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Aggregation and structure of amyloid β-protein. Ono Kenjiro,Watanabe-Nakayama Takahiro Neurochemistry international Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder and is characterized by major pathological hallmarks in the brain, including plaques composed of amyloid β-protein (Aβ) and neurofibrillary tangles of tau protein. Genetic studies, biochemical data, and animal models have suggested that Aβ is a critical species in the pathogenesis of AD. Aβ molecules aggregate to form oligomers, protofibrils (PFs), and mature fibrils. Because of their instability and structural heterogeneity, the misfolding and aggregation of Aβ is a highly complex process, leading to a variety of aggregates with different structures and morphologies. However, the elucidation of Aβ molecules is essential because they are believed to play an important role in AD pathogenesis. Recent combination studies using nuclear magnetic resonance (NMR) and cryo-electron microscopy (cryo-EM) have primarily revealed more detailed information about their aggregation process, including fibril extension and secondary nucleation, and the structural polymorphism of the fibrils under a variety of some conditions, including the actual brain. This review attempts to summarize the existing information on the major properties of the structure and aggregation of Aβ. 10.1016/j.neuint.2021.105208
Alzheimer's disease. Blennow Kaj,de Leon Mony J,Zetterberg Henrik Lancet (London, England) Alzheimer's disease is the most common cause of dementia. Research advances have enabled detailed understanding of the molecular pathogenesis of the hallmarks of the disease--ie, plaques, composed of amyloid beta (Abeta), and tangles, composed of hyperphosphorylated tau. However, as our knowledge increases so does our appreciation for the pathogenic complexity of the disorder. Familial Alzheimer's disease is a very rare autosomal dominant disease with early onset, caused by mutations in the amyloid precursor protein and presenilin genes, both linked to Abeta metabolism. By contrast with familial disease, sporadic Alzheimer's disease is very common with more than 15 million people affected worldwide. The cause of the sporadic form of the disease is unknown, probably because the disease is heterogeneous, caused by ageing in concert with a complex interaction of both genetic and environmental risk factors. This seminar reviews the key aspects of the disease, including epidemiology, genetics, pathogenesis, diagnosis, and treatment, as well as recent developments and controversies. 10.1016/S0140-6736(06)69113-7
The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics. Nature reviews. Drug discovery Many drugs that target amyloid-β (Aβ) in Alzheimer disease (AD) have failed to demonstrate clinical efficacy. However, four anti-Aβ antibodies have been shown to mediate the removal of amyloid plaque from brains of patients with AD, and the FDA has recently granted accelerated approval to one of these, aducanumab, using reduction of amyloid plaque as a surrogate end point. The rationale for approval and the extent of the clinical benefit from these antibodies are under intense debate. With the aim of informing this debate, we review clinical trial data for drugs that target Aβ from the perspective of the temporal interplay between the two pathognomonic protein aggregates in AD - Aβ plaques and tau neurofibrillary tangles - and their relationship to cognitive impairment, highlighting differences in drug properties that could affect their clinical performance. On this basis, we propose that Aβ pathology drives tau pathology, that amyloid plaque would need to be reduced to a low level (~20 centiloids) to reveal significant clinical benefit and that there will be a lag between the removal of amyloid and the potential to observe a clinical benefit. We conclude that the speed of amyloid removal from the brain by a potential therapy will be important in demonstrating clinical benefit in the context of a clinical trial. 10.1038/s41573-022-00391-w
Understanding the Amyloid Hypothesis in Alzheimer's Disease. Paroni Giulia,Bisceglia Paola,Seripa Davide Journal of Alzheimer's disease : JAD The amyloid hypothesis (AH) is still the most accepted model to explain the pathogenesis of inherited Alzheimer's disease (IAD). However, despite the neuropathological overlapping with the non-inherited form (NIAD), AH waver in explaining NIAD. Thus, 30 years after its first statement several questions are still open, mainly regarding the role of amyloid plaques (AP) and apolipoprotein E (APOE). Accordingly, a pathogenetic model including the role of AP and APOE unifying IAD and NIAD pathogenesis is still missing. In the present understanding of the AH, we suggested that amyloid-β (Aβ) peptides production and AP formation is a physiological aging process resulting from a systemic age-related decrease in the efficiency of the proteins catabolism/clearance machinery. In this pathogenetic model Aβ peptides act as neurotoxic molecules, but only above a critical concentration [Aβ]c. A threshold mechanism triggers IAD/NIAD onset only when [Aβ]≥[Aβ]c. In this process, APOE modifies [Aβ]c threshold in an isoform-specific way. Consequently, all factors influencing Aβ anabolism, such as amyloid beta precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) gene mutations, and/or Aβ catabolism/clearance could contribute to exceed the threshold [Aβ]c, being characteristic of each individual. In this model, AP formation does not depend on [Aβ]c. The present interpretation of the AH, unifying the pathogenetic theories for IAD and NIAD, will explain why AP and APOE4 may be observed in healthy aging and why they are not the cause of AD. It is clear that further studies are needed to confirm our pathogenetic model. Nevertheless, our suggestion may be useful to better understand the pathogenesis of AD. 10.3233/JAD-180802
Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. Bloom George S JAMA neurology The defining features of Alzheimer disease (AD) include conspicuous changes in both brain histology and behavior. The AD brain is characterized microscopically by the combined presence of 2 classes of abnormal structures, extracellular amyloid plaques and intraneuronal neurofibrillary tangles, both of which comprise highly insoluble, densely packed filaments. The soluble building blocks of these structures are amyloid-β (Aβ) peptides for plaques and tau for tangles. Amyloid-β peptides are proteolytic fragments of the transmembrane amyloid precursor protein, whereas tau is a brain-specific, axon-enriched microtubule-associated protein. The behavioral symptoms of AD correlate with the accumulation of plaques and tangles, and they are a direct consequence of the damage and destruction of synapses that mediate memory and cognition. Synapse loss can be caused by the failure of live neurons to maintain functional axons and dendrites or by neuron death. During the past dozen years, a steadily accumulating body of evidence has indicated that soluble forms of Aβ and tau work together, independently of their accumulation into plaques and tangles, to drive healthy neurons into the diseased state and that hallmark toxic properties of Aβ require tau. For instance, acute neuron death, delayed neuron death following ectopic cell cycle reentry, and synaptic dysfunction are triggered by soluble, extracellular Aβ species and depend on soluble, cytoplasmic tau. Therefore, Aβ is upstream of tau in AD pathogenesis and triggers the conversion of tau from a normal to a toxic state, but there is also evidence that toxic tau enhances Aβ toxicity via a feedback loop. Because soluble toxic aggregates of both Aβ and tau can self-propagate and spread throughout the brain by prionlike mechanisms, successful therapeutic intervention for AD would benefit from detecting these species before plaques, tangles, and cognitive impairment become evident and from interfering with the destructive biochemical pathways that they initiate. 10.1001/jamaneurol.2013.5847
The complexity of Alzheimer's disease: an evolving puzzle. Ferrari Camilla,Sorbi Sandro Physiological reviews The history of Alzheimer's disease (AD) started in 1907, but we needed to wait until the end of the century to identify the components of pathological hallmarks and genetic subtypes and to formulate the first pathogenic hypothesis. Thanks to biomarkers and new technologies, the concept of AD then rapidly changed from a static view of an amnestic dementia of the presenium to a biological entity that could be clinically manifested as normal cognition or dementia of different types. What is clearly emerging from studies is that AD is heterogeneous in each aspect, such as amyloid composition, tau distribution, relation between amyloid and tau, clinical symptoms, and genetic background, and thus it is probably impossible to explain AD with a single pathological process. The scientific approach to AD suffers from chronological mismatches between clinical, pathological, and technological data, causing difficulty in conceiving diagnostic gold standards and in creating models for drug discovery and screening. A recent mathematical computer-based approach offers the opportunity to study AD in real life and to provide a new point of view and the final missing pieces of the AD puzzle. 10.1152/physrev.00015.2020
The water maze paradigm in experimental studies of chronic cognitive disorders: Theory, protocols, analysis, and inference. Kapadia Minesh,Xu Josie,Sakic Boris Neuroscience and biobehavioral reviews An instrumental step in assessing the validity of animal models of chronic cognitive disorders is to document disease-related deficits in learning/memory capacity. The water maze (WM) is a popular paradigm because of its low cost, relatively simple protocol and short procedure time. Despite being broadly accepted as a spatial learning task, inference of generalized, bona fide "cognitive" dysfunction can be challenging because task accomplishment is also reliant on non-cognitive processes. We review theoretical background, testing procedures, confounding factors, as well as approaches to data analysis and interpretation. We also describe an extended protocol that has proven useful in detecting early performance deficits in murine models of neuropsychiatric lupus and Alzheimer's disease. Lastly, we highlight the need for standardization of inferential criteria on "cognitive" dysfunction in experimental rodents and exclusion of preparations of a limited scientific merit. A deeper appreciation for the multifactorial nature of performance in WM may also help to reveal other deficits that herald the onset of neurodegenerative brain disorders. 10.1016/j.neubiorev.2016.05.016
Drinking water temperature affects cognitive function and progression of Alzheimer's disease in a mouse model. Acta pharmacologica Sinica Lifestyle factors may affect mental health and play a critical role in the development of neurodegenerative diseases including Alzheimer's disease (AD). However, whether the temperatures of daily beverages have any impact on cognitive function and AD development has never been studied. In this study, we investigated the effects of daily drinking water temperatures on cognitive function and AD development and progression in mice and the underlying mechanisms. Cognitive function of mice was assessed using passive avoidance test, open field test, and Morris water maze. Wild-type Kunming mice receiving intragastric water (IW, 10 mL/kg, 2 times/day) at 0 °C for consecutive 15 days displayed significant cognitive defects accompanied by significant decrease in gain of body weight, gastric emptying rate, pepsin activity, and an increase in the energy charge in the cortex when compared with mice receiving the same amount of IW at 25 °C (a temperature mimicking most common drinking habits in human), suggesting the altered neuroenergetics may cause cognitive decline. Similarly, in the transgenic APPwse/PS1De9 familial AD mice and their age- and gender-matched wild-type C57BL/6 mice, receiving IW at 0 °C, but not at 25 °C, for 35 days caused a significant time-dependent decrease in body weight and cognitive function, accompanied by a decreased expression of PI3K, Akt, the glutamate/GABA ratio, as well as neuropathy with significant amyloid lesion in the cortex and hippocampus. All of these changes were significantly aggravated in the APPwse/PS1De9 mice than in the control C57BL/6 mice. These data demonstrate that daily beverage at 0 °C may alter brain insulin-mediated neuroenergetics, glutamate/GABA ratio, cause cognitive decline and neuropathy, and promote AD progression. 10.1038/s41401-020-0407-5
Virtual Morris water maze: opportunities and challenges. Thornberry Conor,Cimadevilla Jose M,Commins Sean Reviews in the neurosciences The ability to accurately recall locations and navigate our environment relies on multiple cognitive mechanisms. The behavioural and neural correlates of spatial navigation have been repeatedly examined using different types of mazes and tasks with animals. Accurate performances of many of these tasks have proven to depend on specific circuits and brain structures and some have become the standard test of memory in many disease models. With the introduction of virtual reality (VR) to neuroscience research, VR tasks have become a popular method of examining human spatial memory and navigation. However, the types of VR tasks used to examine navigation across laboratories appears to greatly differ, from open arena mazes and virtual towns to driving simulators. Here, we examined over 200 VR navigation papers, and found that the most popular task used is the virtual analogue of the Morris water maze (VWM). Although we highlight the many advantages of using the VWM task, there are also some major difficulties related to the widespread use of this behavioural method. Despite the task's popularity, we demonstrate an inconsistency of use - particularly with respect to the environmental setup and procedures. Using different versions of the virtual water maze makes replication of findings and comparison of results across researchers very difficult. We suggest the need for protocol and design standardisation, alongside other difficulties that need to be addressed, if the virtual water maze is to become the 'gold standard' for human spatial research similar to its animal counterpart. 10.1515/revneuro-2020-0149
Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nature protocols The Morris water maze (MWM) is a test of spatial learning for rodents that relies on distal cues to navigate from start locations around the perimeter of an open swimming arena to locate a submerged escape platform. Spatial learning is assessed across repeated trials and reference memory is determined by preference for the platform area when the platform is absent. Reversal and shift trials enhance the detection of spatial impairments. Trial-dependent, latent and discrimination learning can be assessed using modifications of the basic protocol. Search-to-platform area determines the degree of reliance on spatial versus non-spatial strategies. Cued trials determine whether performance factors that are unrelated to place learning are present. Escape from water is relatively immune from activity or body mass differences, making it ideal for many experimental models. The MWM has proven to be a robust and reliable test that is strongly correlated with hippocampal synaptic plasticity and NMDA receptor function. We present protocols for performing variants of the MWM test, from which results can be obtained from individual animals in as few as 6 days. 10.1038/nprot.2006.116
Morris water maze: a versatile and pertinent tool for assessing spatial learning and memory. Experimental animals Since its development about 40 years ago (1981-2021), Morris water maze has turned into a very popular tool for assessing spatial learning and memory. Its many advantages have ensured its pertinence to date. These include its effectiveness in evaluating hippocampal-dependent learning and memory, exemption from motivational differences across diverse experimental manipulations, reliability in various cross-species studies, and adaptability to many experimental conditions with various test protocols. Nonetheless, throughout its establishment, several experimental and analysis loopholes have galvanized researchers to assess ways in which it could be improved and adapted to fill this gap. Therefore, in this review, we briefly summarize these developments since the early years of its establishment through to the most recent advancements in computerized analysis, offering more comprehensive analysis paradigms. In addition, we discuss the adaptability of the Morris water maze across different test versions and analysis paradigms, providing suggestions with regard to the best paradigms for particular experimental conditions. Hence, the proper selection of the experimental protocols, analysis paradigms, and consideration of the assay's limitations should be carefully considered. Given that appropriate measures are taken, with various adaptations made, the Morris water maze will likely remain a relevant tool to assess the mechanisms of spatial learning and memory. 10.1538/expanim.21-0120
A Microfluidic Cell Co-Culture Chip for the Monitoring of Interactions between Macrophages and Fibroblasts. Biosensors Macrophages and fibroblasts are two types of important cells in wound healing. The development of novel platforms for studying the interrelationship between these two cells is crucial for the exploration of wound-healing mechanisms and drug development. In this study, a microfluidic chip composed of two layers was designed for the co-culturing of these two cells. An air valve was employed to isolate fibroblasts to simulate the wound-healing microenvironment. The confluence rate of fibroblasts in the co-culture system with different macrophages was explored to reflect the role of different macrophages in wound healing. It was demonstrated that M2-type macrophages could promote the activation and migration of fibroblasts and it can be inferred that they could promote the wound-healing process. The proposed microfluidic co-culture system was designed for non-contact cell-cell interactions, which has potential significance for the study of cell-cell interactions in biological processes such as wound healing, tumor microenvironment, and embryonic development. 10.3390/bios13010070
Organoid Co-culture Methods to Capture Cancer Cell-Natural Killer Cell Interactions. Methods in molecular biology (Clifton, N.J.) Metastasis is a complex process that has been historically difficult to model in culture. Host immune responses play critical roles in restraining and promoting metastatic tumor cells. Here we describe a method of 3D organotypic co-culture of natural killer cells and tumor organoids to capture interactions between the two cellular populations. These assays can be used to model key aspects of metastatic biology and to screen for the effectiveness of agents that stimulate natural killer cell cytotoxicity. 10.1007/978-1-0716-2160-8_17
A primary neural cell culture model to study neuron, astrocyte, and microglia interactions in neuroinflammation. Goshi Noah,Morgan Rhianna K,Lein Pamela J,Seker Erkin Journal of neuroinflammation BACKGROUND:Interactions between neurons, astrocytes, and microglia critically influence neuroinflammatory responses to insult in the central nervous system. In vitro astrocyte and microglia cultures are powerful tools to study specific molecular pathways involved in neuroinflammation; however, in order to better understand the influence of cellular crosstalk on neuroinflammation, new multicellular culture models are required. METHODS:Primary cortical cells taken from neonatal rats were cultured in a serum-free "tri-culture" medium formulated to support neurons, astrocytes, and microglia, or a "co-culture" medium formulated to support only neurons and astrocytes. Caspase 3/7 activity and morphological changes were used to quantify the response of the two culture types to different neuroinflammatory stimuli mimicking sterile bacterial infection (lipopolysaccharide (LPS) exposure), mechanical injury (scratch), and seizure activity (glutamate-induced excitotoxicity). The secreted cytokine profile of control and LPS-exposed co- and tri-cultures were also compared. RESULTS:The tri-culture maintained a physiologically relevant representation of neurons, astrocytes, and microglia for 14 days in vitro, while the co-cultures maintained a similar population of neurons and astrocytes, but lacked microglia. The continuous presence of microglia did not negatively impact the overall health of the neurons in the tri-culture, which showed reduced caspase 3/7 activity and similar neurite outgrowth as the co-cultures, along with an increase in the microglia-secreted neurotrophic factor IGF-1 and a significantly reduced concentration of CX3CL1 in the conditioned media. LPS-exposed tri-cultures showed significant astrocyte hypertrophy, increase in caspase 3/7 activity, and the secretion of a number of pro-inflammatory cytokines (e.g., TNF, IL-1α, IL-1β, and IL-6), none of which were observed in LPS-exposed co-cultures. Following mechanical trauma, the tri-culture showed increased caspase 3/7 activity, as compared to the co-culture, along with increased astrocyte migration towards the source of injury. Finally, the microglia in the tri-culture played a significant neuroprotective role during glutamate-induced excitotoxicity, with significantly reduced neuron loss and astrocyte hypertrophy in the tri-culture. CONCLUSIONS:The tri-culture consisting of neurons, astrocytes, and microglia more faithfully mimics in vivo neuroinflammatory responses than standard mono- and co-cultures. This tri-culture can be a useful tool to study neuroinflammation in vitro with improved accuracy in predicting in vivo neuroinflammatory phenomena. 10.1186/s12974-020-01819-z
Co-culture of human alveolar epithelial (hAELVi) and macrophage (THP-1) cell lines. Kletting Stephanie,Barthold Sarah,Repnik Urska,Griffiths Gareth,Loretz Brigitta,Schneider-Daum Nicole,de Souza Carvalho-Wodarz Cristiane,Lehr Claus-Michael ALTEX The air-blood barrier is mainly composed of alveolar epithelial cells and macrophages. Whereas the epithelium acts as a diffusional barrier, macrophages represent an immunological barrier, in particular for larger molecules and nanoparticles. This paper describes a new co-culture of human cell lines representing both cell types. Acquiring, culturing and maintaining primary alveolar epithelial cells presents significant logistical and technical difficulties. The recently established human alveolar epithelial lentivirus immortalized cell line, hAELVi, when grown on permeable filters, form monolayers with high functional and morphological resemblance to alveolar type I cells. To model alveolar macrophages, the human cell line THP-1 was seeded on pre-formed hAELVi monolayers. The co-culture was characterized regarding cellular morphology, viability and barrier function. Macrophages were homogenously distributed on the epithelium and could be kept in co-culture for up to 7 days. Transmission electron microscopy showed loose contact between THP-1 and hAELVi cells. When grown at air liquid interface, both cells were covered with extracellular matrix-like structure, which was absent in THP-1 mono culture. In co-culture with macrophages, hAELVi cells displayed similar, sometimes even higher, trans-epithelial electrical resistance than in mono-cultures. When exposed to silver and starch NPs, hAELVi mono-cultures were more tolerant to the particles than THP-1 mono-cultures. The viability in the co-culture was similar to that of hAELVi monocultures. Transport studies with sodium fluorescein in presence/absence of EDTA proved that the co culture acts as functional diffusion barrier. These data demonstrate that hAELVi-/THP-1 co-cultures represent a promising model for safety and permeability studies of inhaled chemicals, drugs and nanoparticles. 10.14573/altex.1607191
Exploring the association between air pollution and Parkinson's disease or Alzheimer's disease: a Mendelian randomization study. Environmental science and pollution research international The correlation between air pollution and neurodegenerative diseases has garnered growing attention. Although observational studies have indicated a potential link between air pollution and neurodegenerative disease, establishing a causal relationship remains uncertain. To address this gap, we performed a two-sample Mendelian randomization analysis utilizing genetic instruments. This analysis aimed to investigate the causal connections between PM, PM, NO, and NO exposure and the occurrence of Parkinson's disease (PD) and Alzheimer's disease (AD). We implemented a series of filtering steps to identify suitable genetic instruments that demonstrated significant associations (P < 5 × 10) with PM, PM, NO, and NO. These instruments were derived from a comprehensive genome-wide association study (GWAS) encompassing up to 456,380 participants in the UK Biobank. To obtain summary statistics for PD (N = 482,730) and AD risk (N = 63,926), we utilized the most recent GWAS datasets available. For our primary analysis, we employed the inverse-variance weighted approach for two-sample MR. A multivariable MR (MVMR) was also performed to verify the impact of air pollution exposure on the risk of PD and AD. To ensure the robustness of our findings, sensitivity analyses and heterogeneity assessments were performed. In two-sample MR, by employing the inverse-variance weighted method, our result suggested that genetically NO exposure showed a significant association with an elevated risk of PD (OR = 4.07, 95% CI: 1.13 to 19.62, P = 0.034) and genetically PM exposure exhibited a significant association with a heightened risk of AD (OR = 1.93, 95% CI: 1.03-3.59, P = 0.040). Further MVMR analysis demonstrated that the causal effect between NO and PD disappeared (OR = 3.489, 95% CI: 0.01 to 2.1e + 03, P = 0.703), and only PM was associated with an increased risk of AD (OR = 6.500, 95% CI: 1.10 to 38.51, P = 0.039). Sensitivity analysis showed no detectable heterogeneity and pleiotropy (P > 0.05). Our findings demonstrate that NO and PM exposure may contribute to a risk of PD and AD, respectively. Future research is necessary to elucidate potential physiopathological mechanisms. 10.1007/s11356-023-31047-w
Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 811 subnational locations, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021. Lancet (London, England) BACKGROUND:Detailed, comprehensive, and timely reporting on population health by underlying causes of disability and premature death is crucial to understanding and responding to complex patterns of disease and injury burden over time and across age groups, sexes, and locations. The availability of disease burden estimates can promote evidence-based interventions that enable public health researchers, policy makers, and other professionals to implement strategies that can mitigate diseases. It can also facilitate more rigorous monitoring of progress towards national and international health targets, such as the Sustainable Development Goals. For three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has filled that need. A global network of collaborators contributed to the production of GBD 2021 by providing, reviewing, and analysing all available data. GBD estimates are updated routinely with additional data and refined analytical methods. GBD 2021 presents, for the first time, estimates of health loss due to the COVID-19 pandemic. METHODS:The GBD 2021 disease and injury burden analysis estimated years lived with disability (YLDs), years of life lost (YLLs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries using 100 983 data sources. Data were extracted from vital registration systems, verbal autopsies, censuses, household surveys, disease-specific registries, health service contact data, and other sources. YLDs were calculated by multiplying cause-age-sex-location-year-specific prevalence of sequelae by their respective disability weights, for each disease and injury. YLLs were calculated by multiplying cause-age-sex-location-year-specific deaths by the standard life expectancy at the age that death occurred. DALYs were calculated by summing YLDs and YLLs. HALE estimates were produced using YLDs per capita and age-specific mortality rates by location, age, sex, year, and cause. 95% uncertainty intervals (UIs) were generated for all final estimates as the 2·5th and 97·5th percentiles values of 500 draws. Uncertainty was propagated at each step of the estimation process. Counts and age-standardised rates were calculated globally, for seven super-regions, 21 regions, 204 countries and territories (including 21 countries with subnational locations), and 811 subnational locations, from 1990 to 2021. Here we report data for 2010 to 2021 to highlight trends in disease burden over the past decade and through the first 2 years of the COVID-19 pandemic. FINDINGS:Global DALYs increased from 2·63 billion (95% UI 2·44-2·85) in 2010 to 2·88 billion (2·64-3·15) in 2021 for all causes combined. Much of this increase in the number of DALYs was due to population growth and ageing, as indicated by a decrease in global age-standardised all-cause DALY rates of 14·2% (95% UI 10·7-17·3) between 2010 and 2019. Notably, however, this decrease in rates reversed during the first 2 years of the COVID-19 pandemic, with increases in global age-standardised all-cause DALY rates since 2019 of 4·1% (1·8-6·3) in 2020 and 7·2% (4·7-10·0) in 2021. In 2021, COVID-19 was the leading cause of DALYs globally (212·0 million [198·0-234·5] DALYs), followed by ischaemic heart disease (188·3 million [176·7-198·3]), neonatal disorders (186·3 million [162·3-214·9]), and stroke (160·4 million [148·0-171·7]). However, notable health gains were seen among other leading communicable, maternal, neonatal, and nutritional (CMNN) diseases. Globally between 2010 and 2021, the age-standardised DALY rates for HIV/AIDS decreased by 47·8% (43·3-51·7) and for diarrhoeal diseases decreased by 47·0% (39·9-52·9). Non-communicable diseases contributed 1·73 billion (95% UI 1·54-1·94) DALYs in 2021, with a decrease in age-standardised DALY rates since 2010 of 6·4% (95% UI 3·5-9·5). Between 2010 and 2021, among the 25 leading Level 3 causes, age-standardised DALY rates increased most substantially for anxiety disorders (16·7% [14·0-19·8]), depressive disorders (16·4% [11·9-21·3]), and diabetes (14·0% [10·0-17·4]). Age-standardised DALY rates due to injuries decreased globally by 24·0% (20·7-27·2) between 2010 and 2021, although improvements were not uniform across locations, ages, and sexes. Globally, HALE at birth improved slightly, from 61·3 years (58·6-63·6) in 2010 to 62·2 years (59·4-64·7) in 2021. However, despite this overall increase, HALE decreased by 2·2% (1·6-2·9) between 2019 and 2021. INTERPRETATION:Putting the COVID-19 pandemic in the context of a mutually exclusive and collectively exhaustive list of causes of health loss is crucial to understanding its impact and ensuring that health funding and policy address needs at both local and global levels through cost-effective and evidence-based interventions. A global epidemiological transition remains underway. Our findings suggest that prioritising non-communicable disease prevention and treatment policies, as well as strengthening health systems, continues to be crucially important. The progress on reducing the burden of CMNN diseases must not stall; although global trends are improving, the burden of CMNN diseases remains unacceptably high. Evidence-based interventions will help save the lives of young children and mothers and improve the overall health and economic conditions of societies across the world. Governments and multilateral organisations should prioritise pandemic preparedness planning alongside efforts to reduce the burden of diseases and injuries that will strain resources in the coming decades. FUNDING:Bill & Melinda Gates Foundation. 10.1016/S0140-6736(24)00757-8
Association of Long-term Exposure to Ambient Air Pollution With Cognitive Decline and Alzheimer's Disease-Related Amyloidosis. Biological psychiatry BACKGROUND:Air pollution induces neurotoxic reactions and may exert adverse effects on cognitive health. We aimed to investigate whether air pollutants accelerate cognitive decline and affect neurobiological signatures of Alzheimer's disease (AD). METHODS:We used a population-based cohort from the Chinese Longitudinal Healthy Longevity Survey with 31,573 participants and a 10-year follow-up (5878 cognitively unimpaired individuals in Chinese Longitudinal Healthy Longevity Survey followed for 5.95 ± 2.87 years), and biomarker-based data from the Chinese Alzheimer's Biomarker and Lifestyle study including 1131 participants who underwent cerebrospinal fluid measurements of AD-related amyloid-β (Aβ) and tau proteins. Cognitive impairment was determined by education-corrected performance on the China-Modified Mini-Mental State Examination. Annual exposures to fine particulate matter (PM), ground-level ozone (O), and nitrogen dioxide (NO) were estimated at areas of residence. Exposures were aggregated as 2-year averages preceding enrollments using Cox proportional hazards or linear models. RESULTS:Long-term exposure to PM (per 20 μg/m) increased the risk of cognitive impairment (hazard ratio, 1.100; 95% CI: 1.026-1.180), and similar associations were observed from separate cross-sectional analyses. Exposures to O and NO yielded elevated risk but with nonsignificant estimates. Individuals exposed to high PM manifested increased amyloid burdens as reflected by cerebrospinal fluid-AD biomarkers. Moreover, PM exposure-associated decline in global cognition was partly explained by amyloid pathology as measured by cerebrospinal fluid-Aβ/Aβ, P-tau/Aβ, and T-tau/Aβ, with mediation proportions ranging from 16.95% to 21.64%. CONCLUSIONS:Long-term exposure to PM contributed to the development of cognitive decline, which may be partly explained by brain amyloid accumulation indicative of increased AD risk. 10.1016/j.biopsych.2022.05.017
Air Pollution and the Risk of Parkinson's Disease: A Review. Movement disorders : official journal of the Movement Disorder Society Parkinson's disease, as well as other neurodegenerative disorders, are primarily characterized by pathological accumulation of proteins, inflammation, and neuron loss. Although there are some known genetic risk factors, most cases cannot be explained by genetics alone. Therefore, it is important to determine the environmental factors that confer risk and the mechanisms by which they act. Recent epidemiological studies have found that exposure to air pollution is associated with an increased risk for development of Parkinson's disease, although not all results are uniform. The variability between these studies is likely due to differences in what components of air pollution are measured, timing and methods used to determine exposures, and correction for other variables. There are several potential mechanisms by which air pollution could act to increase the risk for development of Parkinson's disease, including direct neuronal toxicity, induction of systemic inflammation leading to central nervous system inflammation, and alterations in gut physiology and the microbiome. Taken together, air pollution is an emerging risk factor in the development of Parkinson's disease. A number of potential mechanisms have been implicated by which it promotes neuropathology providing biological plausibility, and these mechanisms are likely relevant to the development of other neurodegenerative disorders such as Alzheimer's disease. This field is in its early stages, but a better understanding of how environmental exposures influence the pathogenesis of neurodegeneration is essential for reducing the incidence of disease and finding disease-modifying therapies. © 2022 International Parkinson and Movement Disorder Society. 10.1002/mds.28922
Air Pollution and Alzheimer's Disease: A Systematic Review and Meta-Analysis. Fu Pengfei,Yung Ken Kin Lam Journal of Alzheimer's disease : JAD BACKGROUND:Ambient air pollution has been associated with Alzheimer's disease (AD) in the elderly. However, its effects on AD have not been meta-analyzed comprehensively. OBJECTIVE:We conducted a systematic review and meta-analysis to assess the associations between air pollution and AD incidence. METHODS:We searched PubMed and Web of Science for indexed publications up to March 2020. Odds risk (OR) and confidence intervals (CI) were estimated for particulate matter (PM)10 (PM10), PM2.5, ozone (O3), nitrogen dioxide (NO2), sulfur dioxide (SO2), and carbon monoxide (CO). The subgroup analysis was conducted based on the pollution levels. RESULTS:Nine studies were included in the meta-analysis and review. The OR per 10μg/m3 increase of PM2.5 was 1.95 (95% CI: 0.88-4.30). The corresponding values per 10μg/m3 increment of other pollutants were 1.03 (95% CI: 0.68-1.57) for O3, 1.00 (95% CI: 0.89-1.13) for NO2, and 0.95 (95% CI: 0.91-0.99) for PM10 (only one study), respectively. Overall OR of the five air pollutants above with AD was 1.32 (95% CI: 1.09-1.61), suggesting a positive association between ambient air pollution and AD incidence. The sub-analysis indicated that the OR (2.20) in heavily polluted regions was notably higher than that in lightly polluted regions (1.06). Although AD risk rate data related to SO2 or CO exposure are still limited, the epidemiologic and toxicological evidence indicated that higher concentration of SO2 or CO exposure increased risks of dementia, implying that SO2 or CO might have a potential impact on AD. CONCLUSION:Air pollution exposure may exacerbate AD development. 10.3233/JAD-200483
Mortality, morbidity, and risk factors in China and its provinces, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet (London, England) BACKGROUND:Public health is a priority for the Chinese Government. Evidence-based decision making for health at the province level in China, which is home to a fifth of the global population, is of paramount importance. This analysis uses data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 to help inform decision making and monitor progress on health at the province level. METHODS:We used the methods in GBD 2017 to analyse health patterns in the 34 province-level administrative units in China from 1990 to 2017. We estimated all-cause and cause-specific mortality, years of life lost (YLLs), years lived with disability (YLDs), disability-adjusted life-years (DALYs), summary exposure values (SEVs), and attributable risk. We compared the observed results with expected values estimated based on the Socio-demographic Index (SDI). FINDINGS:Stroke and ischaemic heart disease were the leading causes of death and DALYs at the national level in China in 2017. Age-standardised DALYs per 100 000 population decreased by 33·1% (95% uncertainty interval [UI] 29·8 to 37·4) for stroke and increased by 4·6% (-3·3 to 10·7) for ischaemic heart disease from 1990 to 2017. Age-standardised stroke, ischaemic heart disease, lung cancer, chronic obstructive pulmonary disease, and liver cancer were the five leading causes of YLLs in 2017. Musculoskeletal disorders, mental health disorders, and sense organ diseases were the three leading causes of YLDs in 2017, and high systolic blood pressure, smoking, high-sodium diet, and ambient particulate matter pollution were among the leading four risk factors contributing to deaths and DALYs. All provinces had higher than expected DALYs per 100 000 population for liver cancer, with the observed to expected ratio ranging from 2·04 to 6·88. The all-cause age-standardised DALYs per 100 000 population were lower than expected in all provinces in 2017, and among the top 20 level 3 causes were lower than expected for ischaemic heart disease, Alzheimer's disease, headache disorder, and low back pain. The largest percentage change at the national level in age-standardised SEVs among the top ten leading risk factors was in high body-mass index (185%, 95% UI 113·1 to 247·7]), followed by ambient particulate matter pollution (88·5%, 66·4 to 116·4). INTERPRETATION:China has made substantial progress in reducing the burden of many diseases and disabilities. Strategies targeting chronic diseases, particularly in the elderly, should be prioritised in the expanding Chinese health-care system. FUNDING:China National Key Research and Development Program and Bill & Melinda Gates Foundation. 10.1016/S0140-6736(19)30427-1
Air pollution, glymphatic impairment, and Alzheimer's disease. Trends in neurosciences Epidemiological evidence demonstrates a link between air pollution exposure and the onset and progression of cognitive impairment and Alzheimer's disease (AD). However, current understanding of the underlying pathophysiological mechanisms is limited. This opinion article examines the hypothesis that air pollution-induced impairment of glymphatic clearance represents a crucial etiological event in the development of AD. Exposure to airborne particulate matter (PM) leads to systemic inflammation and neuroinflammation, increased metal load, respiratory and cardiovascular dysfunction, and sleep abnormalities. All these factors are known to reduce the efficiency of glymphatic clearance. Rescuing glymphatic function by restricting the impact of causative agents, and improving sleep and cardiovascular system health, may increase the efficiency of waste metabolite clearance and subsequently slow the progression of AD. In sum, we introduce air pollution-mediated glymphatic impairment as an important mechanistic factor to be considered when interpreting the etiology and progression of AD as well as its responsiveness to therapeutic interventions. 10.1016/j.tins.2023.08.010
Brain response in asthma: the role of "lung-brain" axis mediated by neuroimmune crosstalk. Frontiers in immunology In addition to typical respiratory symptoms, patients with asthma are frequently accompanied by cognitive decline, mood disorders (anxiety and depression), sleep disorders, olfactory disorders, and other brain response manifestations, all of which worsen asthma symptoms, form a vicious cycle, and exacerbate the burden on families and society. Therefore, studying the mechanism of neurological symptoms in patients with asthma is necessary to identify the appropriate preventative and therapeutic measures. In order to provide a comprehensive reference for related research, we compiled the pertinent literature, systematically summarized the latest research progress of asthma and its brain response, and attempted to reveal the possible "lung-brain" crosstalk mechanism and treatment methods at the onset of asthma, which will promote more related research to provide asthmatic patients with neurological symptoms new hope. 10.3389/fimmu.2023.1240248
Immunology on the brain. Nature reviews. Drug discovery 10.1038/d41573-023-00183-w
Lung-brain axis. Critical reviews in microbiology The appreciation of human microbiome is gaining strong grounds in biomedical research. In addition to gut-brain axis, is the lung-brain axis, which is hypothesised to link pulmonary microbes to neurodegenerative disorders and behavioural changes. There is a need for analysis based on emerging studies to map out the prospects for lung-brain axis. In this review, relevant English literature and researches in the field of 'lung-brain axis' is reported. We recommend all the highlighted prospective studies to be integrated with an interdisciplinary approach. This might require conceptual research approaches based on physiology and pathophysiology. Multimodal aspects should include experimental animal units, while exploring the research gaps and making reference to the already existing human data. The overall microbiome medicine is gaining more ground. Aetiological paths and experimental recommendations as per prospective studies in this review will be an important guideline to develop effective treatments for any lung induced neurodegenerative diseases. An in-depth knowledge of the bi-directional communication between host and microbiome in the lung could help treatment to respiratory infections, alleviate stress, anxiety and enhanced neurological effects. The timely prevention and treatment of neurodegenerative diseases requires paradigm shift of the aetiology and more innovative experimentation.Impact statementThe overall microbiome medicine is gaining more ground. An in-depth knowledge of the bi-directional communication between host and microbiome in the lung could confer treatment to respiratory infections, alleviate stress, anxiety and enhanced neurological effects. Based on this review, we recommend all the highlighted prospective studies to be integrated and be given an interdisciplinary approach. This might require conceptual research approaches based on physiology and pathophysiology. Multimodal aspects should include experimental animal units; while exploring the research gaps and making reference to the already existing human data. 10.1080/1040841X.2021.1960483
Brain-Airway Interactions in Asthma. Advances in experimental medicine and biology Asthma and brain interactions have long been appreciated and initially centered on increased anxiety and depression. Epidemiology studies have shown that early life stressors and situational disadvantages are risk factors for asthma. Conversely, the presence of asthma is a risk for mood and anxiety disorders, thus indicating a bidirectional effect between asthma and brain-related health. To substantiate asthma-brain interactions, validated instruments indicate and elucidate that communication likely exists between asthma and the brain. For example, provocation of an asthmatic response with an allergen challenge modulates how the brain responds to emotion-laden information. As detected by imaging studies, emotion-related brain activation is associated with generating airway inflammation. However, the specific mediators and processes mediating airway communication with the brain have yet to be established.Systemic inflammation is also associated with asthma and can affect other organ systems such as the cardiovascular system and the brain. Epidemiology studies have shown that asthma is a risk factor for dementia and Alzheimer's disease. In support of the importance of asthma as a risk factor for impaired cognitive function, imaging studies have shown changes to the white matter of the brain in asthma patients that resemble neuroinflammation changes seen in Alzheimer's disease and other neurodegenerative diseases. Therefore, bidirectional links between asthma and the brain exist with an important next research step to define asthma-brain interactions linked to neurodegeneration and dementia and explore whether treatments directed toward asthma-related inflammation can prevent the deleterious effects of asthma on brain health. 10.1007/978-3-031-32259-4_9
Alzheimer's disease. Lane C A,Hardy J,Schott J M European journal of neurology Alzheimer's disease, the commonest cause of dementia, is a growing global health concern with huge implications for individuals and society. In this review, current understanding of the epidemiology, genetics, pathology and pathogenesis of Alzheimer's disease is outlined, before its clinical presentation and current treatment strategies are discussed. Finally, the review discusses how our enhanced understanding of Alzheimer pathogenesis, including the recognition of a protracted preclinical phase, is informing new therapeutic strategies with the aim of moving from treatment to prevention. 10.1111/ene.13439
Alzheimer's disease. Lancet (London, England) In this Seminar, we highlight the main developments in the field of Alzheimer's disease. The most recent data indicate that, by 2050, the prevalence of dementia will double in Europe and triple worldwide, and that estimate is 3 times higher when based on a biological (rather than clinical) definition of Alzheimer's disease. The earliest phase of Alzheimer's disease (cellular phase) happens in parallel with accumulating amyloid β, inducing the spread of tau pathology. The risk of Alzheimer's disease is 60-80% dependent on heritable factors, with more than 40 Alzheimer's disease-associated genetic risk loci already identified, of which the APOE alleles have the strongest association with the disease. Novel biomarkers include PET scans and plasma assays for amyloid β and phosphorylated tau, which show great promise for clinical and research use. Multidomain lifestyle-based prevention trials suggest cognitive benefits in participants with increased risk of dementia. Lifestyle factors do not directly affect Alzheimer's disease pathology, but can still contribute to a positive outcome in individuals with Alzheimer's disease. Promising pharmacological treatments are poised at advanced stages of clinical trials and include anti-amyloid β, anti-tau, and anti-inflammatory strategies. 10.1016/S0140-6736(20)32205-4
Analyzing MiRNA-LncRNA Interactions. Paraskevopoulou Maria D,Hatzigeorgiou Artemis G Methods in molecular biology (Clifton, N.J.) Long noncoding RNAs (lncRNAs) are noncoding transcripts usually longer than 200 nts that have recently emerged as one of the largest and significantly diverse RNA families. The biological role and functions of lncRNAs are still mostly uncharacterized. Their target-mimetic, sponge/decoy function on microRNAs was recently uncovered. miRNAs are a class of noncoding RNA species (~22 nts) that play a central role in posttranscriptional regulation of protein coding genes by mRNA cleavage, direct translational repression and/or mRNA destabilization. LncRNAs can act as miRNA sponges, reducing their regulatory effect on mRNAs. This function introduces an extra layer of complexity in the miRNA-target interaction network. This chapter focuses on the study of miRNA-lncRNA interactions with either in silico or experimentally supported analyses. The proposed methodologies can be appropriately adapted in order to become the backbone of advanced multistep functional miRNA analyses. 10.1007/978-1-4939-3378-5_21
Revealing protein-lncRNA interaction. Ferrè Fabrizio,Colantoni Alessio,Helmer-Citterich Manuela Briefings in bioinformatics Long non-coding RNAs (lncRNAs) are associated to a plethora of cellular functions, most of which require the interaction with one or more RNA-binding proteins (RBPs); similarly, RBPs are often able to bind a large number of different RNAs. The currently available knowledge is already drawing an intricate network of interactions, whose deregulation is frequently associated to pathological states. Several different techniques were developed in the past years to obtain protein-RNA binding data in a high-throughput fashion. In parallel, in silico inference methods were developed for the accurate computational prediction of the interaction of RBP-lncRNA pairs. The field is growing rapidly, and it is foreseeable that in the near future, the protein-lncRNA interaction network will rise, offering essential clues for a better understanding of lncRNA cellular mechanisms and their disease-associated perturbations. 10.1093/bib/bbv031
Beyond the RNA-dependent function of LncRNA genes. Ali Tamer,Grote Phillip eLife While long non-coding RNA (lncRNA) genes have attracted a lot of attention in the last decade, the focus regarding their mechanisms of action has been primarily on the RNA product of these genes. Recent work on several lncRNAs genes demonstrates that not only is the produced RNA species important, but also that transcription of the lncRNA locus alone can have regulatory functions. Like the functions of lncRNA transcripts, the mechanisms that underlie these genome-based functions are varied. Here we highlight some of these examples and provide an outlook on how the functional mechanisms of a lncRNA gene can be determined. 10.7554/eLife.60583
LncRNA-mediated posttranslational modifications and reprogramming of energy metabolism in cancer. Tan Yue-Tao,Lin Jin-Fei,Li Ting,Li Jia-Jun,Xu Rui-Hua,Ju Huai-Qiang Cancer communications (London, England) Altered metabolism is a hallmark of cancer, and the reprogramming of energy metabolism has historically been considered a general phenomenon of tumors. It is well recognized that long noncoding RNAs (lncRNAs) regulate energy metabolism in cancer. However, lncRNA-mediated posttranslational modifications and metabolic reprogramming are unclear at present. In this review, we summarized the current understanding of the interactions between the alterations in cancer-associated energy metabolism and the lncRNA-mediated posttranslational modifications of metabolic enzymes, transcription factors, and other proteins involved in metabolic pathways. In addition, we discuss the mechanisms through which these interactions contribute to tumor initiation and progression, and the key roles and clinical significance of functional lncRNAs. We believe that an in-depth understanding of lncRNA-mediated cancer metabolic reprogramming can help to identify cellular vulnerabilities that can be exploited for cancer diagnosis and therapy. 10.1002/cac2.12108
Integrated lncRNA function upon genomic and epigenomic regulation. Molecular cell Although some long noncoding (lnc)RNAs are known since the 1950s, the past 25 years have uncovered myriad lncRNAs with diverse sequences, structures, and functions. The advent of high-throughput and sensitive technologies has further uncovered the vast heterogeneity of lncRNA-interacting molecules and patterns of expressed lncRNAs. We propose a unifying functional theme for the expansive family of lncRNAs. At an elementary level, the genomic program of gene expression is elicited via canonical transcription and post-transcriptional mRNA assembly, turnover, and translation. Building upon this regulation, an epigenomic program refines the basic genomic control by modifying chromatin architecture as well as DNA and RNA chemistry. Superimposed over the genomic and epigenomic programs, lncRNAs create an additional regulatory dimension: by interacting with the proteins and nucleic acids that regulate gene expression in the nucleus and cytoplasm, lncRNAs help establish robust, nimble, and specific transcriptional and post-transcriptional control. We describe our present understanding of lncRNA-coordinated control of protein programs and cell fate and discuss challenges and opportunities as we embark on the next 25 years of lncRNA discovery. 10.1016/j.molcel.2022.05.027
LNCcation: lncRNA localization and function. The Journal of cell biology Subcellular localization of RNAs has gained attention in recent years as a prevalent phenomenon that influences numerous cellular processes. This is also evident for the large and relatively novel class of long noncoding RNAs (lncRNAs). Because lncRNAs are defined as RNA transcripts >200 nucleotides that do not encode protein, they are themselves the functional units, making their subcellular localization critical to their function. The discovery of tens of thousands of lncRNAs and the cumulative evidence involving them in almost every cellular activity render assessment of their subcellular localization essential to fully understanding their biology. In this review, we summarize current knowledge of lncRNA subcellular localization, factors controlling their localization, emerging themes, including the role of lncRNA isoforms and the involvement of lncRNAs in phase separation bodies, and the implications of lncRNA localization on their function and on cellular behavior. We also discuss gaps in the current knowledge as well as opportunities that these provide for novel avenues of investigation. 10.1083/jcb.202009045
TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease. Ulland Tyler K,Song Wilbur M,Huang Stanley Ching-Cheng,Ulrich Jason D,Sergushichev Alexey,Beatty Wandy L,Loboda Alexander A,Zhou Yingyue,Cairns Nigel J,Kambal Amal,Loginicheva Ekaterina,Gilfillan Susan,Cella Marina,Virgin Herbert W,Unanue Emil R,Wang Yaming,Artyomov Maxim N,Holtzman David M,Colonna Marco Cell Elevated risk of developing Alzheimer's disease (AD) is associated with hypomorphic variants of TREM2, a surface receptor required for microglial responses to neurodegeneration, including proliferation, survival, clustering, and phagocytosis. How TREM2 promotes such diverse responses is unknown. Here, we find that microglia in AD patients carrying TREM2 risk variants and TREM2-deficient mice with AD-like pathology have abundant autophagic vesicles, as do TREM2-deficient macrophages under growth-factor limitation or endoplasmic reticulum (ER) stress. Combined metabolomics and RNA sequencing (RNA-seq) linked this anomalous autophagy to defective mammalian target of rapamycin (mTOR) signaling, which affects ATP levels and biosynthetic pathways. Metabolic derailment and autophagy were offset in vitro through Dectin-1, a receptor that elicits TREM2-like intracellular signals, and cyclocreatine, a creatine analog that can supply ATP. Dietary cyclocreatine tempered autophagy, restored microglial clustering around plaques, and decreased plaque-adjacent neuronal dystrophy in TREM2-deficient mice with amyloid-β pathology. Thus, TREM2 enables microglial responses during AD by sustaining cellular energetic and biosynthetic metabolism. 10.1016/j.cell.2017.07.023
TREM2 Regulates Microglial Cholesterol Metabolism upon Chronic Phagocytic Challenge. Nugent Alicia A,Lin Karin,van Lengerich Bettina,Lianoglou Steve,Przybyla Laralynne,Davis Sonnet S,Llapashtica Ceyda,Wang Junhua,Kim Do Jin,Xia Dan,Lucas Anthony,Baskaran Sulochanadevi,Haddick Patrick C G,Lenser Melina,Earr Timothy K,Shi Ju,Dugas Jason C,Andreone Benjamin J,Logan Todd,Solanoy Hilda O,Chen Hang,Srivastava Ankita,Poda Suresh B,Sanchez Pascal E,Watts Ryan J,Sandmann Thomas,Astarita Giuseppe,Lewcock Joseph W,Monroe Kathryn M,Di Paolo Gilbert Neuron Loss-of-function (LOF) variants of TREM2, an immune receptor expressed in microglia, increase Alzheimer's disease risk. TREM2 senses lipids and mediates myelin phagocytosis, but its role in microglial lipid metabolism is unknown. Combining chronic demyelination paradigms and cell sorting with RNA sequencing and lipidomics, we find that wild-type microglia acquire a disease-associated transcriptional state, while TREM2-deficient microglia remain largely homeostatic, leading to neuronal damage. TREM2-deficient microglia phagocytose myelin debris but fail to clear myelin cholesterol, resulting in cholesteryl ester (CE) accumulation. CE increase is also observed in APOE-deficient glial cells, reflecting impaired brain cholesterol transport. This finding replicates in myelin-treated TREM2-deficient murine macrophages and human iPSC-derived microglia, where it is rescued by an ACAT1 inhibitor and LXR agonist. Our studies identify TREM2 as a key transcriptional regulator of cholesterol transport and metabolism under conditions of chronic myelin phagocytic activity, as TREM2 LOF causes pathogenic lipid accumulation in microglia. 10.1016/j.neuron.2019.12.007
TREM2, microglia, and Alzheimer's disease. Qin Qi,Teng Zhaoqian,Liu Changmei,Li Qian,Yin Yunsi,Tang Yi Mechanisms of ageing and development Triggering receptor expressed on myeloid cells 2 (TREM2) has been suggested to play a crucial role in Alzheimer's disease (AD) pathogenesis, as revealed by genome-wide association studies (GWAS). Since then, rapidly increasing literature related to TREM2 has focused on elucidating its role in AD pathology. In this review, we summarize our understanding of TREM2 biology, explore TREM2 functions in microglia, address the multiple mechanisms of TREM2 in AD, and raise key questions for further investigations to elucidate the detailed roles and molecular mechanisms of TREM2 in microglial responses. A major breakthrough in our understanding of TREM2 is based on our hypothesis suggesting that TREM2 may act as a multifaceted player in microglial functions in AD brain homeostasis. We conclude that TREM2 can not only influence microglial functions in amyloid and tau pathologies but also participate in inflammatory responses and metabolism, acting alone or with other molecules, such as apolipoprotein E (APOE). This review provides novel insight into the broad role of TREM2 in microglial function in AD and enables us to develop new strategies aimed at the immune system to treat AD pathogenesis. 10.1016/j.mad.2021.111438
RAGE as a receptor of HMGB1 (Amphoterin): roles in health and disease. Rauvala Heikki,Rouhiainen Ari Current molecular medicine HMGB1/Amphoterin is a ubiquitous, highly conserved DNA-binding protein that can be also released to the extracellular space by various cell types. Extracellular HMGB1 regulates migratory responses of several cell types through binding to RAGE that communicates with the cytoskeleton to regulate cell motility. HMGB1-induced cell signalling has been associated with mechanisms of several diseases, including cancer, sepsis, rheumatoid arthritis, stroke and atherosclerosis. This article reviews the evidence linking the functional roles of HMGB1 to RAGE signalling. Furthermore, we discuss the molecular and cellular mechanisms that may explain the roles of HMGB1/RAGE in diverse disease processes.
Extracellular HMGB1 as a proinflammatory cytokine. Chen Guoqian,Ward Mary F,Sama Andrew E,Wang Haichao Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research High mobility group box-1 protein (HMGB1, formerly known as HMG-1), a highly conserved ubiquitous protein, has been for a long time described as a nuclear DNA-binding protein involved in nucleosome stabilization and gene transcription. Recent discoveries indicate that HMGB1 is released from activated innate immune cells or necrotic cells and functions as an important mediator of endotoxemia, sepsis, arthritis, and local inflammation. Therapeutic agents that inhibit HMGB1 release or action confer significant protection against endotoxemia, sepsis, and arthritis in animal models and thus hold potential for the clinical management of various inflammatory diseases. 10.1089/107999004323142187
Mesenchymal stromal cells alleviate depressive and anxiety-like behaviors via a lung vagal-to-brain axis in male mice. Nature communications Major depressive disorder (MDD) is one of the most common and disabling mental disorders, and current strategies remain inadequate. Although mesenchymal stromal cells (MSCs) have shown beneficial effects in experimental models of depression, underlying mechanisms remain elusive. Here, using murine depression models, we demonstrated that MSCs could alleviate depressive and anxiety-like behaviors not due to a reduction in proinflammatory cytokines, but rather activation of dorsal raphe nucleus (DRN) 5-hydroxytryptamine (5-HT) neurons. Mechanistically, peripheral delivery of MSCs activated pulmonary innervating vagal sensory neurons, which projected to the nucleus tractus solitarius, inducing the release of 5-HT in DRN. Furthermore, MSC-secreted brain-derived neurotrophic factor activated lung sensory neurons through tropomyosin receptor kinase B (TrkB), and inhalation of a TrkB agonist also achieved significant therapeutic effects in male mice. This study reveals a role of peripheral MSCs in regulating central nervous system function and demonstrates a potential "lung vagal-to-brain axis" strategy for MDD. 10.1038/s41467-023-43150-0
Immune regulation of the gut-brain axis and lung-brain axis involved in ischemic stroke. Neural regeneration research Local ischemia often causes a series of inflammatory reactions when both brain immune cells and the peripheral immune response are activated. In the human body, the gut and lung are regarded as the key reactional targets that are initiated by brain ischemic attacks. Mucosal microorganisms play an important role in immune regulation and metabolism and affect blood-brain barrier permeability. In addition to the relationship between peripheral organs and central areas and the intestine and lung also interact among each other. Here, we review the molecular and cellular immune mechanisms involved in the pathways of inflammation across the gut-brain axis and lung-brain axis. We found that abnormal intestinal flora, the intestinal microenvironment, lung infection, chronic diseases, and mechanical ventilation can worsen the outcome of ischemic stroke. This review also introduces the influence of the brain on the gut and lungs after stroke, highlighting the bidirectional feedback effect among the gut, lungs, and brain. 10.4103/1673-5374.380869
Functional Two-Way Crosstalk Between Brain and Lung: The Brain-Lung Axis. Cellular and molecular neurobiology The brain has many connections with various organs. Recent advances have demonstrated the existence of a bidirectional central nervous system (CNS) and intestinal tract, that is, the brain-gut axis. Although studies have suggested that the brain and lung can communicate with each other through many pathways, whether there is a brain-lung axis remains still unknown. Based on previous findings, we put forward a hypothesis: there is a cross-talk between the central nervous system and the lung via neuroanatomical pathway, endocrine pathway, immune pathway, metabolites and microorganism pathway, gas pathway, that is, the brain-lung axis. Beyond the regulation of the physiological state in the body, bi-directional communication between the lung and the brain is associated with a variety of disease states, including lung diseases and CNS diseases. Exploring the brain-lung axis not only helps us to understand the development of the disease from different aspects, but also provides an important target for treatment strategies. 10.1007/s10571-022-01238-z
Air pollution and coronary atherosclerosis. Future cardiology The recently introduced concept of 'exposome' emphasizes the impact of non-traditional threats onto cardiovascular health. Among these, air pollutants - particularly fine particulate matter < 2.5 μm (PM2.5) - have emerged as significant environmental risk factors for cardiovascular disease and mortality. PM2.5 exposure has been shown to induce endothelial dysfunction, chronic low-grade inflammation, and cardiometabolic impairment, contributing to the development and destabilization of atherosclerotic plaques. Both short- and long-term exposure to air pollution considerably increase the incidence of ischemic heart disease (IHD)-related events, with clinical evidence linking pollution to higher mortality and adverse prognosis, especially in vulnerable populations. In this review, we explore the mechanistic pathways through which air pollutants exacerbate atherosclerotic cardiovascular disease (ASCVD) and discuss their clinical impact.Furthermore, special attention will be directed to the outcomes and prognosis of patients with pollution-aggravated coronary atherosclerosis, as well as the potential role of targeted public health interventions. 10.1080/14796678.2025.2451545
When do science recommendations stop being effective? The case of the sprawl of diesel electricity generators in Beirut. PloS one Lebanon, plagued by political and economic crises, experienced a government collapse in early 2020, leading to an electrical nationwide blackout by 2023. Diesel generators were used to compensate for the absence of power production from the national provider, Electricité du Liban (EDL). To investigate the effect of the crisis on the levels of 16 EPA particle bound polycyclic aromatic hydrocarbons (PPAHs), an annual comparative analysis of three locations within Beirut started in 2022 and ended in 2023. The locations are: American University of Beirut (AUB), Beirut Central District (BCD) and Nursing School Makassed University (NSMU). Sampling took place and the PPAHs samples were extracted, quantified using Gas Chromatography-Mass spectrometry (GC-MS) and source apportioned using Positive Matrix Factorization (PMF). Particulate Matter 2.5μm (PM2.5) mean levels at AUB, BCD and NSMU, which was found to be 14.3 μg/m3, 18.3 μg/m3 and 22.6 μg/m3 respectively, beside the high annual PM2.5 mean level (17.19 μg/m3) exceeded the World Health Organization (WHO) standard levels. The factors identified in the three sites are diesel, incineration, and gasoline emissions. The dominant factor in three sites was the diesel emissions, specifically from generators, with 56% in BCD, 42% in AUB and 43% in NSMU. The contribution of diesel emission in AUB has increased by 100% since the last study in 2016-2017. Similarly, the excess cancer risk (ESR) in the three sites was above the EPA threshold with an increase of 53% compared to the one calculated previously in AUB. This situation, where law of enforcement is absent, need for international action to curb emissions and for funding agencies to adopt sustainable, "carbon-free" funding strategies to support urban development in low- and middle-income countries (LMICs). Yet, EDL's failure to fulfill Lebanon's populace electricity requirements infringes upon their electricity entitlements. 10.1371/journal.pone.0313341
The Relationship Between PM2.5 and Eight Common Lung Diseases: A Two-Sample Mendelian Randomization Analysis. Toxics Air pollutants have both acute and chronic impacts on human health, affecting multiple systems and organs. While PM2.5 exposure is commonly assumed to be strongly associated with all respiratory diseases, this relationship has not been systematically analyzed. This study employed a two-sample Mendelian randomization approach to investigate the effects of PM2.5 on eight common lung diseases, using data from GWAS. Additionally, multivariable Mendelian randomization was applied to assess the direct effects of various air pollutants and the mediating roles of common factors such as BMI and smoking. At a significance threshold of 5×10, PM2.5 showed a significant causal relationship with both asthma and COPD. When the screening threshold was relaxed to 5× 10, this exposure continued to demonstrate significant associations not only with asthma and COPD, but also with other respiratory diseases, including pneumonia, emphysema/chronic bronchitis, and lung cancer. In the multivariable Mendelian randomization analysis, which controlled for smoking and bacterial infections, the association with pneumonia became non-significant, while the relationships with the other four diseases persisted. This study provides a systematic exploration of the relationship between PM2.5 and eight pulmonary diseases from a new perspective, deepening our understanding of the impact of air pollution on health and laying the foundation for future efforts to mitigate these effects. 10.3390/toxics12120851
Outdoor air pollution exposure and the risk of type 2 diabetes mellitus: A systematic umbrella review and meta-analysis. Environmental research The association between different air pollutants and Type 2 Diabetes Mellitus (T2DM) is a growing topic of interest in public health research. This umbrella review and meta-analysis aimed to consolidate current literature on the association between various outdoor air pollutants and T2DM. Subgroups and dose-response relationships were also analyzed to further quantify the association, especially by the factors such as the type of pollutants, duration of exposure, and geographical variation, etc. A thorough literature search of three databases revealed a total of 71 records for umbrella review and 1524 records for meta-analysis where 8 studies were included in the final review of umbrella review and 46 studies for meta-analysis. The evaluation of the study's quality in umbrella review and meta-analysis were conducted using the AMSTAR 2 criteria and the Newcastle-Ottawa Scale (NOS), respectively. Exposure to Particulate Matter (PM) 2.5, PM10, Nitrogen dioxides (NO2) and Ozone (O3) were significantly associated with the risk of T2DM [OR = 1.12 (95% Confidence Interval (CI): 1.09, 1.15), 1.12 (95% CI: 1.06, 1.18), 1.09 (95%CI: 1.07, 1.12), 1.05 (95%CI: 1.03, 1.08), respectively] and subgroup analysis further revealed that PM2.5, PM10, and NO2 associations were confounded by factors such as ages, study design, regions of exposure and air pollution concentration levels. Lastly, only exposure to PM10 had a significant dose-response relationship with the risk of T2DM (p-value = 0.000). These findings further emphasized the need for standardized methods in conducting air pollution research and additional research on other air pollutants to further explore the relationships between these air pollutants and T2DM. 10.1016/j.envres.2025.120885
PM2.5 Exposure Triggers Hypothalamic Oxidative and ER Stress Leading to Depressive-like Behaviors in Rats. International journal of molecular sciences Epidemiological studies have linked fine dust pollution to depression, yet the underlying mechanisms remain unclear. Oxidative stress and endoplasmic reticulum (ER) stress are known contributors to depression, but their induction by particulate matter (PM), particularly PM2.5, in animal models has been limited. This study aimed to establish a rat model of PM2.5-induced depression-like behaviors and elucidate the underlying molecular mechanisms. Adult male Sprague-Dawley rats received daily intranasal PM2.5 for four weeks. Behavioral assessments, including the open field test (OFT), forced swim test (FST), and light-dark box (LDB) test, were conducted weekly. PM2.5-exposed rats displayed depressive-like behaviors, particularly in the FST, reflecting decreased motivation and learned helplessness. Molecular analyses indicated a specific increase in ER stress markers (CHOP, eIF2α, GRP78, and P16) and NOX4 in the hypothalamus, while other brain regions (striatum, cortex, and hippocampus) were not as pronounced. Additionally, PM2.5 exposure reduced tyrosine hydroxylase (TH) levels in the hypothalamus, suggesting impaired dopamine synthesis. These findings indicate that PM2.5 induces depressive-like behaviors via hypothalamic ER stress and oxidative stress pathways, leading to dopaminergic dysfunction. Targeting oxidative and ER stress within the hypothalamus may offer new therapeutic strategies for treating depression associated with environmental pollutants. 10.3390/ijms252413527
Impact of air pollution on the clinical exacerbation of central demyelinating disease: A 10-year data from the Northern Thailand MS and NMOSD registry. Multiple sclerosis and related disorders BACKGROUND:Particulate matter (PM) 2.5 (PM2.5) and PM10 are implicated in neurological diseases, yet their impact on central demyelinating diseases like multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) remains unclear. This study aimed to determine the association between the levels of PM2.5 and PM10 and the exacerbation of MS and NMOSD. METHODS:Patients with clinical exacerbations of MS and NMOSD in the Northern Thailand Registry from 2013 to 2022 were enrolled. Eligible patients were categorized based on air pollution exposure (defined as PM2.5 > 15 μg/m and PM10 > 45 μg/m) or no air pollution exposure. Outcomes assessed included clinical characteristics, Expanded Disability Status Scale (EDSS), and functional outcomes. RESULTS:We analyzed 126 exacerbations in the PM2.5 database (mean age: 44.9±14.9 years, 114 NMOSD, 49 first exacerbations) and 135 exacerbations with the PM10 database (mean age: 44.9±14.9 years, 121 NMOSD, 54 first exacerbations), with the highest incidence four months post-peak air pollution. The PM2.5 exposure group had higher severity, showing increased rates of unfavorable EDSS at exacerbation and 90 days (56.3% vs. 23.6%, P < 0.001 and 47.9% vs. 16.4%, P < 0.001, respectively). Gadolinium enhancement in PM2.5 exposure was significantly higher (56.3% vs. 36.4%, P = 0.03). The PM2.5 exposure group also had a higher rate of second-line therapy with plasma exchange (21.1% vs. 7.3%, P = 0.03). PM2.5 exposure, not PM10, was associated with unfavorable EDSS at any time point, active radiological activity, risk of plasma exchange, and prolonged hospitalization. CONCLUSION:Environmental pollution, especially PM2.5, significantly impacts MS and NMOSD patients, influencing disease severity, causing permanent disability, and prolonging hospitalization. A national policy on pollution control is imperative, and further data on long-term exposure, together with other pollutants, is still required. 10.1016/j.msard.2025.106266
Ambient pollution at hip fracture units and impact on mortality and post-operative delirium: A hormetic effect? PloS one There is increasing awareness of the deleterious effects of ambient pollution. The World Health Organisation (WHO) has recently advocated new safe limits of annual exposure for the three pre-dominant pollutants: fine particulate matter (PM2.5), coarse particulate matter (PM10) and nitrogen dioxide; namely 5μg/m3, 15μg/m3 and 10gμ/m3 respectively. Both the USA and UK have recently implemented news standards which are lower than their current values, but still exceed those espoused by WHO. The WHO thresholds are challenging targets. It remains to be determined the proportion of secondary healthcare institutions located in zones with mean ambient pollutant levels in excess of the WHO limits and the impact this has on patients treated at these centres. This is particularly so for elderly patients who are theoretically most vulnerable to the adverse sequel of pollutant exposure. Using the UK National Hip Fracture Database and Defra Data (Department of Environmental, Food & Rural Affairs) we determined the annual mean PM2.5 PM10 and nitrogen dioxide exposure for all the units treating senescent hip fracture patients. We correlated these ambient pollutant levels with all-cause 30-day mortality and incidence of post-operative delirium for hip fracture patients. The vast majority (96%) of hip fracture units were located in zones where mean PM2.5 levels exceeded that required by the WHO guidance. A sizeable proportion also had annual mean exposures that surpassed the WHO PM10 (14.8%) and nitrogen dioxide (63%) recommended thresholds. There was no difference in 30-day mortality between hip fracture patients treated at units located in areas where pollutant titres were subliminal to the WHO guidance levels and those treated at centres where WHO thresholds were exceeded. By way of contrast patients admitted to institutions with mean ambient PM10 and nitrogen dioxide concentrations that surpassed the WHO limits had a lower risk of post-operative delirium compared to those at centres where the mean levels did not breach the WHO limit. For PM10 the relative risk was 0.89 CI:0.82-0.92 (p<0.0001) and that for nitrogen dioxide 0.92 CI: 0.89-0.94 (p<0.0001). The WHO target is ambitious as it relates to healthcare institutions. The majority are in areas that exceed WHO recommended limits. This does not appear to impact upon mortality for hip fracture patients. The decrease in incidence in post-operative delirium in areas of higher exposure raises, again in an epidemiological study, the possibility of the enigmatic phenomenon of hormesis, an adaptive response whereby low-dose exposure to a noxious agent or physiological stress enhances future physiological function. 10.1371/journal.pone.0315824