15 research outputs found
Quadruple abnormal protein aggregates in brainstem pathology and exogenous metal-rich magnetic nanoparticles (and engineered Ti-rich nanorods). The substantia nigrae is a very early target in young urbanites and the gastrointestinal tract a key brainstem portal
Fine particulate air pollution (PM2.5) exposures are linked with Alzheimer's and Parkinson's diseases (AD,PD). AD and PD neuropathological hallmarks are documented in children and young adults exposed lifelong to Metropolitan Mexico City air pollution; together with high frontal metal concentrations (especially iron)–rich nanoparticles (NP), matching air pollution combustion- and friction-derived particles. Here, we identify aberrant hyperphosphorylated tau, ɑ synuclein and TDP-43 in the brainstem of 186 Mexico City 27.29 ± 11.8y old residents. Critically, substantia nigrae (SN) pathology seen in mitochondria, endoplasmic reticulum and neuromelanin (NM) is co-associated with the abundant presence of exogenous, Fe-, Al- and Ti-rich NPs.The SN exhibits early and progressive neurovascular unit damage and mitochondria and NM are associated with metal-rich NPs including exogenous engineered Ti-rich nanorods, also identified in neuroenteric neurons. Such reactive, cytotoxic and magnetic NPs may act as catalysts for reactive oxygen species formation, altered cell signaling, and protein misfolding, aggregation and fibril formation. Hence, pervasive, airborne and environmental, metal-rich and magnetic nanoparticles may be a common denominator for quadruple misfolded protein neurodegenerative pathologies affecting urbanites from earliest childhood. The substantia nigrae is a very early target and the gastrointestinal tract (and the neuroenteric system) key brainstem portals. The ultimate neural damage and neuropathology (Alzheimer's, Parkinson's and TDP-43 pathology included) could depend on NP characteristics and the differential access and targets achieved via their portals of entry. Thus where you live, what air pollutants you are exposed to, what you are inhaling and swallowing from the air you breathe,what you eat, how you travel, and your occupational longlife history are key. Control of NP sources becomes critical. © 2020 Elsevier Inc
Combustion- and friction-derived magnetic air pollution nanoparticles in human hearts
Air pollution is a risk factor for cardiovascular and Alzheimer's disease (AD). Iron-rich, strongly magnetic, combustion- and friction-derived nanoparticles (CFDNPs) are abundant in particulate air pollution. Metropolitan Mexico City (MMC) young residents have abundant brain CFDNPs associated with AD pathology. We aimed to identify if magnetic CFDNPs are present in urbanites' hearts and associated with cell damage. We used magnetic analysis and transmission electron microscopy (TEM) to identify heart CFDNPs and measured oxidative stress (cellular prion protein, PrPC), and endoplasmic reticulum (ER) stress (glucose regulated protein, GRP78) in 72 subjects age 23.8 ± 9.4y: 63 MMC residents, with Alzheimer Continuum vs 9 controls. Magnetite/maghemite nanoparticles displaying the typical rounded crystal morphologies and fused surface textures of CFDNPs were more abundant in MMC residents' hearts. NPs, ∼2–10 × more abundant in exposed vs controls, were present inside mitochondria in ventricular cardiomyocytes, in ER, at mitochondria-ER contact sites (MERCs), intercalated disks, endothelial and mast cells. Erythrocytes were identified transferring ‘hitchhiking’ NPs to activated endothelium. Magnetic CFDNP concentrations and particle numbers ranged from 0.2 to 1.7 μg/g and ∼2 to 22 × 109/g, respectively. Co-occurring with cardiomyocyte NPs were abnormal mitochondria and MERCs, dilated ER, and lipofuscin. MMC residents had strong left ventricular PrPC and bi-ventricular GRP78 up-regulation. The health impact of up to ∼22 billion magnetic NPs/g of ventricular tissue are likely reflecting the combination of surface charge, ferrimagnetism, and redox activity, and includes their potential for disruption of the heart's electrical impulse pathways, hyperthermia and alignment and/or rotation in response to magnetic fields. Exposure to solid NPs appears to be directly associated with early and significant cardiac damage. Identification of strongly magnetic CFDNPs in the hearts of children and young adults provides an important novel layer of information for understanding CVD pathogenesis emphasizing the urgent need for prioritization of particulate air pollution control
Genome Degradation in Brucella ovis Corresponds with Narrowing of Its Host Range and Tissue Tropism
Brucella ovis is a veterinary pathogen associated with epididymitis in sheep. Despite its genetic similarity to the zoonotic pathogens B. abortus, B. melitensis and B. suis, B. ovis does not cause zoonotic disease. Genomic analysis of the type strain ATCC25840 revealed a high percentage of pseudogenes and increased numbers of transposable elements compared to the zoonotic Brucella species, suggesting that genome degradation has occurred concomitant with narrowing of the host range of B. ovis. The absence of genomic island 2, encoding functions required for lipopolysaccharide biosynthesis, as well as inactivation of genes encoding urease, nutrient uptake and utilization, and outer membrane proteins may be factors contributing to the avirulence of B. ovis for humans. A 26.5 kb region of B. ovis ATCC25840 Chromosome II was absent from all the sequenced human pathogenic Brucella genomes, but was present in all of 17 B. ovis isolates tested and in three B. ceti isolates, suggesting that this DNA region may be of use for differentiating B. ovis from other Brucella spp. This is the first genomic analysis of a non-zoonotic Brucella species. The results suggest that inactivation of genes involved in nutrient acquisition and utilization, cell envelope structure and urease may have played a role in narrowing of the tissue tropism and host range of B. ovis
Iron-rich air pollution nanoparticles:An unrecognised environmental risk factor for myocardial mitochondrial dysfunction and cardiac oxidative stress
Exposure to particulate air pollution is a major environmental risk factor for cardiovascular mortality and morbidity, on a global scale. Both acute and chronic cardiovascular impacts have so far been attributed to particulate-mediated oxidative stress in the lung and/or via 'secondary' pathways, including endothelial dysfunction, and inflammation. However, increasing evidence indicates the translocation of inhaled nanoparticles to major organs via the circulation. It is essential to identify the composition and intracellular targets of such particles, since these are likely to determine their toxicity and consequent health impacts. Of potential major concern is the abundant presence of iron-rich air pollution nanoparticles, emitted from a range of industry and traffic-related sources. Bioreactive iron can catalyse formation of damaging reactive oxygen species, leading to oxidative stress and cell damage or death. Here, we identify for the first time, in situ, that exogenous nanoparticles (~15-40 nm diameter) within myocardial mitochondria of young, highly-exposed subjects are dominantly iron-rich, and co-associated with other reactive metals including aluminium and titanium. These rounded, electrodense nanoparticles (up to ~ 10 x more abundant than in lower-pollution controls) are located within abnormal myocardial mitochondria (e.g. deformed cristae; ruptured membranes). Measurements of an oxidative stress marker, PrP C and an endoplasmic reticulum stress marker, GRP78, identify significant ventricular up-regulation in the highly-exposed vs lower-pollution controls. In shape/size/composition, the within-mitochondrial particles are indistinguishable from the iron-rich, combustion- and friction-derived nanoparticles prolific in roadside/urban environments, emitted from traffic/industrial sources. Incursion of myocardial mitochondria by inhaled iron-rich air pollution nanoparticles thus appears associated with mitochondrial dysfunction, and excess formation of reactive oxygen species through the iron-catalyzed Fenton reaction. Ventricular oxidative stress, as indicated by PrP C and GRP78 up-regulation, is evident even in children/young adults with minimal risk factors and no co-morbidities. These new findings indicate that myocardial iron overload resulting from inhalation of airborne, metal-rich nanoparticles is a plausible and modifiable environmental risk factor for cardiac oxidative stress and cardiovascular disease, on an international scale
Reduced repressive epigenetic marks, increased DNA damage and Alzheimer's disease hallmarks in the brain of humans and mice exposed to particulate urban air pollution
Exposure to air pollutants is associated with an increased risk of developing Alzheimer's disease (AD). AD pathological hallmarks and cognitive deficits are documented in children and young adults in polluted cities (e.g. Metropolitan Mexico City, MMC). Iron-rich combustion- and friction-derived nanoparticles (CFDNPs) that are abundantly present in airborne particulate matter pollution have been detected in abundance in the brains of young urbanites. Epigenetic gene regulation has emerged as a candidate mechanism linking exposure to air pollution and brain diseases. A global decrease of the repressive histone post-translational modifications (HPTMs) H3K9me2 and H3K9me3 (H3K9me2/me3) has been described both in AD patients and animal models. Here, we evaluated nuclear levels of H3K9me2/me3 and the DNA double-strand-break marker γ-H2AX by immunostaining in post-mortem prefrontal white matter samples from 23 young adults (age 29 ± 6 years) who resided in MMC (n = 13) versus low-pollution areas (n = 10). Lower H3K9me2/me3 and higher γ-H2A.X staining were present in MMC urbanites, who also displayed the presence of hyperphosphorylated tau and amyloid-β (Aβ) plaques. Transmission electron microscopy revealed abundant CFDNPs in neuronal, glial and endothelial nuclei in MMC residents' frontal samples. In addition, mice exposed to particulate air pollution (for 7 months) in urban Santiago (Chile) displayed similar brain impacts; reduced H3K9me2/me3 and increased γ-H2A.X staining, together with increased levels of AD-related tau phosphorylation. Together, these findings suggest that particulate air pollution, including metal-rich CFDNPs, impairs brain chromatin silencing and reduces DNA integrity, increasing the risk of developing AD in young individuals exposed to high levels of particulate air pollution
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Alzheimer and Parkinson diseases, frontotemporal lobar degeneration and amyotrophic lateral sclerosis overlapping neuropathology start in the first two decades of life in pollution exposed urbanites and brain ultrafine particulate matter and industrial nanoparticles, including Fe, Ti, Al, V, Ni, Hg, Co, Cu, Zn, Ag, Pt, Ce, La, Pr and W are key players. Metropolitan Mexico City health crisis is in progress
The neuropathological hallmarks of Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS) are present in urban children exposed to fine particulate matter (PM2.5), combustion and friction ultrafine PM (UFPM), and industrial nanoparticles (NPs). Metropolitan Mexico City (MMC) forensic autopsies strongly suggest that anthropogenic UFPM and industrial NPs reach the brain through the nasal/olfactory, lung, gastrointestinal tract, skin, and placental barriers. Diesel-heavy unregulated vehicles are a key UFPM source for 21.8 million MMC residents. We found that hyperphosphorylated tau, beta amyloid1-42, α-synuclein, and TAR DNA-binding protein-43 were associated with NPs in 186 forensic autopsies (mean age 27.45 ± 11.89 years). The neurovascular unit is an early NPs anatomical target, and the first two decades of life are critical: 100% of 57 children aged 14.8 ± 5.2 years had AD pathology; 25 (43.9%) AD+TDP-43; 11 (19.3%) AD + PD + TDP-43; and 2 (3.56%) AD +PD. Fe, Ti, Hg, Ni, Co, Cu, Zn, Cd, Al, Mg, Ag, Ce, La, Pr, W, Ca, Cl, K, Si, S, Na, and C NPs are seen in frontal and temporal lobes, olfactory bulb, caudate, substantia nigra, locus coeruleus, medulla, cerebellum, and/or motor cortical and spinal regions. Endothelial, neuronal, and glial damages are extensive, with NPs in mitochondria, rough endoplasmic reticulum, the Golgi apparatus, and lysosomes. Autophagy, cell and nuclear membrane damage, disruption of nuclear pores and heterochromatin, and cell death are present. Metals associated with abrasion and deterioration of automobile catalysts and electronic waste and rare earth elements, i.e., lanthanum, cerium, and praseodymium, are entering young brains. Exposure to environmental UFPM and industrial NPs in the first two decades of life are prime candidates for initiating the early stages of fatal neurodegenerative diseases. MMC children and young adults—surrogates for children in polluted areas around the world—exhibit early AD, PD, FTLD, and ALS neuropathological hallmarks forecasting serious health, social, economic, academic, and judicial societal detrimental impact. Neurodegeneration prevention should be a public health priority as the problem of human exposure to particle pollution is solvable. We are knowledgeable of the main emission sources and the technological options to control them. What are we waiting for? Copyright © 2024 Calderón-Garcidueñas, Stommel, Torres-Jardón, Hernández-Luna, Aiello-Mora, González-Maciel, Reynoso-Robles, Pérez-Guillé, Silva-Pereyra, Tehuacanero-Cuapa, RodrÃguez-Gómez, Lachmann, Galaz-Montoya, Doty, Roy and Mukherjee.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]
Neuroinflammation, hyperphosphorylated tau, diffuse amyloid plaques, and down-regulation of the cellular prion protein in air pollution exposed children and young adults
Air pollution exposures have been linked to neuroinflammation and neuropathology. Autopsy samples of the frontal cortex from control (n = 8) and pollution-exposed (n = 35) children and young adults were analyzed by RT-PCR (n = 43) and microarray analysis (n = 12) for gene expression changes in oxidative stress, DNA damage signaling, NFκB signaling, inflammation, and neurodegeneration pathways. The effect of apolipoprotein E (APOE) genotype on the presence of protein aggregates associated with Alzheimer's disease (AD) patholog