52 Cerebral oxidative stress response to acute diesel exhaust and world trade center dust exposures

Annals of Work Exposures and Health · 2026-04-30

Abstract Background In acute settings, particulate matter related oxidative stress presents a significant risk factor for cerebrovascular disease and stroke. In this study, we aim to investigate the effect of particulate matter from two sources with heterogeneous chemical compositions: diesel exhaust particles (DEP) and World Trade Center dust (WTC). Methods 2-month-old C57BL/6 mice (n = 6/sex/group) were exposed via inhalation for 5 h to DEP or WTC dust at 100ug/m3 concentration or filtered air as a control. After humane euthanasia and PBS perfusion, brains were prepared either in −80 freezing or fixated in PFA. Oxidative stress was measured using whole cell lysate assays (GPx enzyme, PCOOH assay, and 4-HNE) and immunofluorescence for 4-HNE and 8-OHdG. Results In the whole cell lysate cortex assays, antioxidant GPx and PCOOH activity were reduced in DEP and WTC compared to Filter group. 4-HNE increased in the cortex of DEP and WTC animals compared to Filter. On the immunofluorescent analysis in the cortex 8-OHdG was elevated in the DEP group compared to Filter, while in the corpus callosum, both 4-HNE and 8-OHdG increased in DEP group but not in WTC group. Discussion Our data suggests that an acute exposure to chemically different pollutants results in cerebral oxidative stress damage. Both DEP and WTC exposures blunt oxidized lipid detoxification and promotes oxidative stress response, although with variability across brain areas. Further research is needed to characterize biochemical elements contributing to cerebral oxidative stress in exogenous environmental exposure.

The longevity effects of reduced IGF-1 signaling depend on the stability of the mitochondrial genome

Science Advances · 2026-04-03

Suppression of insulin-like growth factor-1 (IGF-1) signaling extends mammalian life span and protects against a range of age-related diseases. Unexpectedly, we found that reduced IGF-1 signaling fails to extend the life span of mitochondrial mutator mice. Most of the longevity pathways that are normally initiated by IGF-1 suppression were either blocked or blunted in the mutator mice. These observations suggest that the prolongevity effects of IGF-1 suppression critically depend on the integrity of the mitochondrial genome, revealing an unexpected hierarchy in the pathways that control mammalian aging. Together, these findings deepen our understanding of the interactions between the hallmarks of aging and underscore the need for interventions that preserve the integrity of the mitochondrial genome.

Induction of ferroptotic and amyloidogenic signatures linked to Alzheimer’s disease by chemically distinct air pollutants

bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-07 · 1 citations

ABSTRACT Air pollution (AirP) exposure is associated with increased Alzheimer’s disease (AD) risk, yet AirP is chemically heterogeneous, complicating identification of shared pathogenic drivers. We examined acute cortical responses to two metal-rich AirP sources, diesel exhaust particles (DEP) and World Trade Center (WTC) dust, and compared them to woodsmoke (WS), a particulate exposure with low metal content. DEP and WTC elicited highly convergent transcriptional responses, sharing over 1200 differentially expressed genes linked to inflammation, ferroptosis, neuronal remodeling, and amyloid processing. These changes were accompanied by impaired antioxidant activity and increased lipid peroxidation within lipid rafts, a membrane microdomain critical for amyloid processing, resulting in increased Aβ generation. In contrast, WS produced a distinct transcriptional signature and failed to induce ferroptotic priming or lipid peroxidation, consistent with its low metal composition. Together, these findings implicate metals as a shared driver linking diverse AirP exposures to amyloidogenic vulnerability and elevated AD risk. Graphical Abstract Acute AirP exposure converges on ferroptotic priming, amyloidogenic processing, and white-matter vulnerability. Acute exposure to metal-rich AirP, such as DEP or WTC introduces redox-active metals and particulate matter that promote lipid peroxidation, amyloidogenesis, and altered transcriptional regulation in the brain. AirP exposure engages xenobiotic metabolism pathways (AhR/ARNT), activates iron and heme handling through ferritinophagy (NCOA4) and heme oxygenase activity (HMOX1), and blunts lipid peroxide detoxification systems, including glutathione peroxidase 4 (GPx4), ferroptosis suppressor protein 1 (FSP1), and glutathione (GSH) synthesis. These changes promote ferroptotic priming and lipid raft oxidation, facilitating amyloid precursor protein (APP) processing by secretases (ADAM10, BACE1, γ-secretase) and increasing amyloid-β (Aβ) generation. In parallel, transcriptional and cell-state remodeling involving neuronal and oligodendrocyte responses contribute to selective white-matter vulnerability, particularly within the corpus callosum. Together, these pathways provide a mechanistic framework linking acute AirP exposure to convergent oxidative, amyloidogenic, and microstructural changes relevant to Alzheimer’s disease pathology.

Down syndrome with Alzheimer's disease brains have increased iron and associated lipid peroxidation consistent with ferroptosis

Alzheimer s & Dementia · 2025-06-01 · 6 citations

INTRODUCTION: Cerebral microbleeds (MBs) are associated with sporadic Alzheimer's disease (AD) and Down syndrome with AD (DSAD). Higher MB iron may cause iron-mediated lipid peroxidation. We hypothesize that amyloid deposition is linked to MB iron and that amyloid precursor protein (APP) triplication increases iron load and lipid peroxidation. METHODS: Prefrontal cortex and cerebellum of cognitively normal control (CTL), AD, and DSAD ApoE3,3 carriers were examined for proteins that mediated iron metabolism, antioxidant response, and amyloid processing in lipid rafts. RESULTS: Iron was twofold higher in DSAD than in CTL and AD. Iron storage proteins and lipid peroxidation were increased in the prefrontal cortex. The glutathione synthesis protein GCLM was decreased by 50% in both AD and DSAD. Activity of lipid raft GPx4, responsible for membrane repair, was decreased by at least 30% in AD and DSAD. DISCUSSION: DSAD shows greater lipid peroxidation than AD, consistent with greater MBs and iron load. HIGHLIGHTS: DSAD has increased ferroptotic-related changes compared to sporadic AD. Lipid rafts that process APP have a loss of protective antioxidant enzymes. Partial and mosaic trisomy lowers the amyloid and iron burden.

Acute air pollution exposure downregulates ferroptosis protection genes causing increases in amyloid peptides and lipid peroxidation

Free Radical Biology and Medicine · 2025-10-30

The hidden costs of imperfection: transcription errors in protein aggregation diseases

Current Opinion in Genetics & Development · 2025-04-28 · 1 citations

The mutational landscape of SARS-CoV-2 provides new insight into viral evolution and fitness

Nature Communications · 2025-07-11 · 8 citations

Although vaccines and treatments have strengthened our ability to combat the COVID-19 pandemic, new variants of SARS-CoV-2 continue to emerge in human populations. Because the evolution of SARS-CoV-2 is driven by mutation, a better understanding of its mutation rate and spectrum could improve our ability to forecast the trajectory of the pandemic. Here, we use circular RNA consensus sequencing (CirSeq) to determine the mutation rate of six SARS-CoV-2 variants and perform a short-term evolution experiment to determine the impact of these mutations on viral fitness. Our analyses indicate that the SARS-CoV-2 genome mutates at a rate of ∼1.5 × 10−6/base per viral passage and that the spectrum is dominated by C → U transitions. Moreover, we find that the mutation rate is significantly reduced in regions that form base-pairing interactions and that mutations that affect these secondary structures are especially harmful to viral fitness. In this work, we show that the biased mutation spectrum of SARS-CoV-2 is likely a result of frequent cytidine deamination and that the secondary structure of the virus plays an important role in this process, providing new insight into the parameters that guide viral evolution and highlighting fundamental weaknesses of the virus that may be exploited for therapeutic purposes. Here, we report the mutation rate of SARS-CoV-2, the virus responsible for COVID-19. We find that the secondary structure of the RNA-encoded viral genome is crucial to modulating the mutation rate and evolves under strong selective constraints.

Down syndrome with Alzheimer’s disease brains have increased iron and associated lipid peroxidation consistent with ferroptosis

bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-06

ABSTRACT INTRODUCTION Cerebral microbleeds (MB) are associated with sporadic Alzheimer’s Disease (AD) and Down Syndrome with AD (DSAD). Higher MB iron may cause iron mediated lipid peroxidation. We hypothesize that amyloid deposition is linked to MB iron and that amyloid precursor protein (APP) triplication increases iron load and lipid peroxidation. METHODS Prefrontal cortex and cerebellum of cognitively normal (CTL), AD and DSAD ApoE3,3 carriers were examined for proteins that mediated iron metabolism, antioxidant response, and amyloid processing in lipid rafts. RESULTS Iron was 2-fold higher in DSAD than CTL and AD. Iron storage proteins and lipid peroxidation were increased in prefrontal cortex, but not in the cerebellum. The glutathione synthesis protein GCLM was decreased by 50% in both AD and DSAD. Activity of lipid raft GPx4, responsible for membrane repair, was decreased by at least 30% in AD and DSAD. DISCUSSION DSAD shows greater lipid peroxidation than AD consistent with greater MBs and iron load. Graphical Abstract Cerebral microbleeds result in increased brain iron and lipid peroxidation in DSAD consistent with ferroptosis as reported for Alzheimer’s disease. Aβ; beta-amyloid peptides, APP; amyloid precursor protein, GCLC; glutathione cysteine ligase catalytic subunit, GCLM; glutathione cysteine modifier subunit, GPx4; glutathione peroxidase 4, HNE; 4-hydroxynonenal. RESEARCH IN CONTEXT Systematic Review: DS is associated with increased microbleeds and brain iron that may be mediated by increased APP from Trisomy 21. To assess potential links between amyloid and iron levels, we examined sporadic and DS with AD brains for amyloid processing and antioxidant enzyme defense in lipid rafts. We further compared DSAD with rare variants of DS: partial and mosaic T21. Interpretation: DSAD brains showed greater oxidation of lipid rafts where APP is processed than sporadic AD. Corresponding decreases in lipid raft antioxidant enzymes, despite increased total levels of these antioxidant enzymes, present a new mechanism for aberrant amyloid processing during AD. Future Directions: Iron chelation therapies in combination with amyloid monoclonals may benefit DSAD.

A narrow range of transcript-error rates across the Tree of Life

Science Advances · 2025-07-11 · 2 citations

Although transcript-error rates are markedly higher than DNA-level mutation rates, a broad perspective on the degree to which they diverge across lineages remains to be developed. Using modified rolling-circle sequencing, we found a narrow range of transcript-error rates across the Tree of Life, with little evidence supporting local control of error rates associated with gene expression levels. Most errors result in missense changes if translated, and, as with a fraction of nonsense errors, these are underrepresented relative to random expectations, suggesting the existence of mechanisms for purging some such errors. To understand how natural selection and random genetic drift might shape transcript-error rates, we present a model based on cell biology and population genetics. However, while this framework helps understand the evolution of this highly conserved trait, as currently structured, it explains only 20% of the variation in the data, suggesting a need for further theoretical work in this area.

Down syndrome with Alzheimer's disease brains have increased iron and associated lipid peroxidation consistent with ferroptosis

Alzheimer s & Dementia · 2025-12-01 · 5 citations

BACKGROUND: Increased brain iron is associated with sporadic Alzheimer Disease (AD) and Down Syndrome with AD (DSAD), which may involve iron from cerebral microhemorrhages (MBs). The prevalence of MBs is higher in DSAD, possibly from the triplication of the amyloid precursor protein on chromosome 21. Increased MB iron could cause oxidative damage through Fenton chemistry and subsequent lipid peroxidation. We hypothesize that iron and APP are intrinsically linked, and that triplication of APP would result in more tissue iron and lipid peroxidation than observed in sporadic AD. METHOD: Prefrontal cortex and cerebellum of cognitively normal, AD, and DSAD(n = 8/group) were examined for iron metabolism, antioxidant response, and amyloid peptides by immunoblot, inductively coupled mass spectrometry, and enzymatic assay. RESULT: Iron was 2-fold higher in DSAD. Iron storage proteins and lipid peroxidation were increased in prefrontal cortex, but not in the cerebellum. The glutathione synthesis protein GCLM was decreased by 50% in both AD and DSAD. Activity of lipid raft GPx4, responsible for membrane repair, was decreased by at least 30% in AD and DSAD. These decreases in GPx4 activity were paralleled by reduced α-secretase activity while β-secretase activity increased. CONCLUSION: DSAD shows greater lipid peroxidation than AD consistent with greater MBs and iron load. DSAD also shares similar and more pronounced features of AD such as decreased protein levels of critical GSH producing enzyme GCLM and other protective mechanisms against lipid peroxidation. The extensive increase of iron and lipid peroxidation suggests their linkage to APP gene dosage. The impairment of these key mechanisms asserts ferroptosis as a key feature during AD.