# Urban air pollution and cerebral hypoperfusion: aging and sex influences

> **NIH NIH P01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $309,546

## Abstract

Joint Effects of Air Pollution and Cerebral Hypoperfusion: Age and Sex Influence
Emerging evidence suggests a strong association between traffic-related air pollution (TRAP) and cognitive
aging. Clinical and experimental studies demonstrate white matter toxicity and hippocampal neuronal atrophy
in the setting of particulate matter (PM) exposure. Little is known, however, about the underlying
pathophysiology and selective vulnerabilities. Evidence supports a critical role for cerebral vascular dysfunction
in the onset and progression of Alzheimer's disease (AD), with cortical hypoperfusion implicated in the
pathogenesis of neuronal dysfunction and cognitive deficits. Studies have demonstrated increased memory
impairment, hippocampal neuronal loss, and altered Aβ metabolism in APPSwInd and APP overexpressing
mice exposed to chronic cerebral hypoperfusion (CCH). Individuals with AD or cognitive impairment may
demonstrate increased susceptibility to deleterious effects of TRAP exposure through vascular mechanisms.
This program leverages experimental models focused exclusively on the cerebrovascular contributions to AD/
cognitive decline. We hypothesize that nanoparticulate matter (nPM) exposure and CCH exhibit synergistic
effects on neurodegenerative pathways from the entorhinal cortex and hippocampus including the perforant
pathway and diffuse white matter tracts. Age and sex variances are evident in AD prevalence, with older
women most affected. These factors also impact cerebrovascular reserve, ischemic injury response, and BBB
permeability. The proposed project seeks to determine age and sex influences on nPM and CCH exposure
alone, and in combination, through the following specific aims: 1) Examine age dependence for the individual/
joint effects of nPM exposure and CCH on white matter toxicity, hippocampal / entorhinal cortex neuronal
injury, and neurocognition, 2) Examine sex differences in the independent/ joint effects of nPM and CCH on the
above outcomes and, 3) Examine mechanistic pathways by which nPM promotes neurodegenerative
processes in the setting of CCH. The nPM exposure model has been used in our group's prior studies. Near
roadside urban nPM is collected by means of innovative particle samplers developed by the USC Aerosol
group (Sioutas). Whole body exposures are administered. The CCH model has been refined and leveraged to
examine inflammatory mediators and BBB. A factorial design will assess independent and combined effects of
nPM and CCH on white matter toxicity, hippocampal/ entorhinal cortex injury, and neurocognition. When
administered together, we expect these exposures to exhibit synergy. Consistent with AD pathologies, we
expect older female mice to demonstrate greatest vulnerability. We hypothesize that effects are associated
with inflammatory upregulation and BBB permeability. Baseline interactions established in wild type mice and
data from Project 3 will be leveraged to study mechanism in EFAD-Transgenic and inducibl...

## Key facts

- **NIH application ID:** 9969326
- **Project number:** 5P01AG055367-03
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** William J Mack
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $309,546
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9969326

## Citation

> US National Institutes of Health, RePORTER application 9969326, Urban air pollution and cerebral hypoperfusion: aging and sex influences (5P01AG055367-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9969326. Licensed CC0.

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