Combustion-Derived Nanoparticles, the Neuroenteric System, Cervical Vagus, Hyperphosphorylated Alpha Synuclein and Tau in Young Mexico City Residents

Mexico City (MC) young residents are exposed to high levels of fine particulate matter (PM2.5), have high frontal concentrations of combustion-derived nanoparticles (CDNPs), accumulation of hyperphosphorylated aggregated α-synuclein (α-Syn) and early Parkinson\u27s disease (PD). Swallowed CDNPs have easy access to epithelium and submucosa, damaging gastrointestinal (GI) barrier integrity and accessing the enteric nervous system (ENS). This study is focused on the ENS, vagus nerves and GI barrier in young MC v clean air controls. Electron microscopy of epithelial, endothelial and neural cells and immunoreactivity of stomach and vagus to phosphorylated ɑ-synuclein Ser129 and Hyperphosphorylated-Tau (Htau) were evaluated and CDNPs measured in ENS. CDNPs were abundant in erythrocytes, unmyelinated submucosal, perivascular and intramuscular nerve fibers, ganglionic neurons and vagus nerves and associated with organelle pathology. ɑSyn and Htau were present in 25/27 MC gastric,15/26 vagus and 18/27 gastric and 2/26 vagus samples respectively. We strongly suggest CDNPs are penetrating and damaging the GI barrier and reaching preganglionic parasympathetic fibers and the vagus nerve. This work highlights the potential role of CDNPs in the neuroenteric hyperphosphorylated ɑ-Syn and tau pathology as seen in Parkinson and Alzheimer\u27s diseases. Highly oxidative, ubiquitous CDNPs constitute a biologically plausible path into Parkinson\u27s and Alzheimer\u27s pathogenesis

Intra-city Differences in Cardiac Expression of Inflammatory Genes and Inflammasomes in Young Urbanites: A Pilot Study

Southwest Mexico City (SWMC) air pollution is characterized by high concentrations of ozone and particulate matter < 10 μm (PM10) containing lipopolysaccharides while in the North PM2.5 is high. These intra-city differences are likely accounting for higher CD14 and IL-1β in SWMC v NMC mice myocardial expression. This pilot study was designed to investigate whether similar intra-city differences exist in the levels of myocardial inflammatory genes in young people. Inflammatory mediator genes and inflammasome arrays were measured in right and left autopsy ventricles of 6 southwest/15 north (18.5 ± 2.6 years) MC residents after fatal sudden accidental deaths. There was a significant S v N right ventricle up-regulation of IL-1β (p=0.008), TNF-α (p=0.001), IL-10 (p=0.001), and CD14 (p=0.002), and a left ventricle difference in TNF-α (p=0.007), and IL-10 (p=0.02). SW right ventricles had significant up-regulation of NLRC1, NLRP3 and of 29/84 inflammasome genes, including NOD factors and caspases. There was significant degranulation of mast cells both in myocardium and epicardial nerve fibers. Differential expression of key inflammatory myocardial genes and inflammasomes are influenced by the location of residence. Myocardial inflammation and inflammasome activation in young hearts is a plausible pathway of heart injury in urbanites and adverse effects on the cardiovascular system are expected

Sleep matters: Neurodegeneration spectrum heterogeneity, combustion and friction ultrafine particles, industrial nanoparticle pollution, and sleep disorders—Denial is not an option

Sustained exposures to ubiquitous outdoor/indoor fine particulate matter (PM2.5), including combustion and friction ultrafine PM (UFPM) and industrial nanoparticles (NPs) starting in utero, are linked to early pediatric and young adulthood aberrant neural protein accumulation, including hyperphosphorylated tau (p-tau), beta-amyloid (Aβ1 − 42), α-synuclein (α syn) and TAR DNA-binding protein 43 (TDP-43), hallmarks of Alzheimer's (AD), Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS). UFPM from anthropogenic and natural sources and NPs enter the brain through the nasal/olfactory pathway, lung, gastrointestinal (GI) tract, skin, and placental barriers. On a global scale, the most important sources of outdoor UFPM are motor traffic emissions. This study focuses on the neuropathology heterogeneity and overlap of AD, PD, FTLD, and ALS in older adults, their similarities with the neuropathology of young, highly exposed urbanites, and their strong link with sleep disorders. Critical information includes how this UFPM and NPs cross all biological barriers, interact with brain soluble proteins and key organelles, and result in the oxidative, endoplasmic reticulum, and mitochondrial stress, neuroinflammation, DNA damage, protein aggregation and misfolding, and faulty complex protein quality control. The brain toxicity of UFPM and NPs makes them powerful candidates for early development and progression of fatal common neurodegenerative diseases, all having sleep disturbances. A detailed residential history, proximity to high-traffic roads, occupational histories, exposures to high-emission sources (i.e., factories, burning pits, forest fires, and airports), indoor PM sources (tobacco, wood burning in winter, cooking fumes, and microplastics in house dust), and consumption of industrial NPs, along with neurocognitive and neuropsychiatric histories, are critical. Environmental pollution is a ubiquitous, early, and cumulative risk factor for neurodegeneration and sleep disorders. Prevention of deadly neurological diseases associated with air pollution should be a public health priority

Up-Regulation of mRNA Ventricular PRNP Prion Protein Gene Expression in Air Pollution Highly Exposed Young Urbanites: Endoplasmic Reticulum Stress, Glucose Regulated Protein 78, and Nanosized Particles

Mexico City Metropolitan Area children and young adults exposed to high concentrations of air pollutants including fine and ultrafine particulate matter (PM) vs. clean air controls, exhibit myocardial inflammation and inflammasome activation with a differential right and left ventricular expression of key inflammatory genes and inflammasomes. We investigated the mRNA expression levels of the prion protein gene PRNP, which plays an important role in the protection against oxidative stress and metal toxicity, and the glucose regulated protein 78, a key protein in endoplasmic reticulum (ER) stress signaling, in ventricular autopsy samples from 30 children and young adults age 19.97 ± 6.8 years with a lifetime of low (n:4) vs. high (n:26) air pollution exposures. Light microscopy and transmission electron microscopy studies were carried out in human ventricles, and electron microscopy studies were also done in 5 young, highly exposed Mexico City dogs. There was significant left ventricular PRNP and bi-ventricular GRP78 mRNA up-regulation in Mexico City young urbanites vs. controls. PRNP up-regulation in the left ventricle was significantly different from the right, p < 0.0001, and there was a strong left ventricular PRNP and GRP78 correlation (p = 0.0005). Marked abnormalities in capillary endothelial cells, numerous nanosized particles in myocardial ER and in abnormal mitochondria characterized the highly exposed ventricles. Early and sustained cardiac ER stress could result in detrimental irreversible consequences in urban children, and while highly complex systems maintain myocardial homeostasis, failure to compensate for chronic myocardial inflammation, oxidative and ER stress, and particles damaging myocardial organelles may prime the development of pathophysiological cardiovascular states in young urbanites. Nanosized PM could play a key cardiac myocyte toxicity role

Up-Regulation of mRNA Ventricular PRNP Prion Protein Gene Expression in Air Pollution Highly Exposed Young Urbanites: Endoplasmic Reticulum Stress, Glucose Regulated Protein 78, and Nanosized Particles

Mexico City Metropolitan Area children and young adults exposed to high concentrations of air pollutants including fine and ultrafine particulate matter (PM) vs. clean air controls, exhibit myocardial inflammation and inflammasome activation with a differential right and left ventricular expression of key inflammatory genes and inflammasomes. We investigated the mRNA expression levels of the prion protein gene PRNP, which plays an important role in the protection against oxidative stress and metal toxicity, and the glucose regulated protein 78, a key protein in endoplasmic reticulum (ER) stress signaling, in ventricular autopsy samples from 30 children and young adults age 19.97 ± 6.8 years with a lifetime of low (n:4) vs. high (n:26) air pollution exposures. Light microscopy and transmission electron microscopy studies were carried out in human ventricles, and electron microscopy studies were also done in 5 young, highly exposed Mexico City dogs. There was significant left ventricular PRNP and bi-ventricular GRP78 mRNA up-regulation in Mexico City young urbanites vs. controls. PRNP up-regulation in the left ventricle was significantly different from the right, p < 0.0001, and there was a strong left ventricular PRNP and GRP78 correlation (p = 0.0005). Marked abnormalities in capillary endothelial cells, numerous nanosized particles in myocardial ER and in abnormal mitochondria characterized the highly exposed ventricles. Early and sustained cardiac ER stress could result in detrimental irreversible consequences in urban children, and while highly complex systems maintain myocardial homeostasis, failure to compensate for chronic myocardial inflammation, oxidative and ER stress, and particles damaging myocardial organelles may prime the development of pathophysiological cardiovascular states in young urbanites. Nanosized PM could play a key cardiac myocyte toxicity role

Combustion-Derived Nanoparticles in Key Brain Target Cells and Organelles in Young Urbanites: Culprit Hidden in Plain Sight in Alzheimer’s Disease Development

Millions of children and young adults are exposed to fine particulate matter (PM2.5) and ozone, associated with Alzheimer’s disease (AD) risk. Mexico City (MC) children exhibit systemic and brain inflammation, low cerebrospinal fluid (CSF) Aβ1-42, breakdown of nasal, olfactory, alveolar-capillary, duodenal, and blood-brain barriers, volumetric and metabolic brain changes, attention and short-term memory deficits, and hallmarks of AD and Parkinson’s disease. Airborne iron-rich strongly magnetic combustion-derived nanoparticles (CDNPs) are present in young urbanites’ brains. Using transmission electron microscopy, we documented CDNPs in neurons, glia, choroid plexus, and neurovascular units of young MC residents versus matched clean air controls. CDNPs are associated with pathology in mitochondria, endoplasmic reticulum (ER), mitochondria-ER contacts (MERCs), axons,and dendrites. There is a significant difference in size and numbers between spherical CDNPs (\u3e85%) and the angular, euhedral endogenous NPs (p = 0.002) are present in neurons, glia, choroid plexus, endothelium, nasal and olfactory epithelium, and in CSF at significantly higher in numbers in MC residents (p \u3c 0.0001). Degenerated MERCs, abnormal mitochondria, and dilated ER are widespread, and CDNPs in close contact with neurofilaments, glial fibers, and chromatin are a potential source for altered microtubule dynamics, mitochondrial dysfunction, accumulation and aggregation of unfolded proteins, abnormal endosomal systems, altered insulin signaling, calcium homeostasis, apoptotic signaling, autophagy, and epigenetic changes. Highly oxidative, ubiquitous CDNPs constitute a novel path into AD pathogenesis. Exposed children and young adults need early neuroprotection and multidisciplinary prevention efforts to modify the course of AD at early stages

Environmentally Toxic Solid Nanoparticles in Noradrenergic and Dopaminergic Nuclei and Cerebellum of Metropolitan Mexico City Children and Young Adults with Neural Quadruple Misfolded Protein Pathologies and High Exposures to Nano Particulate Matter

Quadruple aberrant hyperphosphorylated tau, beta-amyloid, &alpha;-synuclein and TDP-43 neuropathology and metal solid nanoparticles (NPs) are documented in the brains of children and young adults exposed to Metropolitan Mexico City (MMC) pollution. We investigated environmental NPs reaching noradrenergic and dopaminergic nuclei and the cerebellum and their associated ultrastructural alterations. Here, we identify NPs in the locus coeruleus (LC), substantia nigrae (SN) and cerebellum by transmission electron microscopy (TEM) and energy-dispersive X-ray spectrometry (EDX) in 197 samples from 179 MMC residents, aged 25.9 &plusmn; 9.2 years and seven older adults aged 63 &plusmn; 14.5 years. Fe, Ti, Hg, W, Al and Zn spherical and acicular NPs were identified in the SN, LC and cerebellar neural and vascular mitochondria, endoplasmic reticulum, Golgi, neuromelanin, heterochromatin and nuclear pore complexes (NPCs) along with early and progressive neurovascular damage and cerebellar endothelial erythrophagocytosis. Strikingly, FeNPs 4 &plusmn; 1 nm and Hg NPs 8 &plusmn; 2 nm were seen predominantly in the LC and SN. Nanoparticles could serve as a common denominator for misfolded proteins and could play a role in altering and obstructing NPCs. The NPs/carbon monoxide correlation is potentially useful for evaluating early neurodegeneration risk in urbanites. Early life NP exposures pose high risk to brains for development of lethal neurologic outcomes. NP emissions sources ought to be clearly recognized, regulated, and monitored; future generations are at stake

Environmentally Toxic Solid Nanoparticles in Noradrenergic and Dopaminergic Nuclei and Cerebellum of Metropolitan Mexico City Children and Young Adults with Neural Quadruple Misfolded Protein Pathologies and High Exposures to Nano Particulate Matter

Quadruple aberrant hyperphosphorylated tau, beta-amyloid, α-synuclein and TDP-43 neuropathology and metal solid nanoparticles (NPs) are documented in the brains of children and young adults exposed to Metropolitan Mexico City (MMC) pollution. We investigated environmental NPs reaching noradrenergic and dopaminergic nuclei and the cerebellum and their associated ultrastructural alterations. Here, we identify NPs in the locus coeruleus (LC), substantia nigrae (SN) and cerebellum by transmission electron microscopy (TEM) and energy-dispersive X-ray spectrometry (EDX) in 197 samples from 179 MMC residents, aged 25.9 ± 9.2 years and seven older adults aged 63 ± 14.5 years. Fe, Ti, Hg, W, Al and Zn spherical and acicular NPs were identified in the SN, LC and cerebellar neural and vascular mitochondria, endoplasmic reticulum, Golgi, neuromelanin, heterochromatin and nuclear pore complexes (NPCs) along with early and progressive neurovascular damage and cerebellar endothelial erythrophagocytosis. Strikingly, FeNPs 4 ± 1 nm and Hg NPs 8 ± 2 nm were seen predominantly in the LC and SN. Nanoparticles could serve as a common denominator for misfolded proteins and could play a role in altering and obstructing NPCs. The NPs/carbon monoxide correlation is potentially useful for evaluating early neurodegeneration risk in urbanites. Early life NP exposures pose high risk to brains for development of lethal neurologic outcomes. NP emissions sources ought to be clearly recognized, regulated, and monitored; future generations are at stake

Air Pollution, Combustion and Friction Derived Nanoparticles, and Alzheimer’s Disease in Urban Children and Young Adults

Exposures to fine particulate matter (PM2.5) and ozone (O3) ≥US EPA standards are associated with Alzheimer’s disease (AD) risk. The projection of 13.8 million AD cases in the US by the year 2050 obligate us to explore early environmental exposures as contributors to AD risk and pathogenesis. Metropolitan Mexico City children and young adults have lifetime exposures to PM2.5 and O3, and AD starting in the brainstem and olfactory bulb is relentlessly progressing in the first two decades of life. Magnetite combustion and friction-derived nanoparticles reach the brain and are associated with early and progressive damage to the neurovascular unit and to brain cells. In this review: 1) we highlight the interplay environment/genetics in the AD development in young populations; 2) comment upon ApoE ɛ4 and the rapid progression of neurofibrillary tangle stages and higher suicide risk in youth; and 3) discuss the role of combustion-derived nanoparticles and brain damage. A key aspect of this review is to show the reader that air pollution is complex and that profiles change from city to city with common denominators across countries. We explore and compare particulate matter profiles in Mexico City, Paris, and Santiago in Chile and make the point of why we should invest in decreasing PM2.5 to at least our current US EPA standard. Multidisciplinary intervention strategies are critical for prevention or amelioration of cognitive deficits and AD progression and risk of suicide in young individuals. AD pathology evolving from childhood is threating the wellbeing of future generations

High-glucose diets induce mitochondrial dysfunction in Caenorhabditis elegans.

Glucose is an important nutrient that dictates the development, fertility and lifespan of all organisms. In humans, a deficit in its homeostatic control might lead to hyperglucemia and the development of obesity and type 2 diabetes, which show a decreased ability to respond to and metabolize glucose. Previously, we have reported that high-glucose diets (HGD) induce alterations in triglyceride content, body size, progeny, and the mRNA accumulation of key regulators of carbohydrate and lipid metabolism, and longevity in Caenorhabditis elegans (PLoS ONE 13(7): e0199888). Herein, we show that increasing amounts of glucose in the diet induce the swelling of both mitochondria in germ and muscle cells. Additionally, HGD alter the enzymatic activities of the different respiratory complexes in an intricate pattern. Finally, we observed a downregulation of ceramide synthases (hyl-1 and hyl-2) and antioxidant genes (gcs-1 and gst-4), while mitophagy genes (pink-1 and dct-1) were upregulated, probably as part of a mitohormetic mechanism in response to glucose toxicity