# Glymphatic impairment as a crucial factor in particulate matter exposure related development of Alzheimer's disease pathology > **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2024 · $731,256 ## Abstract Environmental toxicants and, more specifically, exposure to ambient particulate matter (PM) air pollution increases the risk of developing Alzheimer's Disease (AD) and AD-Related Dementias (ADRD). Yet, our current understanding of the mechanisms by which PM exposure augments the progression of ADRD-related pathology and cognitive impairment is very limited. We posit that airborne ultrafine particles (UFP, <100 nm diameter) are causally related to the development or progression of AD/ADRD. The glymphatic pathway is emerging as a key to maintaining brain health and its dysfunction is implicated in several neurological disorders. This glial- dependent clearance pathway is dedicated to draining soluble waste proteins and its existence has been documented in the brain of multiple species, including humans. The proposal is based on preliminary studies showing that exposure to model UFP significantly suppresses glymphatic fluid transport and increases the β amyloid load in a murine model of AD pathology. We hypothesize that airborne UFP are transported to the brain upon inhalation exposure and cause both systemic and neuroinflammation, thus either indirectly or directly impairing glymphatic fluid flow and accelerating AD/ADRD-like pathology and behavioral deficits in a mouse model of AD. The proposed aims will test our hypothesis by addressing the following questions: Aim 1: How does short (3 days) or repeated (3 months intermittent) exposure to UFP affect glymphatic fluid transport and cognitive performance in young (3 months) and aged (15 months) wildtype mice? Aim 2: Can glymphatic impairment resulting from UFP exposure change the progression of Aβ deposition in a murine AD/ADRD model? Aim 3: Will UFP accumulate and interact with cells along the major glymphatic fluid transport segments? We will here use high-resolution analytical scanning transmission electron microscopy to analyze precisely where in the brain parenchyma the UFP accumulate and interact. Aim 4: We will explore the molecular mechanisms of UFP exposure-related glymphatic impairment and pathological progression in a murine AD/ADRD model via pharmacological inhibition of adrenergic signaling. Moreover, a detailed study of AQP4 vascular polarization response to air particulate matter exposure, sleep disruption and how do adrenergic inhibition reverse these signatures of pathology, would also be explored? The innovative aspects of the proposal build upon a unique multidisciplinary approach where expertise in particulate matter toxicology (Elder), basic and applied chemistry with particular focus on the study of UFP in living systems (Graham), neurobiology of diseases and regenerative mechanisms (Hussain), and fundamentals of waste products and metabolites clearance (Nedergaard), will be combined to address the question if and how do UFP enter, distribute, accumulate, and ultimately undergo bioprocessing and efflux from the brain. The proposed experiments represent the first fundamental an... ## Key facts - **NIH application ID:** 10909296 - **Project number:** 5R01AG083020-02 - **Recipient organization:** UNIVERSITY OF ROCHESTER - **Principal Investigator:** Alison Elder - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $731,256 - **Award type:** 5 - **Project period:** 2023-09-01 → 2028-05-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10909296 ## Citation > US National Institutes of Health, RePORTER application 10909296, Glymphatic impairment as a crucial factor in particulate matter exposure related development of Alzheimer's disease pathology (5R01AG083020-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10909296. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*