80 research outputs found
Microglia in Motor Neuron Disease
No full textMotor Neuron Disease (MND) is a fatal neurodegenerative condition, which is characterised by the selective loss of the upper and lower motor neurons. At the sites of motor neuron injury, accumulations of activated microglia, the primary immune cells of the central nervous system, are commonly observed in both human post-mortem studies and animal models of MND. Microglial activation has been found to correlate with many clinical features and importantly, the speed of disease progression in humans. Both anti-inflammatory and pro-inflammatory microglial responses have been shown to influence disease progression in humans and models of MND. As such, microglia could both contribute to and protect against inflammatory mechanisms of pathogenesis in MND. While murine models have characterised the microglial response to MND, these studies have painted a complex and often -contradictory picture, indicating a need for further characterisation in humans. This review examines the potential role microglia play in MND, in human and animal studies. Both the pro-inflammatory and anti-inflammatory responses will be addressed, throughout the course of disease, followed by the potential of microglia as a target in the development of disease modifying treatments for MND
Investigating amyloid-related imaging abnormalities (ARIA) using neurosurgical biopsies of CAA-related inflammation (CAA-ri): what constitutes a neuropathological diagnosis of CAA-ri?
No full textBackground: spontaneous cerebral amyloid angiopathy–related inflammation (CAA-ri) has been proposed as a model for the amyloid-related imaging abnormalities (ARIA) seen following amyloid-beta (Aβ) immunotherapy. CAA-ri encompasses mild perivascular inflammation to severe angiitis/vasculitis, and consensus neuropathological criteria do not currently exist. We describe the histological features of biopsy-diagnosed CAA-ri compared to cases of non-inflammatory CAA (ni-CAA).Methods: neurosurgical biopsies and anonymised pathology reports from 19 CAA-ri and 44 ni-CAA cases from four centres were identified by BRAIN UK. They were examined to determine the distribution and severity of vascular Aβ, immune infiltrate, vasculopathy and concurrent Alzheimer's pathology.Results: CAA-ri was associated with more severe vascular Aβ deposition (extension into the surrounding neuropil, p = 0.016) and more frequent capillary angiopathy (p = 0.025) than ni-CAA. The size and composition of the inflammatory infiltrate varied. Intramural inflammation was observed in 68.4% of cases of CAA-ri. Features of vasculopathy, plaque removal and hemosiderin deposition were more frequent in CAA-ri than ni-CAA (p < 0.001, p < 0.001 and p = 0.001, respectively).Discussion: neurosurgical biopsies of CAA-ri are readily available and a powerful resource for further study into the pathophysiology of CAA-ri and ARIA. CAA-ri represents a spectrum of disease, and the minimum severity of inflammation required for diagnosis is unknown. Attributing inflammation primarily to vascular Aβ requires neuropathological judgement and clinical context. This can be particularly challenging in limited and fragile biopsy material. The specific pathological factors associated with CAA-ri that correlate with clinical/radiological severity are poorly understood. Analysis of the degree and composition of inflammation in our cohort is ongoing
TDP-43 Pathology in the Population: Prevalence and Associations with Dementia and Age
No full textBackground: The significance of TDP-43 pathology in relation to aging and dementia in the population is unclear. Objective: We aimed to determine the prevalence of transactive response DNA-binding protein of 43 kDA (TDP-43) neuronal inclusions in a population-based sample, and associations with age group at death (≤90 and >90 years) and clinical dementia status prior to death. Further, we investigate associations between TDP-43 inclusions and other key dementia-related neuropathologies (plaques, tangles, and neuronal loss) within the hippocampus and entorhinal and temporal cortices. Methods: All brain donors within the Cambridge City over-75 s Cohort (CC75C), which is population-based and longitudinally tracked (n = 228), were included. Age at death ranged from 78 to 106 years. TDP-43 neuronal inclusions were assessed in the hippocampus, entorhinal cortex, and temporal cortex. These data were combined with existing clinical and neuropathological data. Results: TDP-43 neuronal inclusions were present in 27% of the sample, 36% of those with clinical dementia and 18% without dementia. Individuals who died later (>90 years) or with clinical dementia were more likely to show TDP-43 inclusions. Hippocampal and entorhinal TDP-43 inclusions were significantly associated with dementia severity and increasing age, taking into account other neuropathologies. TDP-43 neuronal inclusions appeared to be co-localize with severe neuronal loss. Conclusion: Findings indicate that hippocampal and entorhinal TDP-43 inclusions are important substrates of late onset dementia which appear to co-localize with severe neuronal loss, but not with Alzheimer's disease markers of amyloid and tau. This broadens the accepted view of TDP-43 pathology in dementias.Hannah A.D. Keage, Sally Hunter, Fiona E. Matthews, Paul G. Ince, John Hodges, Suvi R.K. Hokkanen, J. Robin Highley, Tom Dening, Carol Brayne (and on behalf of the Cambridge City over 75s Cohort
ALS-linked FUS mutations confer loss and gain of function in the nucleus by promoting excessive formation of dysfunctional paraspeckles
No full textMutations in the FUS gene cause amyotrophic lateral sclerosis (ALS-FUS). Mutant FUS is known to confer cytoplasmic gain of function but its effects in the nucleus are less understood. FUS is an essential component of paraspeckles, subnuclear bodies assembled on a lncRNA NEAT1. Paraspeckles may play a protective role specifically in degenerating spinal motor neurons. However it is still unknown how endogenous levels of mutant FUS would affect NEAT1/paraspeckles. Using novel cell lines with the FUS gene modified by CRISPR/Cas9 and human patient fibroblasts, we found that endogenous levels of mutant FUS cause accumulation of NEAT1 isoforms and paraspeckles. However, despite only mild cytoplasmic mislocalisation of FUS, paraspeckle integrity is compromised in these cells, as confirmed by reduced interaction of mutant FUS with core paraspeckle proteins NONO and SFPQ and increased NEAT1 extractability. This results in NEAT1 localisation outside paraspeckles, especially prominent under conditions of paraspeckle-inducing stress. Consistently, paraspeckle-dependent microRNA production, a readout for functionality of paraspeckles, is impaired in cells expressing mutant FUS. In line with the cellular data, we observed paraspeckle hyper-assembly in spinal neurons of ALS-FUS patients. Therefore, despite largely preserving its nuclear localisation, mutant FUS leads to loss (dysfunctional paraspeckles) and gain (excess of free NEAT1) of function in the nucleus. Perturbed fine structure and functionality of paraspeckles accompanied by accumulation of non-paraspeckle NEAT1 may contribute to the disease severity in ALS-FUS
Writing on Borderlines : Anglo-Welsh Relations in Thomas Churchyard's The Worthines of Wales
No full textThis chapter explores representations of community and identity in George Peele's Edward I, focusing in particular on Peele's characterization of the Welsh rebel Lluellen, his caricature of Llywelyn ap Gruffydd, last of the Welsh princes of Wales. Edward I enacts the eponymous king's conquest of Wales, but Peele's treatment of the Welsh rebels is less patriotically English than we might otherwise expect in a play written for the London stage. Edward I, Highley writes, uses past Anglo-Welsh conflict as a screen onto which misgivings, anxieties, and fantasies about the English presence in Ireland are projected and interrogated'. Edward I also benefits from the stereotypes of alterity provided by the wild west' of Wales where Lluellen is based. Both Robin and Lluellen are outlaws, located far from Peele's stage, and far enough in the past to be comfortable to a London audience
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