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Journal ArticleDOI

Long-term Air Pollution Exposure Is Associated with Neuroinflammation, an Altered Innate Immune Response, Disruption of the Blood-Brain Barrier, Ultrafine Particulate Deposition, and Accumulation of Amyloid β-42 and α-Synuclein in Children and Young Adults:

TL;DR: Air pollution causes neuroinflammation, an altered brain innate immune response, and accumulation of Aβ42 and α-synuclein starting in childhood, and carriers of the APOE 4 allele could have a higher risk of developing Alzheimer’s disease if they reside in a polluted environment.
Abstract: Air pollution is a serious environmental problem. We investigated whether residency in cities with high air pollution is associated with neuroinflammation/neurodegeneration in healthy children and young adults who died suddenly. We measured mRNA cyclooxygenase-2, interleukin-1beta, and CD14 in target brain regions from low (n = 12) or highly exposed residents (n = 35) aged 25.1 +/- 1.5 years. Upregulation of cyclooxygenase-2, interleukin-1beta, and CD14 in olfactory bulb, frontal cortex, substantia nigrae and vagus nerves; disruption of the blood-brain barrier; endothelial activation, oxidative stress, and inflammatory cell trafficking were seen in highly exposed subjects. Amyloid beta42 (Abeta42) immunoreactivity was observed in 58.8% of apolipoprotein E (APOE) 3/3 < 25 y, and 100% of the APOE 4 subjects, whereas alpha-synuclein was seen in 23.5% of < 25 y subjects. Particulate material (PM) was seen in olfactory bulb neurons, and PM < 100 nm were observed in intraluminal erythrocytes from lung, frontal, and trigeminal ganglia capillaries. Exposure to air pollution causes neuroinflammation, an altered brain innate immune response, and accumulation of Abeta42 and alpha-synuclein starting in childhood. Exposure to air pollution should be considered a risk factor for Alzheimer's and Parkinson's diseases, and carriers of the APOE 4 allele could have a higher risk of developing Alzheimer's disease if they reside in a polluted environment.
Citations
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Journal ArticleDOI
TL;DR: Recent findings detailing the mechanisms through which air pollution reaches the brain and activates the resident innate immune response to become a chronic source of pro-inflammatory factors and ROS, culminating in CNS disease are summarized.

1,085 citations

Journal ArticleDOI
TL;DR: This review provides an overview of air pollution and health, including assessment of exposure, impact on CV outcomes, mechanistic underpinnings, and impact ofAir pollution reduction strategies to mitigate CV risk, and concludes with future challenges.

630 citations


Cites background from "Long-term Air Pollution Exposure Is..."

  • ...Ultrafine particulates, nanomaterials, and ozone may either directly disrupt the blood-brain barrier or result in circulating factors that may influence neuronal function in humans and mice (95,101,126,127)....

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Journal ArticleDOI
TL;DR: This review seeks to give an overview on the variety of health risks air pollution poses with a focus on epidemiological studies to give the reader a comprehensive impression on the large number of health effects of air pollution.
Abstract: ACS,American Cancer Society;AD,Alzheimer’s disease;AMI,acute myocardial infarction;APHEA,air pollution and health effects—a European approach;APHENA,air pollution and health: a European and North A...

581 citations


Cites background or result from "Long-term Air Pollution Exposure Is..."

  • ...Animal models have shown that inhaled or nasally instilled particles translocate into the brain in rodents (Oberdorster et al., 2004) and very recently PM was also identified in the human brain (Calderon-Garciduenas et al., 2008b)....

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  • ...These findings were recently confirmed in further animal studies and also in humans (CalderonGarciduenas et al., 2008a; Calderon-Garciduenas et al., 2008b)....

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  • ...Calderón-Garciduenas et al. (2008c) detected significantly lower levels of sICAM-1 and s-VCAM-1 in children living in Mexico City compared to children living in a less polluted control area....

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  • ...Children from Mexico City, a highly polluted area, also showed no difference in vWF concentrations compared to control children from a cleaner city (Calderon-Garciduenas et al., 2008c)....

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Journal ArticleDOI
TL;DR: This article reviews the current approaches to source apportionment of ambient particles and the latest evidence for their health effects, and describes the current metrics, policies and legislation for the protection of public health from ambient particles.
Abstract: The diversity of ambient particle size and chemical composition considerably complicates pinpointing the specific causal associations between exposure to particles and adverse human health effects, the contribution of different sources to ambient particles at different locations, and the consequent formulation of policy action to most cost-effectively reduce harm caused by airborne particles. Nevertheless, the coupling of increasingly sophisticated measurements and models of particle composition and epidemiology continue to demonstrate associations between particle components and sources (and at lower concentrations) and a wide range of adverse health outcomes. This article reviews the current approaches to source apportionment of ambient particles and the latest evidence for their health effects, and describes the current metrics, policies and legislation for the protection of public health from ambient particles. A particular focus is placed on particles in the ultrafine fraction. The review concludes with an extended evaluation of emerging challenges and future requirements in methods, metrics and policy for understanding and abating adverse health outcomes from ambient particles.

580 citations

Journal ArticleDOI
TL;DR: In this large population-based cohort study, living close to heavy traffic was associated with a higher incidence of dementia, but not with Parkinson's disease or multiple sclerosis.

568 citations

References
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Journal ArticleDOI
TL;DR: Evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the beta-amyloid precursor protein by the protease called gamma-secretase has spurred progress toward novel therapeutics and provided discrete biochemical targets for drug screening and development.
Abstract: Rapid progress in deciphering the biological mechanism of Alzheimer's disease (AD) has arisen from the application of molecular and cell biology to this complex disorder of the limbic and association cortices. In turn, new insights into fundamental aspects of protein biology have resulted from research on the disease. This beneficial interplay between basic and applied cell biology is well illustrated by advances in understanding the genotype-to-phenotype relationships of familial Alzheimer's disease. All four genes definitively linked to inherited forms of the disease to date have been shown to increase the production and/or deposition of amyloid β-protein in the brain. In particular, evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the β-amyloid precursor protein by the protease called γ-secretase has spurred progress toward novel therapeutics. The finding that presenilin itself may be the long-sought γ-...

5,890 citations


"Long-term Air Pollution Exposure Is..." refers background in this paper

  • ...Chronic inflammatory processes in the CNS play an important role in the progressive neuronal death seen in neurodegenerative diseases such as Alzheimer’s (Akiyama et al. 2000; McGeer et al., 2006; Selkoe 2001, 2002)....

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  • ...Both Aβ42 and α-synuclein are proteins capable of aggregation and misfolding, leading to progressive neurodegeneration that develops insidiously over the lifetime of the individual (Jellinger 2003; McGeer et al. 2006; Nguyen et al. 2002; Selkoe 2001, 2002)....

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  • ...Highly exposed subjects also exhibited a significant neuronal and astrocytic accumulation of the 42 amino acid-isoform (Aβ42) of β amyloid, which is more hydrophobic and prone to aggregation than other Aβ isoforms (Selkoe 2001, 2002)....

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Journal ArticleDOI
TL;DR: By better understanding AD inflammatory and immunoregulatory processes, it should be possible to develop anti-inflammatory approaches that may not cure AD but will likely help slow the progression or delay the onset of this devastating disorder.

4,319 citations


"Long-term Air Pollution Exposure Is..." refers background in this paper

  • ..., Tlaxcala); (2) dog necropsies from these cities have shown minimal pathology in lungs and hearts (Calderón-Garcidueñas et al....

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  • ...Exposure to air pollution should be considered a risk factor for Alzheimer’s and Parkinson’s diseases, and carriers of the APOE 4 allele could have a higher risk of developing Alzheimer’s disease if they reside in a polluted environment....

    [...]

  • ...Long-term exposure to air pollution should be considered a risk factor for both Alzheimer’s and Parkinson’s diseases, and APOE ε 4 allele carriers could have a higher risk of developing AD if they reside in a polluted environment....

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  • ...Rupture of the vascular basement membrane and leakage of prothrombin are described in the prefrontal cortex of Alzheimer’s patients (Zipser et al. 2007)....

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  • ...Author to whom requests for reprints should be addressed: William Reed, PhD, Center for Environmental Medicine, Asthma & Lung Biology CB#7310, University of North Carolina at Chapel Hill, 104 Mason Farm Road, Chapel Hill, NC 27599; e-mail: william_reed@med.unc.edu Abbreviations: Aβ42, beta amyloid; AD, Alzheimer’s disease; APO E, apolipoprotein E; APP, amyloid precursor protein; BBB, blood-brain barrier; COX2, cyclooxygenase 2; GFAP, glial fibrillary acidic protein; HLA-DR, human leukocyte antigen-DR; IL-1β, interleukin-1β; ICAM-1, intercellular adhesion molecule-1; IHC, immunohistochemistry; LPS, lipopolysaccharide; MC, Mexico City; MTBE, methyl-ter-butyl ether; NFκB, transcription factor nuclear factor kappa-B; NSE, neuron specific enolase; O3, ozone; OB, olfactory bulb; PD, Parkinson’s disease; PM, particulate matter; PNS, peripheral nervous system; PT, prothrombin; RBC, red blood cells; SNC, substantia nigrae pars compacta; TLR, toll-like receptor; UFPM, ultrafine PM; VCAM-1, vascular adhesion molecule-1; ZO-1, zonula occludens-1....

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Journal ArticleDOI
TL;DR: The evidence for adverse effects on health of selected air pollutants is discussed, and it is unclear whether a threshold concentration exists for particulate matter and ozone below which no effect on health is likely.

4,010 citations


"Long-term Air Pollution Exposure Is..." refers background in this paper

  • ...Exposure to air pollution is associated with respiratory, cardiovascular, and stroke-related sickness and death (Banauch et al. 2006; Brunekreef and Holgate 2002)....

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Journal ArticleDOI
25 Oct 2002-Science
TL;DR: Mounting evidence suggests that this syndrome begins with subtle alterations of hippocampal synaptic efficacy prior to frank neuronal degeneration, and that the synaptic dysfunction is caused by diffusible oligomeric assemblies of the amyloid β protein.
Abstract: In its earliest clinical phase, Alzheimer's disease characteristically produces a remarkably pure impairment of memory. Mounting evidence suggests that this syndrome begins with subtle alterations of hippocampal synaptic efficacy prior to frank neuronal degeneration, and that the synaptic dysfunction is caused by diffusible oligomeric assemblies of the amyloid β protein.

3,941 citations


"Long-term Air Pollution Exposure Is..." refers background in this paper

  • ...Chronic inflammatory processes in the CNS play an important role in the progressive neuronal death seen in neurodegenerative diseases such as Alzheimer’s (Akiyama et al. 2000; McGeer et al., 2006; Selkoe 2001, 2002)....

    [...]

  • ...Both Aβ42 and α-synuclein are proteins capable of aggregation and misfolding, leading to progressive neurodegeneration that develops insidiously over the lifetime of the individual (Jellinger 2003; McGeer et al. 2006; Nguyen et al. 2002; Selkoe 2001, 2002)....

    [...]

  • ...Highly exposed subjects also exhibited a significant neuronal and astrocytic accumulation of the 42 amino acid-isoform (Aβ42) of β amyloid, which is more hydrophobic and prone to aggregation than other Aβ isoforms (Selkoe 2001, 2002)....

    [...]

Journal ArticleDOI
22 Nov 1999-Oncogene
TL;DR: It is argued that NF-κB functions more generally as a central regulator of stress responses and pairing stress responsiveness and anti-apoptotic pathways through the use of a common transcription factor may result in increased cell survival following stress insults.
Abstract: Sixteen years have passed since the description of the nuclear factor-кB (NF-кB) as a regulator of к light-chain gene expression in murine B lymphocytes (Sen & Baltimore, 1986a) During that time, over 4,000 publications have appeared, characterizing the family of Rel/NF-кB transcription factors involved in the control of a large number of normal and pathological cellular processes The physiological functions of NF-кB proteins include immunological and inflammatory responses, developmental processes, cellular growth and modulating effects on apoptosis In addition, these factors are activated in a number of diseases, including cancer, arthritis, acute and chronic inflammatory states, asthma, as well as neurodegenerative and heart diseases

3,728 citations


"Long-term Air Pollution Exposure Is..." refers background in this paper

  • ...NFκB activation depends on varied stimuli such as cytokines, LPS, and DNA damage (Pahl 1999); activation is tightly regulated and quickly shortened through feedback inhibition following the initial activating stimulus (Xiao et al. 2006)....

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