Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 147, Issue -, Pages 242-251Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2019.12.023
Keywords
A beta; Lipid raft; Oxidative stress; Air pollutant; Alzheimer's disease; N-acetyl-cysteine (NAC)
Funding
- Cure Alzheimer's Fund
- National Institute on Aging [R21AG050201, R01AG051521, P50AG05142-31]
- National Institute of Environmental Health Sciences (NIEHS) [ES023864]
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Traffic-related air pollution particulate matter (TRAP-PM) is associated with increased risk of Alzheimer Disease (AD). Rodent models respond to nano-sized TRAP-PM (nPM) with increased production of amyloid A beta peptides, concurrently with oxidative damage. Because pro-A beta processing of the amyloid precursor protein (APP) occurs on subcellular lipid rafts, we hypothesized that oxidative stress from nPM exposure would alter lipid rafts to favor A beta production. This hypothesis was tested with J20 mice and N2a cells transgenic for hAPPswe (familial AD). Exposure of J20-APPswe mice to nPM for 150 h caused increased lipid oxidation (4-HNE) and increased the pro-amyloidogenic processing of APP in lipid raft fractions in cerebral cortex; the absence of these changes in cerebellum parallels the AD brain region selectivity for A beta deposits. In vitro, nPM induced similar oxidative responses in N2a-APPswe cells, with dose-dependent production of NO, oxidative damage (4-HNE, 3NT), and lipid raft alterations of APP with increased A beta peptides. The antioxidant N-acetyl-cysteine (NAC) attenuated nPM-induced oxidative damage and lipid raft alterations of APP processing. These findings identify neuronal lipid rafts as novel targets of oxidative damage in the pro-amyloidogenic effects of air pollution.
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