiological Homeostasis><Play><Population><Poverty><Prevention><Primary Senile Degenerative Dementia><Proteins><Psychologic Stress><Psychological Stress><Psychosocial Stress><Public Health><QOL><Quality of life><Redox><Reporting><Research><Risk><Risk Factors><Role><Senile Plaques><Sex Bias><Socio-economic status><Socioeconomic Status><Source><Stress><Stressful Event><Subway><System><Testing><Time><Toxic effect><Toxicities><Trace Elements><Trace Mineral><Ultrafine Particulates><Unemployment><Work><adulthood><advanced age><air contaminant><alzheimer risk><amyloid beta plaque><amyloid-b plaque><astrocytic glia><astrogliosis><aβ plaques><behavior intervention><behavior outcome><behavioral intervention><behavioral outcome><biologic><bloodbrain barrier><brain Fe><brain iron><cerebral Fe><cerebral iron><cognitive dysfunction><cognitive loss><colcothar><cored plaque><dementia risk><design><designing><developmental><diffuse plaque><disease phenotype><disparity in health><environment enrichment><environment enrichment for laboratory animals><environmental enrichment><environmental enrichment for laboratory animals><environmental stresses><environmental stressor><epidemiologic><epidemiological><experience><experiment><experimental research><experimental study><experiments><female bias><female preponderance><ferric oxide><fine particles><fine particulate matter><frontal cortex><frontal lobe><geriatric><gitter cell><glutamatergic><health care policy><health disparity><healthcare policy><heavy metal Pb><heavy metal lead><hippocampal><improved><incomes><iron in the brain><iron metabolism><iron oxide><jobless><joblessness><life span><lifespan><low SES><low socio-economic position><low socio-economic status><low socioeconomic position><low socioeconomic status><magnetite><magnetite ferrosoferric oxide><memory decline><memory dysfunction><mesoglia><meter><microglial cell><microgliocyte><microtubule bound tau><microtubule-bound tau><mild cognitive disorder><mild cognitive impairment><mouse model><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><nerve cell death><nerve cell loss><neural degeneration><neural inflammation><neurobiological mechanism><neurodegeneration><neurodegenerative><neuroinflammation><neuroinflammatory><neurological degeneration><neuron cell death><neuron cell loss><neuron death><neuron loss><neuron toxicity><neuronal><neuronal cell death><neuronal cell loss><neuronal death><neuronal degeneration><neuronal loss><neuronal toxicity><neuropathologic><neuropathological><neuropathology><neurotoxicity><olfactory bulb><out of work><oxidation reduction reaction><p-tau><p-τ><particle><perceived stress><perception of stress><perivascular glial cell><phospho-tau><phospho-τ><phosphorylated tau><pollutant><post-translational modification of tau><posttranslational modification of tau><prevent><preventing><primary degenerative dementia><processing speed><psychosocial stresses><psychosocial stressors><red iron oxide><resilience><resilient><risk factor for dementia><risk for dementia><risk mitigation><scaffold><scaffolding><segregation><self-reported stress><senile dementia of the Alzheimer type><senior citizen><social role><socio-economic position><socioeconomic position><stress perception><stressful experience><stressful life event><stressful life experience><stressor><tau><tau Proteins><tau factor><tau phosphorylation><tau posttranslational modification><tau-1><ultrafine particle><ultrafine particulate matter><unemployed><white matter damage><women's preponderance><τ Proteins><τ phosphorylation>