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Brain iron accumulation in neurodegenerative disorders: Does air pollution play a role?

Award Number: F30AG102058
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/21/2027
PERIOD OF PERFORMANCE END DATE: 01/20/2028

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Brain iron accumulation in neurodegenerative disorders: Does air pollution play a role? - Abstract Epidemiological evidence links air pollution (AP) to neurodegenerative disorder risk, both Alzheimer’s disease (AD) and Parkinson’s disease (PD). Neurodegeneration is characterized by elevated brain iron (Fe) or “Fe Overload”. What has yet to be considered is the contribution of AP-derived inhaled Fe to Fe Overload and neurodegeneration. AP is a dynamic and complex mixture of gases and particulate matter (PM), with the latter including organic and metallic contaminants, specifically Fe. Ambient Fe concentrations are around 0.1-0.2 ug/m3, but Fe can reach extremely high levels in U.S. subways (329 µg/m3). These small Fe oxides are 30-50 nm in diameter and pose unique health risks because the small size allows direct translocation into brain and large surface area to volume ratio allows for greater reactivity. Our studies show that real-world ultrafine particle (UFP) exposures, which include Fe, produce brain metal dyshomeostasis, alterations in myelination, and ventriculomegaly. Our overarching hypothesis is that AP-derived Fe-oxides contribute to Fe overload, Fe dyshomeostasis, and neurotoxicity seen in neurodegenerative disorders. Our preliminary data show Fe inhalation (mostly Fe3O4) elevates tau and hyperphosphorylated tau, a key AD biomarker, in female mouse hippocampus and frontal cortex, with concomitant deficits in memory assays. Fe exposed male mice show motor deficits and MRI-based volume changes in substantia nigra. MRI data also indicate sex-dependent diffusivity differences, suggesting white matter changes. Human MRI studies indicate sex-dependent white matter development can underlie sex-dependent effects of AP on the largest white matter tract in the brain, the corpus callosum (CC). Our previous studies have repeatedly revealed that CC development is sensitive to UFP exposures with metal composition, sex, and age at exposure influencing UFP-induced hyper or hypo- myelination. New technologies (small animal MRI) will allow us, for the first time, to evaluate AP induced macrostructural white matter damage, while simultaneously evaluating concomitant ultra- and micro-structural axonal damage via transmission electron microscopy (TEM) and immunohistochemistry (IHC). This technology will allow these endpoints to be evaluated in the same animals. These data will inform how nanoparticles damage axonal myelin and how myelin damage and repair can influence macrostructural white matter tracts and MRI diffusivity measures. These data are translationally relevant as MRI human cohort studies have begun to utilize AP modeling to evaluate risk. We predict that Fe oxide transport along axons results in ultra, micro, and macrostructural white matter damage. To test these predictions, Aim 1 will utilize MRI to quantify diffusivity changes followed by TEM and IHC to correlate ultra- and micro-structural myelin changes. Aim 2 will investigate anosmia, a prodromal feature of neurodegenerative disorders, to help translate the white matter damage to functional loss. Our data will help identify if and how Fe oxides increase sex-dependent neurodegenerative risk.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $55,114 )
2026	2026	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Aging Research	000	1	7/21/2026	NEW	$55,114
														Subtotal = $55,114

Grand Total All Awards = $55,114

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Brain iron accumulation in neurodegenerative disorders: Does air pollution play a role?

Award Number: F30AG102058

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/21/2027

PERIOD OF PERFORMANCE END DATE: 01/20/2028

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