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Research on epigenetic‒environmental interactions in the development of Alzheimer's disease (AD) has accelerated rapidly in recent decades. Numerous studies have demonstrated the contribution of ambient particulate matter (PM) to the onset of AD. Emerging evidence indicates that non-coding RNAs (ncRNAs), including long non-coding RNAs, circular RNAs, and microRNAs, play a role in the pathophysiology of AD. In this review, we provide an overview of PM-altered ncRNAs in the brain, with emphasis on their potential roles in the pathogenesis of AD. These results suggest that these PM-altered ncRNAs are involved in the regulation of amyloid-beta pathology, microtubule-associated protein Tau pathology, synaptic dysfunction, damage to the blood‒brain barrier, microglial dysfunction, dysmyelination, and neuronal loss. In addition, we utilized in silico analysis to explore the biological functions of PM-altered ncRNAs in the development of AD. This review summarizes the knowns and unknowns of PM-altered ncRNAs in AD pathogenesis and discusses the current dilemma regarding PM-altered ncRNAs as promising biomarkers of AD. Altogether, this is the first thorough review of the connection between PM exposure and ncRNAs in AD pathogenesis, which may offer novel insights into the prevention, diagnosis, and treatment of AD associated with ambient PM exposure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The association between cognitive neurodegenerative disease and oral diseases has been under great interest recently. Several studies have suggested a connection between periodontitis and Alzheimer's disease (AD) or other neurodegenerative disorders., Objective: This study aimed to review the potential mechanisms between oral diseases and neurodegenerative diseases., Methods: The study was executed as a literature review of English-language publications from 2018-2022. The databases used for the search were PubMed, Cochrane, Scopus, and Web of Science. The search phrases used were " neurodegenerative diseases " AND " oral health " and " neurodegenerative diseases " AND " oral diseases .", Results: The linkage between the two disease groups was observed in several distinct publications and several potential mechanisms were found. The link between periodontitis and AD proved to be the most significant. The effect was accentuated in elderly people where individuals possessed also other risk factors for neurodegenerative diseases and had generally worse oral health conditions., Conclusions: Oral diseases may be risks for neurodegenerative changes along many different pathways. Good oral health should be acknowledged as a potential preventative or risk-reducing act against neurodegenerative diseases., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Airborne ultrafine particulate matter (PM 0.1 ) can enter the brain, induce microglia activation, and promote the development of Alzheimer's disease (AD). Circular RNAs (circRNAs) are also involved in AD pathogenesis. However, the role of AD-related circRNAs in PM 0.1 -induced microglia activation remains unclear. Therefore, we explore cytotoxicity, microglia activation, and AD-associated circRNA expression in human microglial HMC3 cells treated with PM 0.1 , and further examined circRNA expression in mice and cognitively impaired individuals. The results revealed that PM 0.1 exposure decreased cell viability, increased lactate dehydrogenase activity, caused microglia activation, elevated microglial M1 maker expression, downregulated microglial M2 maker expression, and reduced AD-related circ_0061183 expression in vitro. Functionally, circ_0061183 silencing enhanced microglia activation and microglial M1 polarization, but inhibited microglial M2 polarization. Mechanistically, circ_0061183 can bind to miR-98-5p to co-regulate M2 microglial-related IL10 expression, which may affect transforming growth factor-β signaling to regulate PM 0.1 -inhibited microglial M2 polarization. Moreover, circ_0061183 downregulation was observed in the brain of PM 2.5 -exposed mice and AD mice and in the blood of cognitively impaired individuals. Furthermore, circ_0061183 was positively related to mini-mental state examination scores and amyloid-β42 peptide expression in elderly individuals. Overall, the current work offers epigenetic insights into the regulatory mechanisms of circRNAs on microglial activation caused by environmental pollutants., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Major depressive disorder (MDD) is the most common mental health problem worldwide. Increased levels of inflammation are associated with MDD, though this relationship has been suggested to be bidirectional. The first incidence of a depressive episode usually occurs during adolescence. Hence, examining depressed, drug-naïve adolescents is important to understand the role of inflammation in the pathophysiology of MDD. Cytokines might play a crucial role in inflammation associated with MDD. Therefore, this article aims to investigate the changes in the levels of peripheral blood cytokines in adolescents with MDD., Methods: We conducted a systematic review and meta-analysis to assess the changes in peripheral blood cytokines in drug-naïve adolescents (10-18 years) with MDD. A comprehensive search across four databases was performed to identify original research articles. Studies in which the diagnosis of MDD was set by semi-structured interview were included., Results: Of 2291 articles, 12 met the inclusion criteria for the review, with seven suitable for meta-analysis & including up to five studies per cytokine. The meta-analysis revealed significant associations between tumor necrosis factor (TNF)-α (n = 222, Hedge's g = 0.51, p <0.01) and MDD in adolescents compared to healthy individuals. However, other blood cytokines, including interleukin (IL)-1β, IL-4, IL-6, IL-8, and interferon (IFN)-γ, did not significantly correlate with MDD in adolescents., Conclusion: TNF-α was significantly elevated in drug-naïve adolescents with MDD. To further understand the role of TNF-α in MDD, a thorough investigation is required, taking into account the diversity, subtypes, chronicity, and severity of MDD., Competing Interests: Declaration of competing interest The authors declare that they do not have any conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Studies have correlated living close to major roads with Alzheimer's disease (AD) risk. However, the mechanisms responsible for this link remain unclear., Methods: We exposed olfactory mucosa (OM) cells of healthy individuals and AD patients to diesel emissions (DE). Cytotoxicity of exposure was assessed, mRNA, miRNA expression, and DNA methylation analyses were performed. The discovered altered pathways were validated using data from the human population-based Rotterdam Study., Results: DE exposure resulted in an almost four-fold higher response in AD OM cells, indicating increased susceptibility to DE effects. Methylation analysis detected different DNA methylation patterns, revealing new exposure targets. Findings were validated by analyzing data from the Rotterdam Study cohort and demonstrated a key role of nuclear factor erythroid 2-related factor 2 signaling in responses to air pollutants., Discussion: This study identifies air pollution exposure biomarkers and pinpoints key pathways activated by exposure. The data suggest that AD individuals may face heightened risks due to impaired cellular defenses., Highlights: Healthy and AD olfactory cells respond differently to DE exposure. AD cells are highly susceptible to DE exposure. The NRF2 oxidative stress response is highly activated upon air pollution exposure. DE-exposed AD cells activate the unfolded protein response pathway. Key findings are also confirmed in a population-based study., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Fine particulate matter (PM 2.5 ) can cause brain damage and diseases. Of note, ultrafine particles (UFPs) with an aerodynamic diameter less than or equal to 100 nm are a growing concern. Evidence has suggested toxic effects of PM 2.5 and UFPs on the brain and links to neurological diseases. However, the underlying mechanism has not yet been fully illustrated due to the variety of the study models, different endpoints, etc. The adverse outcome pathway (AOP) framework is a pathway-based approach that could systematize mechanistic knowledge to assist health risk assessment of pollutants. Here, we constructed AOPs by collecting molecular mechanisms in PM-induced neurotoxicity assessments. We chose particulate matter (PM) as a stressor in the Comparative Toxicogenomics Database (CTD) and identified the critical toxicity pathways based on Ingenuity Pathway Analysis (IPA). We found 65 studies investigating the potential mechanisms linking PM 2.5 and UFPs to neurotoxicity, which contained 2, 675 genes in all. IPA analysis showed that neuroinflammation signaling and glucocorticoid receptor signaling were the common toxicity pathways. The upstream regulator analysis (URA) of PM 2.5 and UFPs demonstrated that the neuroinflammation signaling was the most initially triggered upstream event. Therefore, neuroinflammation was recognized as the MIE. Strikingly, there is a clear sequence of activation of downstream signaling pathways with UFPs, but not with PM 2.5 . Moreover, we found that inflammation response and homeostasis imbalance were key cellular events in PM 2.5 and emphasized lipid metabolism and mitochondrial dysfunction, and blood-brain barrier (BBB) impairment in UFPs. Previous AOPs, which only focused on phenotypic changes in neurotoxicity upon PM exposure, we for the first time propose AOP framework in which PM 2.5 and UFPs may activate pathway cascade reactions, resulting in adverse outcomes associated with neurotoxicity. Our toxicity pathway-based approach not only advances risk assessment for PM-induced neurotoxicity but shines a spotlight on constructing AOP frameworks for new chemicals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Whether differences in lifestyle between co-twins are reflected in differences in their internal or external exposome profiles remains largely underexplored. We therefore investigated whether within-pair differences in lifestyle were associated with within-pair differences in exposome profiles across four domains: the external exposome, proteome, metabolome and epigenetic age acceleration (EAA). For each domain, we assessed the similarity of co-twin profiles using Gaussian similarities in up to 257 young adult same-sex twin pairs (54% monozygotic). We additionally tested whether similarity in one domain translated into greater similarity in another. Results suggest that a lower degree of similarity in co-twins' exposome profiles was associated with greater differences in their behavior and substance use. The strongest association was identified between excessive drinking behavior and the external exposome. Overall, our study demonstrates how social behavior and especially substance use are connected to the internal and external exposomes, while controlling for familial confounders., (© 2024. The Author(s).)

Alzheimer's disease (AD) is the most common cause of dementia. Despite intensive research efforts, there are currently no effective treatments to cure and prevent AD. There is growing evidence that dysregulation of iron homeostasis may contribute to the pathogenesis of AD. Given the important role of the transferrin receptor 1 (TfR1) in regulating iron distribution in the brain, as well as in the drug delivery, we investigated its expression in the brain cortex and isolated brain microvessels from female 8-month-old 5xFAD mice mimicking advanced stage of AD. Moreover, we explored the association between the TfR1 expression and the activation of the HIF-1 signaling pathway, as well as oxidative stress and inflammation in 5xFAD mice. Finally, we studied the impact of Aβ 1-40 and Aβ 1-42 on TfR1 expression in the brain endothelial cell line hCMEC/D3. In the present study, we revealed that an increase in TfR1 protein levels observed in the brain cortex of 5xFAD mice was associated with activation of the HIF-1 signaling pathway as well as accompanied by oxidative stress and inflammation. Interestingly, incubation of Aβ peptides in hCMEC/D3 cells did not affect the expression of TfR1, which supported our findings of unaltered TfR1 expression in the isolated brain microvessels in 5xFAD mice. In conclusion, the study provides important information about the expression of TfR1 in the 5xFAD mouse model and the potential role of HIF-1 signaling pathway in the regulation of TfR1 in AD, which could represent a promising strategy for the development of therapies for AD., (© 2024. The Author(s).)

Constituents of air pollution, the ultrafine particles (UFP) with a diameter of ≤0.1 μm, are considerably related to traffic emissions. Several studies link air pollution to Alzheimer's disease (AD), yet the exact relationship between the two remains poorly understood. Mitochondria are known targets of environmental toxicants, and their dysfunction is associated with neurodegenerative diseases. The olfactory mucosa (OM), located at the rooftop of the nasal cavity, is directly exposed to the environment and in contact with the brain. Mounting evidence suggests that the UFPs can impact the brain directly through the olfactory tract. By using primary human OM cultures established from nasal biopsies of cognitively healthy controls and individuals diagnosed with AD, we aimed to decipher the effects of traffic-related UFPs on mitochondria. The UFP samples were collected from the exhausts of a modern heavy-duty diesel engine (HDE) without aftertreatment systems, run with renewable diesel (A0) and petroleum diesel (A20), and from an engine of a 2019 model diesel passenger car (DI-E6d) equipped with state-of-the-art aftertreatment devices and run with renewable diesel (Euro6). OM cells were exposed to three different UFPs for 24-h and 72-h, after which cellular processes were assessed on the functional and transcriptomic levels. Our results show that UFPs impair mitochondrial functions in primary human OM cells by hampering oxidative phosphorylation (OXPHOS) and redox balance, and the responses of AD cells differ from cognitively healthy controls. RNA-Seq and IPA® revealed inhibition of OXPHOS and mitochondrial dysfunction in response to UFPs A0 and A20. Functional validation confirmed that A0 and A20 impair cellular respiration, decrease ATP levels, and disturb redox balance by altering NAD and glutathione metabolism, leading to increased ROS and oxidative stress. RNA-Seq and functional assessment revealed the presence of AD-related alterations in human OM cells and that different fuels and engine technologies elicit differential effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Per- and polyfluoroalkyl substances (PFAS) are endocrine disruptors with unambiguous neurotoxic effects. However, due to variability in experimental models, population characteristics, and molecular endpoints, the elucidation of mechanisms underlying PFAS-induced neurotoxicity remains incomplete. In this review, we utilized the adverse outcome pathway (AOP) framework, a comprehensive tool for evaluating toxicity across multiple biological levels (molecular, cellular, tissue and organ, individual, and population), to elucidate the mechanisms of neurotoxicity induced by PFAS. Based on 271 studies, the reactive oxygen species (ROS) generation emerged as the molecular initiating event 1 (MIE1). Subsequent key events (KEs) at the cellular level include oxidative stress, neuroinflammation, apoptosis, altered Ca 2+ signal transduction, glutamate and dopamine signaling dyshomeostasis, and reduction of cholinergic and serotonin. These KEs culminate in synaptic dysfunction at organ and tissue levels. Further insights were offered into MIE2 and upstream KEs associated with altered thyroid hormone levels, contributing to synaptic dysfunction and hypomyelination at the organ and tissue levels. The inhibition of Na + /I - symporter (NIS) was identified as the MIE2, initiating a cascade of KEs at the cellular level, including altered thyroid hormone synthesis, thyroid hormone transporters, thyroid hormone metabolism, and binding with thyroid hormone receptors. All KEs ultimately result in adverse outcomes (AOs), including cognition and memory impairment, autism spectrum disorders, attention deficit hyperactivity disorders, and neuromotor development impairment. To our knowledge, this review represents the first comprehensive and systematic AOP analysis delineating the intricate mechanisms responsible for PFAS-induced neurotoxic effects, providing valuable insights for risk assessments and mitigation strategies against PFAS-related health hazards., Competing Interests: The authors declare no competing financial interest., (© 2024 The Author(s).)

Introduction: Air pollution is a significant contributor to morbidity and mortality globally and has been linked to an increased risk of dementia. Previous studies within the Betula cohort in Northern Sweden have demonstrated associations between air pollution and dementia, as well as distinctive metabolomic profiles in dementia patients compared to controls. This study aimed to investigate whether air pollution is associated with quantitative changes in metabolite levels within this cohort, and whether future dementia status would modify this association., Methods: Both short-term and long-term exposure to air pollution were evaluated using high spatial resolution models and measured data. Air pollution from vehicle exhaust and woodsmoke were analyzed separately. Metabolomic profiling was conducted on 321 participants, including 58 serum samples from dementia patients and a control group matched for age, sex, and education level, using nuclear magnetic resonance spectroscopy., Results: No statistically significant associations were found between any metabolites and any measures of short-term or long-term exposure to air pollution. However, there were trends potentially suggesting associations between both long-term and short-term exposure to air pollution with lactate and glucose metabolites. Notably, these associations were observed despite the lack of correlation between long-term and short-term air pollution exposure in this cohort. There were also tendencies for associations between air pollution from woodsmoke to be more pronounced in participants that would later develop dementia, suggesting a potential effect depending on urban/rural factors., Discussion: While no significant associations were found, the trends observed in the data suggest potential links between air pollution exposure and changes in lactate and glucose metabolites. These findings provide some new insights into the link between air pollution and metabolic markers in a low-exposure setting. However, addressing existing limitations is crucial to improve the robustness and applicability of future research in this area. The pronounced associations in participants who later developed dementia may indicate an influence of urban/rural factors, warranting further investigation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Raza, Öhman, Kanninen, Jalava, Zeng, de Crom, Ikram and Oudin.)

The aim of this study was to investigate the relationship between source-specific ambient particulate air pollution concentrations and the incidence of dementia. The study encompassed 70,057 participants from the Västerbotten intervention program cohort in Northern Sweden with a median age of 40 years at baseline. High-resolution dispersion models were employed to estimate source-specific particulate matter (PM) concentrations, such as PM 10 and PM 2.5 from traffic, exhaust, and biomass (mainly wood) burning, at the residential addresses of each participant. Cox regression models, adjusted for potential confounding factors, were used for the assessment. Over 884,847 person-years of follow-up, 409 incident dementia cases, identified through national registers, were observed. The study population's average exposure to annual mean total PM 10 and PM 2.5 lag 1-5 years was 9.50 µg/m 3 and 5.61 µg/m 3 , respectively. Increased risks were identified for PM 10 -Traffic (35% [95% CI 0-82%]) and PM 2.5 -Exhaust (33% [95% CI - 2 to 79%]) in the second exposure tertile for lag 1-5 years, although no such risks were observed in the third tertile. Interestingly, a negative association was observed between PM 2.5 -Wood burning and the risk of dementia. In summary, this register-based study did not conclusively establish a strong association between air pollution exposure and the incidence of dementia. While some evidence indicated elevated risks for PM 10 -Traffic and PM 2.5 -Exhaust, and conversely, a negative association for PM 2.5 -Wood burning, no clear exposure-response relationships were evident., (© 2024. The Author(s).)

Respiratory viruses have a significant impact on health, as highlighted by the COVID-19 pandemic. Exposure to air pollution can contribute to viral susceptibility and be associated with severe outcomes, as suggested by recent epidemiological studies. Furthermore, exposure to particulate matter (PM), an important constituent of air pollution, is linked to adverse effects on the brain, including cognitive decline and Alzheimer's disease (AD). The olfactory mucosa (OM), a tissue located at the rooftop of the nasal cavity, is directly exposed to inhaled air and in direct contact with the brain. Increasing evidence of OM dysfunction related to neuropathogenesis and viral infection demonstrates the importance of elucidating the interplay between viruses and air pollutants at the OM. This study examined the effects of subacute exposure to urban PM 0.2 and PM 10-2.5 on SARS-CoV-2 infection using primary human OM cells obtained from cognitively healthy individuals and individuals diagnosed with AD. OM cells were exposed to PM and subsequently infected with the SARS-CoV-2 virus in the presence of pollutants. SARS-CoV-2 entry receptors and replication, toxicological endpoints, cytokine release, oxidative stress markers, and amyloid beta levels were measured. Exposure to PM did not enhance the expression of viral entry receptors or cellular viral load in human OM cells. However, PM-exposed and SARS-CoV-2-infected cells showed alterations in cellular and immune responses when compared to cells infected only with the virus or pollutants. These changes are highly pronounced in AD OM cells. These results suggest that exposure of human OM cells to PM does not increase susceptibility to SARS-CoV-2 infection in vitro, but it can alter cellular immune responses to the virus, particularly in AD. Understanding the interplay of air pollutants and COVID-19 can provide important insight for the development of public health policies and interventions to reduce the negative influences of air pollution exposure., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Katja Kannienen reports financial support was provided by Research Council of Finland. Katja Kannienen reports financial support was provided by Sigrid Jusélius Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Exposure to PM 2.5 has been linked to neurodegenerative diseases, with limited understanding of constituent-specific contributions., Objectives: To explore the associations between long-term exposure to PM 2.5 constituents and neurodegenerative diseases., Methods: We recruited 148,274 individuals aged ≥ 60 from four cities in the Pearl River Delta region, China (2020 to 2021). We calculated twenty-year average air pollutant concentrations (PM 2.5 mass, black carbon (BC), organic matter (OM), ammonium (NH 4 + ), nitrate (NO 3 - ) and sulfate (SO 4 2- )) at the individuals' home addresses. Neurodegenerative diseases were determined by self-reported doctor-diagnosed Alzheimer's disease (AD) and Parkinson's disease (PD). Generalized linear mixed models were employed to explore associations between pollutants and neurodegenerative disease prevalence., Results: PM 2.5 and all five constituents were significantly associated with a higher prevalence of AD and PD. The observed associations generally exhibited a non-linear pattern. For example, compared with the lowest quartile, higher quartiles of BC were associated with greater odds for AD prevalence (i.e., the adjusted odds ratios were 1.81; 95% CI, 1.45-2.27; 1.78; 95% CI, 1.37-2.32; and 1.99; 95% CI, 1.54-2.57 for the second, third, and fourth quartiles, respectively)., Conclusions: Long-term exposure to PM 2.5 and its constituents, particularly combustion-related BC, OM, and SO 4 2- , was significantly associated with higher prevalence of AD and PD in Chinese individuals., Environmental Implication: PM 2.5 is a routinely regulated mixture of multiple hazardous constituents that can lead to diverse adverse health outcomes. However, current evidence on the specific contributions of PM 2.5 constituents to health effects is scarce. This study firstly investigated the association between PM 2.5 constituents and neurodegenerative diseases in the moderately to highly polluted Pearl River Delta region in China, and identified hazardous constituents within PM 2.5 that have significant impacts. This study provides important implications for the development of targeted PM 2.5 prevention and control policies to reduce specific hazardous PM 2.5 constituents., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Membrane transporters playing an important role in the passage of drugs, metabolites and nutrients across the membranes of the brain cells have been shown to be involved in pathogenesis of Alzheimer's disease (AD). However, little is known about sex-specific changes in transporter protein expression at the brain in AD. Here, we investigated sex-specific alterations in protein expression of three ATP-binding cassette (ABC) and five solute carriers (SLC) transporters in the prefrontal cortex of a commonly used model of familial AD (FAD), 5xFAD mice. Sensitive liquid chromatography tandem mass spectrometry-based quantitative targeted absolute proteomic analysis was applied for absolute quantification of transporter protein expression. We compared the changes in transporter protein expressions in 7-month-old male and female 5xFAD mice versus sex-matched wild-type mice. The study revealed a significant sex-specific increase in protein expression of ABCC1 ( p = 0.007) only in male 5xFAD mice as compared to sex-matched wild-type animals. In addition, the increased protein expression of glucose transporter 1 ( p = 0.01), 4F2 cell-surface antigen heavy chain ( p = 0.01) and long-chain fatty acid transport protein 1 ( p = 0.02) were found only in female 5xFAD mice as compared to sex-matched wild-type animals. Finally, protein expression of alanine/serine/cysteine/threonine transporter 1 was upregulated in both male ( p = 0.02) and female ( p = 0.002) 5xFAD mice. The study provides important information about sex-specific changes in brain cortical transporter expression in 5xFAD mice, which will facilitate drug development of therapeutic strategies for AD targeting these transporters and drug delivery research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Puris, Saveleva, Auriola, Gynther, Kanninen and Fricker.)

Background: Air pollution is recognized as an emerging environmental risk factor for neurological diseases. Large-scale epidemiological studies associate traffic-related particulate matter (PM) with impaired cognitive functions and increased incidence of neurodegenerative diseases such as Alzheimer's disease. Inhaled components of PM may directly invade the brain via the olfactory route, or act through peripheral system responses resulting in inflammation and oxidative stress in the brain. Microglia are the immune cells of the brain implicated in the progression of neurodegenerative diseases. However, it remains unknown how PM affects live human microglia., Results: Here we show that two different PMs derived from exhausts of cars running on EN590 diesel or compressed natural gas (CNG) alter the function of human microglia-like cells in vitro. We exposed human induced pluripotent stem cell (iPSC)-derived microglia-like cells (iMGLs) to traffic related PMs and explored their functional responses. Lower concentrations of PMs ranging between 10 and 100 µg ml -1 increased microglial survival whereas higher concentrations became toxic over time. Both tested pollutants impaired microglial phagocytosis and increased secretion of a few proinflammatory cytokines with distinct patterns, compared to lipopolysaccharide induced responses. iMGLs showed pollutant dependent responses to production of reactive oxygen species (ROS) with CNG inducing and EN590 reducing ROS production., Conclusions: Our study indicates that traffic-related air pollutants alter the function of human microglia and warrant further studies to determine whether these changes contribute to adverse effects in the brain and on cognition over time. This study demonstrates human iPSC-microglia as a valuable tool to study functional microglial responses to environmental agents., (© 2024. The Author(s).)

Integrins are receptors that have been linked to various brain disorders, including Alzheimer's disease (AD), the most prevalent neurodegenerative disorder. While Integrin beta-3 (ITGB3) is known to participate in multiple cellular processes such as adhesion, migration, and signaling, its specific role in AD remains poorly understood, particularly in astrocytes, the main glial cell type in the brain. In this study, we investigated alterations in ITGB3 gene and protein expression during aging in different brain regions of the 5xFAD mouse model of AD and assessed the interplay between ITGB3 and astrocytes. Primary cultures from adult mouse brains were used to gain further insight into the connection between ITGB3 and amyloid beta (Aβ) in astrocytes. In vivo studies showed a correlation between ITGB3 and the astrocytic marker GFAP in the 5xFAD brains, indicating its association with reactive astrocytes. In vitro studies revealed increased gene expression of ITGB3 upon Aβ treatment. Our findings underscore the potential significance of ITGB3 in astrocyte reactivity in the context of Alzheimer's disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Global emphasis on enhancing prevention and treatment strategies necessitates an increased understanding of the biological mechanisms of psychopathology. Plasma proteomics is a powerful tool that has been applied in the context of specific mental disorders for biomarker identification. The p-factor, also known as the "general psychopathology factor", is a concept in psychopathology suggesting that there is a common underlying factor that contributes to the development of various forms of mental disorders. It has been proposed that the p-factor can be used to understand the overall mental health status of an individual. Here, we aimed to discover plasma proteins associated with the p-factor in 775 young adults in the FinnTwin12 cohort. Using liquid chromatography-tandem mass spectrometry, 13 proteins with a significant connection with the p-factor were identified, 8 of which were linked to epidermal growth factor receptor (EGFR) signaling. This exploratory study provides new insight into biological alterations associated with mental health status in young adults., (© 2024. The Author(s).)

Background: The influence of genetics and environment on the association of the plasma proteome with body mass index (BMI) and changes in BMI remains underexplored, and the links to other omics in these associations remain to be investigated. We characterized protein-BMI trajectory associations in adolescents and adults and how these connect to other omics layers., Methods: Our study included two cohorts of longitudinally followed twins: FinnTwin12 (N = 651) and the Netherlands Twin Register (NTR) (N = 665). Follow-up comprised 4 BMI measurements over approximately 6 (NTR: 23-27 years old) to 10 years (FinnTwin12: 12-22 years old), with omics data collected at the last BMI measurement. BMI changes were calculated in latent growth curve models. Mixed-effects models were used to quantify the associations between the abundance of 439 plasma proteins with BMI at blood sampling and changes in BMI. In FinnTwin12, the sources of genetic and environmental variation underlying the protein abundances were quantified by twin models, as were the associations of proteins with BMI and BMI changes. In NTR, we investigated the association of gene expression of genes encoding proteins identified in FinnTwin12 with BMI and changes in BMI. We linked identified proteins and their coding genes to plasma metabolites and polygenic risk scores (PRS) applying mixed-effects models and correlation networks., Results: We identified 66 and 14 proteins associated with BMI at blood sampling and changes in BMI, respectively. The average heritability of these proteins was 35%. Of the 66 BMI-protein associations, 43 and 12 showed genetic and environmental correlations, respectively, including 8 proteins showing both. Similarly, we observed 7 and 3 genetic and environmental correlations between changes in BMI and protein abundance, respectively. S100A8 gene expression was associated with BMI at blood sampling, and the PRG4 and CFI genes were associated with BMI changes. Proteins showed strong connections with metabolites and PRSs, but we observed no multi-omics connections among gene expression and other omics layers., Conclusions: Associations between the proteome and BMI trajectories are characterized by shared genetic, environmental, and metabolic etiologies. We observed few gene-protein pairs associated with BMI or changes in BMI at the proteome and transcriptome levels., (© 2023. The Author(s).)

Ultrafine particles (UFP) with a diameter of ≤0.1 μm, are contributors to ambient air pollution and derived mainly from traffic emissions, yet their health effects remain poorly characterized. The olfactory mucosa (OM) is located at the rooftop of the nasal cavity and directly exposed to both the environment and the brain. Mounting evidence suggests that pollutant particles affect the brain through the olfactory tract, however, the exact cellular mechanisms of how the OM responds to air pollutants remain poorly known. Here we show that the responses of primary human OM cells are altered upon exposure to UFPs and that different fuels and engines elicit different adverse effects. We used UFPs collected from exhausts of a heavy-duty-engine run with renewable diesel (A0) and fossil diesel (A20), and from a modern diesel vehicle run with renewable diesel (Euro6) and compared their health effects on the OM cells by assessing cellular processes on the functional and transcriptomic levels. Quantification revealed all samples as UFPs with the majority of particles being ≤0.1 μm by an aerodynamic diameter. Exposure to A0 and A20 induced substantial alterations in processes associated with inflammatory response, xenobiotic metabolism, olfactory signaling, and epithelial integrity. Euro6 caused only negligible changes, demonstrating the efficacy of aftertreatment devices. Furthermore, when compared to A20, A0 elicited less pronounced effects on OM cells, suggesting renewable diesel induces less adverse effects in OM cells. Prior studies and these results suggest that PAHs may disturb the inflammatory process and xenobiotic metabolism in the OM and that UFPs might mediate harmful effects on the brain through the olfactory route. This study provides important information on the adverse effects of UFPs in a human-based in vitro model, therefore providing new insight to form the basis for mitigation and preventive actions against the possible toxicological impairments caused by UFP exposure., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Katja Kanninen reports financial support was provided by The Academy of Finland. Katja Kanninen reports financial support was provided by The Sigrid Juselius Foundation. Katja Kanninen reports financial support was provided by Horizon 2020 European Innovation Council Fast Track to Innovation. Tarja Malm reports financial support was provided by Horizon 2020 European Innovation Council Fast Track to Innovation. Pasi Jalava reports financial support was provided by Horizon 2020 European Innovation Council Fast Track to Innovation. Laura Mussalo reports financial support was provided by Kuopio Area Respiratory Foundation. Laura Mussalo reports financial support was provided by Finnish Brain Foundation. Laura Mussalo reports financial support was provided by Yrjö Jahnsson Foundation. Laura Mussalo reports financial support was provided by Päivikki and Sakari Sohlberg Foundation. Laura Mussalo reports financial support was provided by University of Eastern Finland., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Mental disorders among children and adolescents pose a significant global challenge. The exposome framework covering the totality of internal, social and physical exposures over a lifetime provides opportunities to better understand the causes of and processes related to mental health, and cognitive functioning. The paper presents a conceptual framework on exposome, mental health, and cognitive development in children and adolescents, with potential mediating pathways, providing a possibility for interventions along the life course. The paper underscores the significance of adopting a child perspective to the exposome, acknowledging children's specific vulnerability, including differential exposures, susceptibility of effects and capacity to respond; their susceptibility during development and growth, highlighting neurodevelopmental processes from conception to young adulthood that are highly sensitive to external exposures. Further, critical periods when exposures may have significant effects on a child's development and future health are addressed. The paper stresses that children's behaviour, physiology, activity pattern and place for activities make them differently vulnerable to environmental pollutants, and calls for child-specific assessment methods, currently lacking within today's health frameworks. The importance of understanding the interplay between structure and agency is emphasized, where agency is guided by social structures and practices and vice-versa. An intersectional approach that acknowledges the interplay of social and physical exposures as well as a global and rural perspective on exposome is further pointed out. To advance the exposome field, interdisciplinary efforts that involve multiple scientific disciplines are crucial. By adopting a child perspective and incorporating an exposome approach, we can gain a comprehensive understanding of how exposures impact children's mental health and cognitive development leading to better outcomes., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Irene van Kamp reports financial support was provided by European Comission. One of the co-authors of the present submission (Angel M. Dzhambov) is also a VSI co-editor and a collaborator of another co-editor of the VSI (Iana Markevych, (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The neurological effects of the coronavirus disease of 2019 (COVID-19) raise concerns about potential long-term consequences, such as an increased risk of Alzheimer's disease (AD). Neuroinflammation and other AD-associated pathologies are also suggested to increase the risk of serious SARS-CoV-2 infection. Anosmia is a common neurological symptom reported in COVID-19 and in early AD. The olfactory mucosa (OM) is important for the perception of smell and a proposed site of viral entry to the brain. However, little is known about SARS-CoV-2 infection at the OM of individuals with AD., Methods: To address this gap, we established a 3D in vitro model of the OM from primary cells derived from cognitively healthy and AD individuals. We cultured the cells at the air-liquid interface (ALI) to study SARS-CoV-2 infection under controlled experimental conditions. Primary OM cells in ALI expressed angiotensin-converting enzyme 2 (ACE-2), neuropilin-1 (NRP-1), and several other known SARS-CoV-2 receptor and were highly vulnerable to infection. Infection was determined by secreted viral RNA content and confirmed with SARS-CoV-2 nucleocapsid protein (NP) in the infected cells by immunocytochemistry. Differential responses of healthy and AD individuals-derived OM cells to SARS-CoV-2 were determined by RNA sequencing., Results: Results indicate that cells derived from cognitively healthy donors and individuals with AD do not differ in susceptibility to infection with the wild-type SARS-CoV-2 virus. However, transcriptomic signatures in cells from individuals with AD are highly distinct. Specifically, the cells from AD patients that were infected with the virus showed increased levels of oxidative stress, desensitized inflammation and immune responses, and alterations to genes associated with olfaction. These results imply that individuals with AD may be at a greater risk of experiencing severe outcomes from the infection, potentially driven by pre-existing neuroinflammation., Conclusions: The study sheds light on the interplay between AD pathology and SARS-CoV-2 infection. Altered transcriptomic signatures in AD cells may contribute to unique symptoms and a more severe disease course, with a notable involvement of neuroinflammation. Furthermore, the research emphasizes the need for targeted interventions to enhance outcomes for AD patients with viral infection. The study is crucial to better comprehend the relationship between AD, COVID-19, and anosmia. It highlights the importance of ongoing research to develop more effective treatments for those at high risk of severe SARS-CoV-2 infection., (© 2023. The Author(s).)

This study evaluated how exposure to the ubiquitous air pollution component, ultrafine particles (UFPs), alters the olfactory bulb (OB) transcriptome. The study utilised a whole-body inhalation chamber to simulate real-life conditions and focused on UFPs due to their high translocation and deposition ability in OBs as well as their prevalence in ambient air. Female C57BL/6J mice were exposed to clean air or to freshly generated combustion derived UFPs for two weeks, after which OBs were dissected and mRNA transcripts were investigated using RNA sequencing analysis. For the first time, transcriptomics was applied to determine changes in mRNA expression levels occurring after subacute exposure to UFPs in the OBs. We found forty-five newly described mRNAs to be involved in air pollution-induced responses, including genes involved in odorant binding, synaptic regulation, and myelination signalling pathway, providing new gene candidates for future research. This study provides new insights for the environmental science and neuroscience fields and nominates future research directions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background The exposome approach can be a powerful tool for understanding the intertwining of social, physical, and internal influences that shape mental health and cognitive development throughout childhood. To distil conceptual models for subsequent analyses, the EU-funded project Early Environmental quality and Life-course mental health effects (Equal-Life) has conducted literature reviews on potential mediators linking the exposome to these outcomes. We report on a scoping review and a conceptual model of the role of restorative possibilities and physical activity. Methods Peer-reviewed studies published since the year 2000 in English, on the association between the exposome and mental health/cognition in children/adolescents, and quantitatively investigating restoration/restorative quality as a mediating variable were considered. Database searches were last updated in December 2022. We used an unstructured expert-driven approach to fill in gaps in the reviewed literature. Results Five records of three distinct studies were identified, indicating a scarcity of empirical evidence in this newly developing research area. Not only were these studies few in numbers, but also cross-sectional, lending only tentative support to the idea that perceived restorative quality of adolescent's living environment might mediate the association between greenspace and mental health. Physical activity emerged as a mediator leading to better psychological outcomes in restorative environments. We provide a critical discussion of potential caveats when investigating the restoration mechanism in children and propose a hierarchical model including restoration, physical activity, and relational dynamics between children and their environment, including social context, as well as restorative environments other than nature. Conclusions It is justified to further explore the role of restoration and physical activity as mediators in the association between early-life exposome and mental health/cognitive development. It is important to consider the child perspective and specific methodological caveats. Given the evolving conceptual definitions/operationalizations, Equal-Life will attempt to fill in a critical gap in the literature., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Clozapine (CZP) is the only effective drug in schizophrenia resistant to typical antipsychotics. However, existing dosage forms (oral or orodispersible tablets, suspensions or intramuscular injection) show challenging limitations. After oral administration, CZP has low bioavailability due to a large first-pass effect, while the i.m. route is often painful, with low patient compliance and requiring specialised personnel. Moreover, CZP has a very low aqueous solubility. This study proposes the intranasal route as an alternative route of administration for CZP, through its encapsulation in polymeric nanoparticles (NPs) based on Eudragit ® RS100 and RL100 copolymers. Slow-release polymeric NPs with dimensions around 400-500 nm were formulated to reside and release CZP in the nasal cavity, where it can be absorbed through the nasal mucosa and reach the systemic circulation. CZP-EUD-NPs showed a controlled release of CZP for up to 8 h. Furthermore, to reduce mucociliary clearance and increase the residence time of NPs in the nasal cavity to improve drug bioavailability, mucoadhesive NPs were formulated. This study shows that the NPs already exhibited strong electrostatic interactions with mucin at time zero due to the presence of the positive charge of the used copolymers. Furthermore, to improve the solubility, diffusion and adsorption of CZPs and the storage stability of the formulation, it was lyophilised using 5% ( w / v ) HP-β-CD as a cryoprotectant. It ensured the preservation of the NPs' size, PDI and charge upon reconstitution. Moreover, physicochemical characterisation studies of solid-state NPs were performed. Finally, toxicity studies were performed in vitro on MDCKII cells and primary human olfactory mucosa cells and in vivo on the nasal mucosa of CD-1 mice. The latter showed non-toxicity of B-EUD-NPs and mild CZP-EUD-NP-induced tissue abnormalities.

Adolescence is often a challenging time in which psychiatric issues have a strong connection to mental health disorders later in life. The early identification of the problems can reduce the burden of disease. To date, the effective identification of adolescents at risk of developing mental health problems remains understudied. Altogether, the interaction between circulating cell-free mtDNA (ccf-mtDNA) and inflammatory cytokines in adolescents is insufficiently understood regarding experienced mental health difficulties. Our study selected the participants based on the Strength and Difficulty Questionnaire (SDQ) score using the cut-off points of 3 and 18 for the low and the high score groups, respectively. The answers of the SDQ at the age of 12.2-15.7 years contributed to the investigation of (i) whether ccf-mtDNA units are associated with cytokines, and (ii) if an interaction model for predicting risk of mental health issues is observed. We discovered a sex-specific correlation between the screened markers associated with mental health problems in the low and high SDQ score groups among the male participants and in the low SDQ score group among the female participants. The mitochondrial MT-ND4 and MT-CO1 genes correlated significantly with interleukin-12p70 (IL-12p70) in males and with monocyte chemoattractant protein-1 (MCP-1) in females. Due to the nature of the explorative study, the studied markers alone did not indicate statistical significance for the prediction of mental health problems. Our analysis provided new insight into potential plasma-based biomarkers to predict mental health issues.

Membrane transporters such as ATP-binding cassette (ABC) and solute carrier (SLC) transporters expressed at the neurovascular unit (NVU) play an important role in drug delivery to the brain and have been demonstrated to be involved in Alzheimer's disease (AD) pathogenesis. However, our knowledge of quantitative changes in transporter absolute protein expression and functionality in vivo in NVU in AD patients and animal models is limited. The study aim was to investigate alterations in protein expression of ABC and SLC transporters in the isolated brain microvessels and brain prefrontal cortices of a widely used model of familial AD, 5xFAD mice (8 months old), using a sensitive liquid chromatography tandem mass spectrometry-based quantitative targeted absolute proteomic approach. Moreover, we examined alterations in brain prefrontal cortical and plasmatic levels of transporter substrates in 5xFAD mice compared to age-matched wild-type (WT) controls. ASCT1 (encoded by Slc1a4) protein expression in the isolated brain microvessels and brain prefrontal cortices of 5xFAD mice was twice higher compared to WT controls (p = 0.01). Brain cortical levels of ASCT1 substrate, serine, were increased in 5xFAD mice compared to WT animals. LAT1 (encoded by Slc7a5) and 4F2hc (encoded by Slc3a2) protein expressions were significantly altered in the isolated brain microvessels of 5xFAD mice compared to WT controls (p = 0.008 and p = 0.05, respectively). Overall, the study provides important information, which is crucial for the optimal use of the 5xFAD mouse model in AD drug development and for investigating novel drug delivery approaches. In addition, the findings of the study shed light on the novel potential mechanisms underlying AD pathogenesis., (© 2022. The Author(s).)

Hypoxia induces changes in the secretion of extracellular vesicles (EVs) in several non-neuronal cells and pathological conditions. EVs are packed with biomolecules, such as microRNA(miR)-21-5p, which respond to hypoxia. However, the true EV association of miR-21-5p, and its functional or biomarker relevance, are inadequately characterised. Neurons are extremely sensitive cells, and it is not known whether the secretion of neuronal EVs and miR-21-5p are altered upon hypoxia. Here, we characterised the temporal EV secretion profile and cell viability of neurons under hypoxia. Hypoxia induced a rapid increase of miR-21a-5p secretion in the EVs, which preceded the elevation of hypoxia-induced tissue or cellular miR-21a-5p. Prolonged hypoxia induced cell death and the release of morphologically distinct EVs. The EVs protected miR-21a-5p from enzymatic degradation but a remarkable fraction of miR-21a-5p remained fragile and non-EV associated. The increase in miR-21a-5p secretion may have biomarker potential, as high blood levels of miR-21-5p in stroke patients were associated with significant disability at hospital discharge. Our data provides an understanding of the dynamic regulation of EV secretion from neurons under hypoxia and provides a candidate for the prediction of recovery from ischemic stroke., (© 2022 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.)