# Age-sex-ApoE allele interactions in neuronal and white matter vulnerability to air pollution

> **NIH NIH P01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $322,531

## Abstract

Project 3 Abstract: Caleb Finch, with Todd Morgan and Christian Pike
Age-Sex-ApoE Allele Interactions in White Matter Vulnerability to Air Pollution.
To reviewers: new text is italicized. Accelerated cognitive aging is strongly associated with air pollution fine-
sized particulate matter (PM2.5u) in two recent reports of community-living elderly 1, 2). Besides cognitive
deficits and loss of white matter, the WHIMS cohort incurred higher risk of dementia (Project 1).
 In mouse models, nano-sized PM (nPM) from traffic-related air pollution (TRAP-nPM) is pro-
amyloidogenic. In our experimental model, mice receive whole body exposure to TRAP-nPM for 150 hours
intermittently during 10 weeks (Core C2). Besides brain-wide inflammatory responses, TRAP-nPM causes
selective damage to hippocampal CA1 myelinated neurons (Fig. 4) that are most vulnerable in AD and to
cerebrovascular ischemia. Because AD risk is elevated in women, particularly in apoE4 carriers, we propose to
study age-sex-ApoE allele interactions in the vulnerability of myelinated pathways to nPM using EFAD mice.
We also examine the blood-brain barrier (BBB), which shows greater age-related leakiness in human ApoE4
carriers. New data show that nPM increases activity in a TLR4 inflammatory pathway that mediates post-
ischaemic neurodegeneration. We hypothesize that TRAP increases AD risk by TLR4-related inflammatory
processes that synergize with CA1-specific hippocampal neurodegenerative mechanisms.
Aim 1 (refocused): Age and sex in brain susceptibility of C57BL/6 (B6) mice to nPM. Both sexes of B6 mice will
be exposed to nPM at ages 2 mo, 10, and 18 mo, spanning reproductive senescence. We will assay
hippocampus mediated learning and hippocampal subregional analysis of myelin degeneration and neuron
atrophy. Microglial and TLR4-TNFα pathway responses will be evaluated by immunohistochemistry and
Western blots. Cerebrovascular and white matter tract responses to nPM exposure is assessed in Core B2 by
in vivo multiphoton imaging for regional CBF and BBB permeability and angiography. DTI-MRI at 80µm
isotropic spatial resolution will provide fractional anisotropy maps for white matter connectivity. BBB cellular
integrity is assessed by confocal microscopy. Collaboration with Project 4 examines B6 brains for synergies of
nPM with chronic cerebral hypoperfusion (CCH).
Aim 2: Age-Sex-ApoE allele interactions in EFAD mouse responses to nPM. The Aim 1 parameters of age and
sex for hippocampal-mediated learning and neurodegeneration in hippocampal subfields are examined in
EFAD mice. Cerebrovascular amyloid and microbleeds will be evaluated in EFAD mice. We hypothesize that
nPM will show female bias in accelerating AD changes.
Aim 3 (major revisions): Role of TLR4. A new mouse model with inducible macrophage/microglial-
specificTLR4 knockout (i-mTLR4-ko) will evaluate TLR4 contributions to nPM-induced myelin degeneration
and neurite atrophy. This new model will identify targets of TLR4 pathway componen...

## Key facts

- **NIH application ID:** 9969325
- **Project number:** 5P01AG055367-03
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** CALEB E FINCH
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $322,531
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9969325

## Citation

> US National Institutes of Health, RePORTER application 9969325, Age-sex-ApoE allele interactions in neuronal and white matter vulnerability to air pollution (5P01AG055367-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9969325. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*