Anti-inflammatories in Alzheimer’s disease – potential therapy or spurious correlate?

Epidemiological evidence suggests non-steroidal anti-inflammatories (NSAIDs) reduce the risk of Alzheimer’s disease. However, clinical trials have found no evidence of NSAID efficacy. This incongruence may be due to the wrong NSAIDs being tested in robust clinical trials or the epidemiological findings being caused by confounding factors. Therefore, this study used logistic regression and the innovative approach of negative binomial generalised linear mixed modelling to investigate both prevalence and cognitive decline, respectively, in the Alzheimer’s Disease NeuroImaging dataset for each commonly used NSAID and paracetamol. Use of most NSAIDs were associated with reduced Alzheimer’s disease prevalence yet no effect on cognitive decline was observed. Paracetamol had a similar effect on prevalence to these NSAIDs suggesting this association is independent of the anti-inflammatory effects and that previous results may be due to spurious associations. Interestingly, diclofenac use was significantly associated with both reduce incidence and slower cognitive decline warranting further research into the potential therapeutic effects of diclofenac in Alzheimer’s disease

‘Plasticosis’: Characterising macro- and microplastic-associated fibrosis in seabird tissues

As biota are increasingly exposed to plastic pollution, there is a need to closely examine the sub-lethal 'hidden' impacts of plastic ingestion. This emerging field of study has been limited to model species in controlled laboratory settings, with little data available for wild, free-living organisms. Highly impacted by plastic ingestion, Flesh-footed Shearwaters (Ardenna carneipes) are thus an apt species to examine these impacts in an environmentally relevant manner. A Masson's Trichrome stain was used to document any evidence of plastic-induced fibrosis, using collagen as a marker for scar tissue formation in the proventriculus (stomach) of 30 Flesh-footed Shearwater fledglings from Lord Howe Island, Australia. Plastic presence was highly associated with widespread scar tissue formation and extensive changes to, and even loss of, tissue structure within the mucosa and submucosa. Additionally, despite naturally occurring indigestible items, such as pumice, also being found in the gastrointestinal tract, this did not cause similar scarring. This highlights the unique pathological properties of plastics and raises concerns for other species impacted by plastic ingestion. Further, the extent and severity of fibrosis documented in this study gives support for a novel, plastic-induced fibrotic disease, which we define as 'Plasticosis,'.Copyright © 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). The attached file is the published version of the article.NHM Repositor

Stroke Induces Prolonged Changes in Lipid Metabolism, the Liver and Body Composition in Mice

Acknowledgements We would like to thank the Biological Services Facility at the University of Manchester for expert animal husbandry and Karen Davies who helped with the MRI. The Histology Facility equipment that was used in this study was purchased by the University of Manchester Strategic Fund. Special thanks goes to Peter Walker for their help with the histology. Funding information This work was supported by the Kohn Foundation, an Edward Bonham Carter Doctoral Scholarship, an EPSRC/MRC Centre for Doctoral Training in Regenerative Medicine studentship grant (EP/L014904/1), and the Medical Research Council (MR/K501311/1).Peer reviewedPublisher PD

Zinc status alters Alzheimer’s disease progression through NLRP3-dependent inflammation

Alzheimer’s disease is a devastating neurodegenerative disease with a dramatically increasing prevalence and no disease-modifying treatment. Inflammatory lifestyle factors increase the risk of developing Alzheimer’s disease. Zinc deficiency is the most prevalent malnutrition in the world and may be a risk factor for Alzheimer’s disease potentially through enhanced inflammation, although evidence for this is limited. Here we provide epidemiological evidence suggesting that zinc supplementation was associated with reduced risk and slower cognitive decline, in people with Alzheimer’s disease and mild cognitive impairment. Using the APP/PS1 mouse model of Alzheimer’s disease fed a control (35mg/kg zinc) or diet deficient in zinc (3mg/kg zinc), we determined that zinc deficiency accelerated Alzheimer’s-like memory deficits without modifying amyloid beta (β) plaque burden in the brains of male mice. The NLRP3-inflammasome complex is one of the most important regulators of inflammation and we show here that zinc deficiency in immune cells, including microglia, potentiated NLRP3 responses to inflammatory stimuli in vitro including amyloid oligomers, while zinc supplementation inhibited NLRP3 activation. APP/PS1 mice deficient in NLRP3 were protected against the accelerated cognitive decline with zinc deficiency. Collectively, this research suggests that zinc status is linked to inflammatory reactivity and may be modified in people to reduce the risk and slow the progression of Alzheimer’s disease

Boletín Oficial de la Provincia de Oviedo: Número 238 - 1961 octubre 18

Cannabis sativa is an herbaceous plant that when consumed produces a number of well-known effects on the body, primarily elicited by two G-protein coupled receptors: cannabinoid receptor type 1 (CBI) and type 2 (CBII). Activation of the CBII receptor suppresses the inflammatory response of the immune system. Research has suggested that inflammation can be pathological in central nervous system (CNS) injuries and during early development the brain may be more sensitive to inflammation. Therefore, this research aimed to assess if CBII selective agonists could be neuroprotective in an animal model of childhood cerebral hypoxia (CCH) through an anti-inflammatory mechanism. A previously established model of CCH, that involved the ligation of the left carotid artery of a P26 rat, followed by a fixed hypoxic period, was chosen because of age suitability and its applicability to both asphyxia and stroke pathologies. Investigations into the variability of infarction in the established model, lead to the development of a new model that ended following a clonic tonic seizure. This new model caused significantly less variable brain infarctions compared to the previously reported model and was named Variable hypoxia ischemia (Variable HI). Two CBII agonists were then tested for neuroprotective properties in Variable HI using a partial agonist (GW405833) and a full agonist (HU910). Both single and multiple drug administration strategies were tested and found to provide no substantial tissue protection. Furthermore, behavioral tests were performed following the multiple administration strategy and no differences were found in any functional outcome. Therefore, the anti-inflammatory effects of CBII agonists are unlikely to be substantially therapeutic following CCH. It was argued that this lack of efficacy was caused by the possibility that inflammation is not truly pathological following CCH

Plastic debris increases circadian temperature extremes in beach sediments

Plastic pollution is the focus of substantial scientific and public interest, leading many to believe the issue is well documented and managed, with effective mitigation in place. However, many aspects are poorly understood, including fundamental questions relating to the scope and severity of impacts (e.g., demographic consequences at the population level). Plastics accumulate in significant quantities on beaches globally, yet the consequences for these terrestrial environments are largely unknown. Using real world, in situ measurements of circadian thermal fluctuations of beach sediment on Henderson Island and Cocos (Keeling) Islands, we demonstrate that plastics increase circadian temperature extremes. Particular plastic levels were associated with increases in daily maximum temperatures of 2.45 °C and decreases of daily minimum by − 1.50 °C at 5 cm depth below the accumulated plastic. Mass of surface plastic was high on both islands (Henderson: 571 ± 197 g/m2; Cocos: 3164 ± 1989 g/m2), but did not affect thermal conductivity, specific heat capacity, thermal diffusivity, or moisture content of beach sediments. Therefore, we suggest plastic effects sediment temperatures by altering thermal inputs and outputs (e.g., infrared radiation absorption). The resulting circadian temperature fluctuations have potentially significant implications for terrestrial ectotherms, many of which have narrow thermal tolerance limits and are functionally important in beach habitats.Copyright © 2021, The Authors. This document is the author’s final accepted version of the journal article. You are advised to consult the published version if you wish to cite from it

The one-two punch of plastic exposure: Macro- and micro-plastics induce multi-organ damage in seabirds

Plastic pollution in the world's oceans is ubiquitous and increasing. The environment is inundated with microplastics (< 1 mm), and the health effects of these less conspicuous pollutants is poorly known. In addition, there is now evidence that macroplastics can release microplastics in the form of shedding or digestive fragmentation, meaning there is potential for macroplastic exposure to induce direct and indirect pathology through microplastics. Therefore, there is an urgent need for data from wild populations on the relationship between macro- and microplastic exposure and the potential compounding pathological effects of these forms of plastics. We investigated the presence and impact of microplastics in multiple tissues from Flesh-footed Shearwaters Ardenna carneipes, a species that ingests considerable quantities of plastics, and used histopathological techniques to measure physiological responses and inflammation from the plastics. All organs examined (kidney, spleen, proventriculus) had embedded microplastic particles and this correlated with macroplastic exposure. Considerable tissue damage was recorded, including a significant reduction in tubular glands and rugae in the proventriculus, and evidence of inflammation, fibrosis, and loss of organ structures in the kidney and spleen. This indicates macroplastics can induce damage directly at the site of exposure, while microplastics can be mobilised throughout the body causing widespread pathology. Collectively, these results indicate the scope and severity of the health impacts of plastic pollution may be grossly underestimated.Copyright © 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) The attached file is the published version of the article

Determination of the mass distribution in the Galactic centre from the stellar motions

We present an implementation of the statistical approach to the stars-gas mass exchange cycle into an N-body code. First, we summarize available data on stellar mass-loss and derive the time-dependency of the mass-loss rate of a single stellar population. Since the adopted probabilistic scheme that served as a basis for our implementation was limited to the linear star formation law while observations seem to suggest a non-linearity, we derive the non-linear star formation scheme. Both sides of the mass exchange cycle are then implemented into the code with stellar and gaseous particles and compared with an analytic recipe to test their reliability. In the next step, the comparison of such an extended statistical approach with deterministic scheme is performed for a fully dynamical model. The aim of the comparison is to explore divergence between both models of different natures. As an illustration of the code application and sensitivity of the resulting galaxy disk dynamics, several comparisons with varying the key parameters are performed.Astronomický ústav UKAstronomical Institute of Charles UniversityFaculty of Mathematics and PhysicsMatematicko-fyzikální fakult

Mitochondrial Abnormalities and Synaptic Loss Underlie Memory Deficits Seen in Mouse Models of Obesity and Alzheimer's Disease

Obesity is associated with impaired memory in humans, and obesity induced by high-fat diets leads to cognitive deficits in rodents and in mouse models of Alzheimer’s disease (AD). However, it remains unclear how high-fat diets contribute to memory impairment. Therefore, we tested the effect of a high-fat diet on memory in male and female control non-transgenic (Non-Tg) and triple-transgenic AD (3xTgAD) mice and determined if a high-fat diet caused similar ultrastructural abnormalities to those observed in AD. Behavior was assessed in mice on control or high-fat diet at 4, 8, or 14 months of age and ultrastructural analysis at 8 months of age. A high-fat diet increased body weight, fat weight, and insulin levels with some differences in these metabolic responses observed between Non-Tg and 3xTgAD mice. In both sexes, high-fat feeding caused memory impairments in Non-Tg mice and accelerated memory deficits in 3xTgAD mice. In 3xTgAD mice, changes in hippocampal mitochondrial morphology were observed in capillaries and brain neuropil that were accompanied by a reduction in synapse number. A high-fat diet also caused mitochondria abnormalities and a reduction in synapse number in Non-Tg mice, but did not exacerbate the changes seen in 3xTgAD mice. Our data demonstrate that a high-fat diet affected memory in Non-Tg mice and produced similar impairments in mitochondrial morphology and synapse number comparable to those seen in AD mice, suggesting that the detrimental effects of a high-fat diet on memory might be due to changes in mitochondrial morphology leading to a reduction in synaptic number