Traffic-related air pollutants (TRAP-PM) promote neuronal amyloidogenesis through oxidative damage to lipid rafts

Cacciottolo, Mafalda; Morgan, Todd E.; Saffari, Arian; Shirmohammadi, Farimah; Forman, Henry Jay; Sioutas, Constantinos; Finch, Caleb E.

doi:10.1016/j.freeradbiomed.2019.12.023

Cited by 60 publications

(53 citation statements)

References 52 publications

(81 reference statements)

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“…Oxidative stress and mitochondrial dysfunction has been reported to occur in diverse cell types exposed to PM [4,42,[44][45][46][47]. Our findings of increased oxidative stress in hOM cells upon PM exposure are in line with published findings in an immortalized nasal epithelial cell line showing increased levels of ROS upon exposure to PM 2.5-1 [48].…”

Section: Discussionsupporting

confidence: 91%

Urban air particulate matter induces mitochondrial dysfunction in human olfactory mucosal cells

et al. 2020

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Background: The adverse effects of air pollutants including particulate matter (PM) on the central nervous system is increasingly reported by epidemiological, animal and post-mortem studies in the last decade. Oxidative stress and inflammation are key consequences of exposure to PM although little is known of the exact mechanism. The association of PM exposure with deteriorating brain health is speculated to be driven by PM entry via the olfactory system. How air pollutants affect this key entry site remains elusive. In this study, we investigated effects of urban size-segregated PM on a novel cellular model: primary human olfactory mucosal (hOM) cells. Results: Metabolic activity was reduced following 24-h exposure to PM without evident signs of toxicity. Results from cytometric bead array suggested a mild inflammatory response to PM exposure. We observed increased oxidative stress and caspase-3/7 activity as well as perturbed mitochondrial membrane potential in PM-exposed cells. Mitochondrial dysfunction was further verified by a decrease in mitochondria-dependent respiration. Transient suppression of the mitochondria-targeted gene, neuronal pentraxin 1 (NPTX1), was carried out, after being identified to be up-regulated in PM 2.5-1 treated cells via RNA sequencing. Suppression of NPTX1 in cells exposed to PM did not restore mitochondrial defects resulting from PM exposure. In contrast, PM-induced adverse effects were magnified in the absence of NPTX1, indicating a critical role of this protein in protection against PM effects in hOM cells. Conclusion: Key mitochondrial functions were perturbed by urban PM exposure in a physiologically relevant cellular model via a mechanism involving NPTX1. In addition, inflammatory response and early signs of apoptosis accompanied mitochondrial dysfunction during exposure to PM. Findings from this study contribute to increased understanding of harmful PM effects on human health and may provide information to support mitigation strategies targeted at air pollution.

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Section: Discussionsupporting

confidence: 91%

Urban air particulate matter induces mitochondrial dysfunction in human olfactory mucosal cells

et al. 2020

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“…Increasing evidence implicates urban air pollution as a contributor to neurodegenerative diseases, such as AD [ 2 , 58 ], but the underlying mechanisms are poorly understood. While studies have demonstrated that urban air pollution induces neuroinflammation and increases oxidative stress [ 11 , 37 , 59 ], little is known about how air pollution regulates these neuroimmune responses. Here, we demonstrate that DE exposure, a model of urban air pollution, impairs expression of TREM2, dysregulates mRNA expression of markers of the DAM phenotype, and reduces microglial association with the neurovasculature.…”

Section: Discussionmentioning

confidence: 99%

“…More specifically, components of urban air pollution are associated not only with pulmonary and cardiovascular diseases, but also with central nervous system (CNS) diseases and conditions, including Alzheimer’s disease (AD) [ 2 – 4 ], cognitive decline [ 5 – 8 ], and dementia [ 9 , 10 ]. Accumulating research with murine models demonstrates that components of air pollution impact the CNS and AD-like pathology [ 11 , 12 ]. However, at present, the mechanisms underlying the link between air pollution and AD remain poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Diesel exhaust impairs TREM2 to dysregulate neuroinflammation

Greve

Mumaw

Messenger

et al. 2020

J Neuroinflammation

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Background Air pollution has been linked to neurodegenerative diseases, including Alzheimer’s disease (AD), and the underlying neuroimmune mechanisms remain poorly understood. TREM2 is a myeloid cell membrane receptor that is a key regulator of disease-associated microglia (DAM) cells, where loss-of-function TREM2 mutations are associated with an increased risk of AD. At present, the basic function of TREM2 in neuroinflammation is a point of controversy. Further, the impact of air pollution on TREM2 and the DAM phenotype is largely unknown. Using diesel exhaust (DE) as a model of urban air pollution exposure, we sought to address its impact on TREM2 expression, the DAM phenotype, the association of microglia with the neurovasculature, and the role of TREM2 in DE-induced neuroinflammation. Methods WYK rats were exposed for 4 weeks to DE (0, 50, 150, 500 μg/m3) by inhalation. DE particles (DEP) were administered intratracheally once (600 μg/mouse) or 8 times (100 μg/mouse) across 28 days to male mice (Trem2+/+, Trem2−/−, PHOX+/+, and PHOX−/−). Results Rats exposed to DE exhibited inverted-U patterns of Trem2 mRNA expression in the hippocampus and frontal cortex, while TREM2 protein was globally diminished, indicating impaired TREM2 expression. Analysis of DAM markers Cx3Cr1, Lyz2, and Lpl in the frontal cortex and hippocampus showed inverted-U patterns of expression as well, supporting dysregulation of the DAM phenotype. Further, microglial-vessel association decreased with DE inhalation in a dose-dependent manner. Mechanistically, intratracheal administration of DEP increased Tnf (TNFα), Ncf1 (p47PHOX), and Ncf2 (p67PHOX) mRNA expression in only Trem2+/+ mice, where Il1b (IL-1β) expression was elevated in only Trem2−/− mice, emphasizing an important role for TREM2 in DEP-induced neuroinflammation. Conclusions Collectively, these findings reveal a novel role for TREM2 in how air pollution regulates neuroinflammation and provides much needed insight into the potential mechanisms linking urban air pollution to AD.

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“…Moreover, the direct exposure allowed us to identify the relative importance of primary anthropogenic and secondary PM, and related sources of emissions, on the effects determined in exposed cells and to find interesting correlation with human biomarkers of exposure [98,100]. Significantly, our approach was performed without complex procedures aimed at replicating airborne PM [101,102]. Despite the intrinsic relevance of direct exposure approaches, the number of papers reporting them is still limited, particularly in relation to the significant number of online monitors required to characterize particles during exposure.…”

Section: Ultrafine Pmmentioning

confidence: 99%

Fifteen Years of Airborne Particulates in Vitro Toxicology in Milano: Lessons and Perspectives Learned

Longhin

Mantecca

Gualtieri

2020

IJMS

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Air pollution is one of the world’s leading environmental causes of death. The epidemiological relationship between outdoor air pollution and the onset of health diseases associated with death is now well established. Relevant toxicological proofs are now dissecting the molecular processes that cause inflammation, reactive species generation, and DNA damage. In addition, new data are pointing out the role of airborne particulates in the modulation of genes and microRNAs potentially involved in the onset of human diseases. In the present review we collect the relevant findings on airborne particulates of one of the biggest hot spots of air pollution in Europe (i.e., the Po Valley), in the largest urban area of this region, Milan. The different aerodynamic fractions are discussed separately with a specific focus on fine and ultrafine particles that are now the main focus of several studies. Results are compared with more recent international findings. Possible future perspectives of research are proposed to create a new discussion among scientists working on the toxicological effects of airborne particles.

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Traffic-related air pollutants (TRAP-PM) promote neuronal amyloidogenesis through oxidative damage to lipid rafts

Cited by 60 publications

References 52 publications

Urban air particulate matter induces mitochondrial dysfunction in human olfactory mucosal cells

Urban air particulate matter induces mitochondrial dysfunction in human olfactory mucosal cells

Diesel exhaust impairs TREM2 to dysregulate neuroinflammation

Fifteen Years of Airborne Particulates in Vitro Toxicology in Milano: Lessons and Perspectives Learned

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