Prior work has associated air pollution with accelerated atherosclerosis and with the incidence of stroke. Moreover, recent epidemiological studies associate air pollution with accelerated cognitive decline of normal aging. Associations with Alzheimer disease are being studied, supported by postmortem findings that humans exposed to extreme urban pollution have premature brain inflammation and deposits of diffuse amyloid-beta (Abeta). Rodent models support these emerging associations of cognitive dysfunctions with air pollution. After exposure to various urban air pollutants, several rodent genotypes show synaptic changes and increased Abeta, as well as induction of TNFa and other inflammatory responses. Our model uses chronic exposure of mice to nano-scale PM (nPM) derived from urban traffic, which shows greater cytotoxicity than larger PM. Under controlled exposure by duration and dose (nPM density), mice show a 30% decrease of the hippocampal GluA1 AMPA receptor subunit, with little change in other AMPA receptor subunits, or in NMDA receptor subunits, while in vitro studies show that nPM exposure increases excitotoxic damage. Because of its role in fast excitatory transmission and in spatial memory, GluA1 decreases could contribute to cognitive decline in association with air pollutants. Another potential link to brain aging involves interactions of AMPA receptor subunits with Abeta. This proposal addresses key gaps in experimental models for epidemiological associations and postmortem findings: the impact of nPM exposure on hippocampal neuronal physiology associated with cognitive processes, and associations of pro-amyloidogenic amyloid precursor protein (APP) processing with GluA1 changes. These studies use C57BL/6 mice of both sexes, because gender effects of air pollution on brain functions are understudied.
Aim 1 : Effects of chronic nPM exposure on hippocampal-dependent learning and cellular correlates. After behavioral testing of chronic nPM exposed mice, hippocampal slices will be analyzed for changes in the AMPA GluA1 vs GluA2 receptor subunits at excitatory Schaffer-collateral hippocampal synapses and in long-term potentiation (LTP). Subcellular fractionation of cortical tissue will address alterations in AMPA receptor trafficking, which regulates synaptic plasticity. The processing of the APP will also be examined in relation to glutamate receptor function.
Aim 2 : Manipulation of APP processing in male mice with two drugs: a novel gamma secretase modulator (BPN-15606) and with memantine to test the role of endogenous Abeta in cognitive changes and down- regulation of GluA1 during chronic in vivo nPM exposure. Indications of glutamatergic involvement in responses to air pollution nPM are relevant to the epidemiological findings of cognitive impairment because of the role of glutamate receptors in learning and memory and because of AMPA receptor sensitivity to Abeta. Findings will enable deeper analysis of synaptotoxic mechanisms of air pollution, which are needed to identify therapeutic neuroprotection and to adjust permissible environmental limits of ultrafine PM.

Public Health Relevance

We are developing a mouse model for the association of air pollution nano-sized particles with cognitive dysfunctions in humans and with the Abeta of Alzheimer disease. These findings will provide further evidence for reviewing the permissible limits of ultrafine airborne particles from fossil fuel combustion.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AG050201-02
Application #
9248851
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Wise, Bradley C
Project Start
2016-04-01
Project End
2018-03-31
Budget Start
2017-04-15
Budget End
2018-03-31
Support Year
2
Fiscal Year
2017
Total Cost
$185,625
Indirect Cost
$73,125
Name
University of Southern California
Department
Type
Other Domestic Higher Education
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90033
Lovett, Christopher; Sowlat, Mohammad H; Saliba, Najat A et al. (2018) Oxidative Potential of Ambient Particulate Matter in Beirut during Saharan and Arabian Dust Events. Atmos Environ (1994) 188:34-42
Woodward, Nicholas C; Pakbin, Payam; Saffari, Arian et al. (2017) Traffic-related air pollution impact on mouse brain accelerates myelin and neuritic aging changes with specificity for CA1 neurons. Neurobiol Aging 53:48-58
Woodward, Nicholas C; Levine, Morgan C; Haghani, Amin et al. (2017) Toll-like receptor 4 in glial inflammatory responses to air pollution in vitro and in vivo. J Neuroinflammation 14:84
Cacciottolo, M; Wang, X; Driscoll, I et al. (2017) Particulate air pollutants, APOE alleles and their contributions to cognitive impairment in older women and to amyloidogenesis in experimental models. Transl Psychiatry 7:e1022