Age-Related Neuroinflammatory Changes Negatively Impact on Neuronal Function

Neuroinflammatory changes, characterized by an increase in microglial activation and often accompanied by upregulation of inflammatory cytokines like interleukin-1β (IL-1β), are common to many, if not all, neurodegenerative diseases. Similar, though less dramatic neuroinflammatory changes, are also known to occur with age. Among the consequences of these changes is an impairment in synaptic function and the evidence suggests that inflammatory cytokines may be the primary contributory factor responsible for the deficits in synaptic plasticity which have been identified in aged rodents. Specifically a decrease in the ability of aged rats to sustain long-term potentiation (LTP) in perforant path-granule cells of the hippocampus is associated with increased microglial activation. This review considers the evidence which suggests a causal relationship between these changes and the factors which contribute to the age-related microglial activation, and reflects on data which demonstrate that agents which inhibit microglial activation also improve ability of rats to sustain LTP

A case for seeking sex-specific treatments in Alzheimer’s disease

There is no satisfactory explanation for the sex-related differences in the incidence of many diseases and this is also true of Alzheimer’s disease (AD), where females have a higher lifetime risk of developing the disease and make up about two thirds of the AD patient population. The importance of understanding the cause(s) that account for this disproportionate distribution cannot be overestimated, and is likely to be a significant factor in the search for therapeutic strategies that will combat the disease and, furthermore, potentially point to a sex-targeted approach to treatment. This review considers the literature in the context of what is known about the impact of sex on processes targeted by drugs that are in clinical trial for AD, and existing knowledge on differing responses of males and females to these drugs. Current knowledge strongly supports the view that trials should make assessing sex-related difference in responses a priority with a focus on exploring the sex-stratified treatments

Anti-TLR2 antibody triggers oxidative phosphorylation in microglia and increases phagocytosis of β-amyloid

Microglia are multifunctional cells that are primarily neuroprotective and a deficit in their functional integrity is likely to be a contributory factor in the deteriorating neuronal function that occurs with age and neurodegeneration. One aspect of microglial dysfunction is reduced phagocytosis, and this is believed to contribute to the accumulation of amyloid-β (Aβ) in Alzheimer’s disease (AD). Therefore, improving phagocytosis should be beneficial in limiting the amyloidosis that characterises AD

With mouse age comes wisdom : a review and suggestions of relevant mouse models for age-related conditions

Ageing is a complex multifactorial process that results in many changes in physiological changes processes that ultimately increase susceptibility to a wide range of diseases. As such an ageing population is resulting in a pressing need for more and improved treatments across an assortment of diseases. Such treatments can come from a better understanding of the pathogenic pathways which, in turn, can be derived from models of disease. Therefore the more closely the model resembles the disease situation the more likely relevant the data will be that is generated from them. Here we review the state of knowledge of mouse models of a range of diseases and aspects of an ageing physiology that are all germane to ageing. We also give recommendations on the most common mouse models on their relevance to the clinical situations occurring in aged patients and look forward as to how research in ageing models can be carried out. As we continue to elucidate the pathophysiology of disease, often through mouse models, we also learn what is needed to refine these models. Such factors can include better models, reflecting the ageing patient population, or a better phenotypic understanding of existing models

Analysis of the Impact of CD200 on Neurodegenerative Diseases

Neuroinflammation, accompanied by neuronal loss and dysfunction, is a characteristic of neurodegenerative disorders like Alzheimer’s disease (AD) and Parkinson’s disease (PD). It is well documented that inappropriate activation of glia is the primary cause of neuroinflammation (Masocha, 2009), but their role in the pathogenesis of neurodegenerative diseases is not known. However it is certainly the case that dying neurons act to stimulate glia since they release alarmins which activate pathogen recognition receptors (PRR) and therefore the possibility exists that activation of glia especially microglia, may be a consequence, rather than a cause, of neurodegenerative processes which characterize diseases like AD and PD. Understanding microglial function remains a major goal since it is widely believed that modulating glial function will provide a possible strategy for limiting the progression of neurodegenerative diseases. Consequently it is imperative to increase our understanding of the factors which control microglial function and the mechanisms by which expression of these factors are controlled

Sleep disturbance in movement disorders:insights, treatments and challenges

Sleep and circadian rhythm disturbances are central features of many movement disorders, exacerbating motor and non-motor symptoms and impairing quality of life. Understanding these disturbances to sleep is clinically important and may further our understanding of the underlying movement disorder. This review evaluates the current anatomical and neurochemical understanding of normal sleep and the recognised primary sleep disorders. In addition, we undertook a systematic review of the evidence for disruption to sleep across multiple movement disorders. Rapid eye movement sleep behaviour disorder has emerged as the most reliable prodromal biomarker for the alpha synucleinopathies, including Parkinson’s disease and multiple system atrophy, often preceding motor symptom onset by several years. Abnormal sleep has also been described for many other movement disorders, but further evidence is needed to determine whether this is a primary or secondary phenotypic component of the underlying condition. Medication used in the treatment of motor symptoms also affects sleep and can aggravate or cause certain sleep disorders. Within the context of movement disorders, there is also some suggestion of a shared underlying mechanism for motor and sleep pathophysiology, with evidence implicating thalamic and brainstem structures and monoaminergic neurotransmission. This review highlights the need for an understanding of normal and abnormal sleep within the movement disorder clinic, an ability to screen for specific causes of poor sleep and to treat sleep disturbance to improve quality of life. Key sleep disorders also act as important biomarkers and have implications in diagnosis, prognosis and the development of future therapies

Pollen Evidence of Medicine from an Embalming Jar Associated with Vittoria della Rovere, Florence, Italy

Various samples of human viscera fragments, sponges, and cloth were collected from embalming jars belonging to members of the Medici family of Florence. One jar was labeled with the name Vittoria della Rovere, who died in March of 1694. This jar contained viscera fragments that were identified as a section of collapsed intestine. The intestine of the Vittoria della Rovere sample contained a large concentration of pollen belonging to the Myrtaceae family. The Myrtaceae pollen was sometimes observed in clusters during analysis, which is indicative of purposeful ingestion of flowers, buds, or a substance derived from floral structures. Thus, the high concentrations and clustering of Myrtaceae pollen grains recovered from this sample are reflective of dietary or medicinal practices. Scanning electron microscopy indicated that the pollen was from cloves, Syzygium aromaticum. It is most likely that Vittoria della Rovere consumed cloves for medicinal or culinary reasons shortly before death

Protocol of the adaptive study of IL-2 dose frequency on regulatory T cells in type 1 diabetes (DILfrequency): a mechanistic, non-randomised, repeat dose, open-label, response-adaptive study.

INTRODUCTION: Type 1 diabetes (T1D) is caused by autoimmune destruction of the insulin-producing β cells in the pancreatic islets, leading to insulinopenia and hyperglycaemia. Genetic analyses indicate that alterations of the interleukin-2 (IL-2) pathway mediating immune activation and tolerance predispose to T1D, specifically the polymorphic expression of the IL-2 receptor-α chain (CD25) on T lymphocytes. Replacement of physiological doses of IL-2 could restore self-tolerance and prevent further autoimmunity by enhancing the function of CD4(+) T regulatory cells (Tregs) to limit the activation of auto reactive T effector cells (Teffs). In this experimental medicine study, we use an adaptive trial design to determine the optimal dosing regimen for IL-2 to improve Treg function while limiting activation of Teffs in participants with T1D. METHODS AND ANALYSIS: The Adaptive study of IL-2 dose frequency on Tregs in type 1 diabetes(DILfrequency) is a mechanistic, non-randomised, repeat dose open-label, response-adaptive study of 36 participants with T1D. The objective is to establish the optimal dose and frequency of ultra-low dose IL-2: to increase Treg frequency within the physiological range, to increase CD25 expression on Tregs, without increasing CD4(+) Teffs. DILfrequency has an initial learning phase where 12 participants are allocated to six different doses and frequencies followed by an interim statistical analysis. After analysis of the learning phase, the Dose and Frequency Committee will select the optimal targets for Treg frequency, Treg CD25 expression and Teff frequency. Three groups of eight participants will be treated consecutively in the confirming phase. Each dose and frequency selected will be based on statistical analysis of all data collected from the previous groups. ETHICS: Ethical approval for DILfrequency was granted on 12 August 2014. RESULTS: The results of this study will be reported, through peer-reviewed journals, conference presentations and an internal organisational report. TRIAL REGISTRATION NUMBERS: NCT02265809, ISRCTN40319192, CRN17571.This work is funded by The Sir Jules Thorn Award for Biomedical Research 2013 (13/JTA), the JDRF (9-2011-253), the Wellcome Trust (091157) and the National Institute for Health Research Cambridge Biomedical Research Centre. The Cambridge Institute for Medical Research is in receipt of a Wellcome Trust Strategic Award (100140). AM was supported by the Medical Research Council [grant number G0800860] and the National Institute for Health Research Cambridge Biomedical Research Centre.This is the final version of the article. It was first available from BMJ via http://dx.doi.org/10.1136/bmjopen-2015-00979

Early Career Researchers (a dialogue)

This dialogue approaches the experiences and reflections of early career researchers (ECRs), that is, those academics who have completed their PhDs either recently or within the last 5–7 years. The dialogue brings to the forefront recollections of how the COVID pandemic changed research and teaching practices in higher education, emphasising, in particular, the challenges affecting ECRs, who often are on precarious contracts, are still developing their own pedagogical approaches, and have not yet built a network of support. These circumstances make the experiences of ECRs different from those of more experienced academics and university teachers. The dialogues aim to bring to the discussion how these experiences have shaped the way that ECRs engage with research and teaching. The dialogue brings interesting reflections on the way that the aftermath of the pandemic has brought more inclusive practices for participation, promoted collaborations, and inspired novel teaching approaches. However, it also notes how ECRs have been left in many cases to their own initiatives and without adequate mentorship or support, often overloaded by added challenges and feelings of isolation. Finally, the dialogue suggests improvements to current higher education practices and policies, which can significantly and positively impact the development of ECRs