Medication-wide association study of dementia

Dataset from medication-wide association study of dementia, using the Secure Anonymised Information Linkage databank Dementia electronic Cohort (SAIL-DeC). This dataset contains the hazard ratios and p-values for all medications included in the analysis (744 drugs in total). These results are from the full study population (n=551,344), of whom 16,998 developed dementia during follow-up. Numbers <10 have been masked to preserve de-identification of study participants.Wilkinson, Tim; Schnier, Christian. (2020). Medication-wide association study of dementia, [dataset]. University of Edinburgh. Usher Institute. https://doi.org/10.7488/ds/2777

Supplementary Figures: Interleukin-1 receptor antagonist treatment in acute ischaemic stroke does not alter systemic markers of anti-microbial defence

Supplementary Figures from the manuscript "Interleukin-1 receptor antagonist treatment in acute ischaemic stroke does not alter systemic markers of anti-microbial defence". ## ABSTRACT ## ### Background ### Blockade of the cytokine interleukin-1 (IL-1) with IL-1 receptor antagonist (IL-1Ra) is a candidate treatment for stroke entering phase II/III trials, which acts by inhibiting harmful inflammatory responses. Infection is a common complication after stroke that significantly worsens outcome and is related to stroke-induced deficits in systemic immune function thought to be mediated by the sympathetic nervous system. Therefore, immunomodulatory treatments for stroke, such as IL-1Ra, carry a risk of aggravating stroke-associated infection. Our primary objective was to determine if factors associated with antibody-mediated antibacterial defences were further compromised in patients treated with IL-1Ra after stroke. ### Methods ### We assessed plasma concentrations of immunoglobulin isotypes and complement components in stroke patients treated with IL-1Ra or placebo and untreated non-stroke controls using multiplex protein assays. Activation of the SNS was determined by measuring noradrenaline, a major SNS mediator. ### Results ### There were significantly lower plasma concentrations of IgM, IgA, IgG1 and IgG4 in stroke-patients compared to non-stroke controls, however there were no differences between stroke patients treated with placebo or IL-1Ra. Concentrations of complement components associated with the classical pathway were increased and those associated with the alternative pathways decreased in stroke patients, neither being affected by treatment with IL-1Ra. Noradrenaline concentrations were increased after stroke in both placebo and IL-1Ra-treated stroke patients compared to non-stroke controls. ### Conclusion ### These data show treatment with IL-1Ra after stroke does not alter circulating immunoglobulin and complement concentrations and is therefore unlikely to further aggravate stroke-associated infection susceptibility through reduced availability of these key anti-microbial mediators.McCulloch, Laura. (2019). Supplementary Figures: Interleukin-1 receptor antagonist treatment in acute ischaemic stroke does not alter systemic markers of anti-microbial defence, [dataset]. University of Edinburgh. UK Dementia Research Institute. https://doi.org/10.7488/ds/2545

Fan cells in lateral entorhinal cortex directly influence medial entorhinal cortex through synaptic connections in layer 1

Data used to generate figures and statistical outputs for https://www.biorxiv.org/content/10.1101/2022.08.25.505296v1. Analysis code used for this dataset can be found at https://github.com/MattNolanLab/lec_to_mec. # Abstract of the study: # Standard models for spatial and episodic memory suggest that the lateral entorhinal cortex (LEC) and medial entorhinal cortex (MEC) send parallel independent inputs to the hippocampus, each carrying different types of information. Here, we evaluate the possibility that information is integrated between divisions of the entorhinal cortex prior to reaching the hippocampus. We demonstrate that fan cells in layer 2 (L2) of LEC that receive neocortical inputs, and that project to the hippocampal dentate gyrus, also send axon collaterals to layer 1 (L1) of the MEC. Activation of inputs from fan cells evokes monosynaptic glutamatergic excitation of stellate and pyramidal cells in L2 of the MEC, typically followed by inhibition that contains fast and slow components mediated by GABAA and GABAB receptors, respectively. Inputs from fan cells also directly activate interneurons in L1 and L2 of MEC, with synaptic connections from L1 interneurons accounting for slow feedforward inhibition of L2 principal cell populations. The relative strength of excitation and inhibition following fan cell activation differs substantially between neurons and is largely independent of anatomical location. Our results demonstrate that the LEC, in addition to directly influencing the hippocampus, can activate or inhibit major hippocampal inputs arising from the MEC. Thus, local circuits in the superficial MEC may combine spatial information with sensory and higher order signals from the LEC, providing a substrate for integration of ‘what’ and ‘where’ components of episodic memories

Supplementary files supporting the paper "Microarray profiling emphasizes transcriptomic differences between hippocampal in vivo tissue and in vitro cultures"

Differential expression was performed using the R package "limma" (R package version 3.44.3) (Supplementary files 1-4; 1_diff_expr_WT_cell_vs_tissue, 2_diff_expr_101LL_cell_vs_tissue, 3_diff_expr_cell_WT_ vs_101LL, 4_diff_expr_tissue_WT_ vs_101LL) and gene ontology analysis was performed using the R package "topGO" (R package version 2.40.0) (Supplementary files 5-6; 5_go_all_bp_WT_cell_vs_tissue, 6_go_all_bp_101LL_cell_vs_tissue). Primary hippocampal cell cultures are routinely used as an experimentally accessible model platform for the hippocampus and brain tissue in general. Containing multiple cell types including neurons, astrocytes and microglia in a state that can be readily analysed optically, biochemically and electrophysiologically, such cultures have been used in many in vitro studies. To what extent the in vivo environment is recapitulated in primary cultures in an on-going question. Here we compare the transcriptomic profiles of primary hippocampal cell cultures and intact hippocampal tissue. In addition, by comparing profiles from wild type and the PrP 101LL transgenic model of prion disease, we also demonstrate that gene conservation is predominantly conserved across genetically altered lines.King, Declan. (2021). Supplementary files supporting the paper "Microarray profiling emphasizes transcriptomic differences between hippocampal in vivo tissue and in vitro cultures", [dataset]. University of Edinburgh. Roslin Institute. https://doi.org/10.7488/ds/3015

Microarray data CEL files supporting the paper "Microarray profiling emphasizes transcriptomic differences between hippocampal in vivo tissue and in vitro cultures"

Affymetrix microarray processing produced 16 (4 WT cell, 4 101LL cell, 4 WT tissue, 4 101LL tissue) probe cell intensity data (CEL) files. Primary hippocampal cell cultures are routinely used as an experimentally accessible model platform for the hippocampus and brain tissue in general. Containing multiple cell types including neurons, astrocytes and microglia in a state that can be readily analysed optically, biochemically and electrophysiologically, such cultures have been used in many in vitro studies. To what extent the in vivo environment is recapitulated in primary cultures in an on-going question. Here we compare the transcriptomic profiles of primary hippocampal cell cultures and intact hippocampal tissue. In addition, by comparing profiles from wild type and the PrP 101LL transgenic model of prion disease, we also demonstrate that gene conservation is predominantly conserved across genetically altered lines.King, Declan. (2021). Microarray data CEL files supporting the paper "Microarray profiling emphasizes transcriptomic differences between hippocampal in vivo tissue and in vitro cultures", [dataset]. University of Edinburgh. Roslin Institute. https://doi.org/10.7488/ds/3016

Thesis Movies - 'Mechanisms of kidney vascularisation and the roles of macrophages in renal organogenesis'

Movies for the doctoral thesis 'Mechanisms of kidney vascularisation and the roles of macrophages in renal organogenesis'.Munro, David. (2018). Thesis Movies - 'Mechanisms of kidney vascularisation and the roles of macrophages in renal organogenesis', [moving image]. University of Edinburgh. http://dx.doi.org/10.7488/ds/2413

An Investigation of Synaptic Dysfunction in Alzheimer’s Disease - Chapter 5 - Thresholding Macros

Alzheimer’s disease (AD) is characterized by the presence of aggregates of amyloid beta (Aβ) in senile plaques and tau in neurofibrillary tangles, as well as marked neuron and synapse loss. Of these pathological changes, synapse loss correlates most strongly with cognitive decline. Understanding the contributions of different risk factors, toxic proteins, and protein networks to synaptic dysfunction is essential to understanding and one day curing this disease. Oligomeric species of Aβ are implicated in synapse loss as is tau, however the interaction between them requires further exploration. The first aim of this thesis was to investigate the interaction of Aβ and tau in a novel mouse model AD. In this model APP/PS1 mice were crossed with mice expressing full length wild type human tau (hTau). Expression of hTau in APP/PS1 mice increased plaque size by~50% and increased plaque-associated dystrophic neurites. However, no increase in neurite curvature, neuron loss, or synapse loss was observed in the hTau APP/PS1 animals compared with APP/PS1 alone. The underlying cause of most cases of AD is not known, however genetic risk factors have been identified, the strongest of which is the APOE ε4 allele. APOE ε4 is associated with increased risk of developing AD and increased rates of cognitive decline compared to the more common APOE ε3 allele. The second aim of this thesis was to detect differences in the AD synaptic proteome compared with controls and to also investigate the effect of an APOE ε4 allele on those changes. Unbiased label free LC-MS/MS based proteomics of synapses isolated from AD and control post-mortem brains of known APOE genotypes was used. Of the 1043 proteins detected in 20 synaptic preparations 17% (173) were found to differ significantly (p1.2) in AD compared with control. A significant sub-set of these proteins were affected by APOE ε4 allele genotype. One of these was Clusterin which was not only increased in the AD synapse but further increased in cases with an APOE ε4 allele. Clusterin is closely related to ApoE has also been genetically linked to AD in genome-wide association studies. Aim three was to further investigate the involvement of Clusterin at the synapse and the interaction of ApoE with Clusterin using array tomography. Array tomography confirmed an increase in Clusterin co-localization with presynapses and postsynapses in AD cases compared with controls and found a further increase in cases with an APOE ε4 allele. Array tomography also found an increase in synapses which co-localized with Clusterin and Aβ together in cases with an APOE ε4 allele. This implies that Clusterin is important in Aβ mediated synapse loss in AD. To further investigate the role of synapse loss in AD aim 4 of this thesis was to develop a novel human based model of Aβ mediated synapse loss. This model uses cortical neurons derived from induced pluripotent stem cells from a control individual that are challenged with Aβ extracted from brains from AD and control individuals. This model shows a significant and concentration dependent reduction in the number of synapses in response Aβ from AD brain but not to control brain extract or AD brain extract immunodepleted of Aβ. The work presented in this thesis has investigated two novel models of AD to assess the effect of known toxic proteins in AD related synapse degeneration. This work also shows that profound protein changes occur at the synapse in AD and that many of these are affected by APOE genotype. Many of these changes potentially cause or contribute to synaptic dysfunction in AD and therefore could be important for therapeutic interventions.Jackson, Rosemary. (2017). An Investigation of Synaptic Dysfunction in Alzheimer’s Disease - Chapter 5 - Thresholding Macros, [dataset]. University of Edinburgh, Deanary of Biomedical Sciences. http://dx.doi.org/10.7488/ds/2135

Innervation of the developing kidney in vivo and in vitro

Within the adult kidney, renal neurites can be observed alongside the arteries where they play a role in regulating blood flow. However, their role and localization during development has so far not been described in detail. In other tissues, such as the skin of developing limb buds, neurons play an important role during arterial differentiation. Here we aim to investigate whether renal nerves could potentially carry out a similar role during arterial development in the mouse kidney. In order to do so, we used whole mount immunofluorescence staining to identify whether the timing of neuronal innervation correlates with the recruitment of arterial smooth muscle cells. Our results show that neurites innervate the kidney between day 13.5 and 14.5 of development, arriving after the recruitment of smooth muscle actin-positive cells to the renal arteries. It can therefore be concluded that neurons are not required to initiate arterial smooth muscle cell recruitment within the kidney. The dataset is related to the upcoming publication Tarnick et al. (in submission), "Innervation of the developing kidney in vivo and in vitro"

An Investigation of Synaptic Dysfunction in Alzheimer’s Disease - Chapter 5 - Matlab Scripts

Alzheimer’s disease (AD) is characterized by the presence of aggregates of amyloid beta (Aβ) in senile plaques and tau in neurofibrillary tangles, as well as marked neuron and synapse loss. Of these pathological changes, synapse loss correlates most strongly with cognitive decline. Understanding the contributions of different risk factors, toxic proteins, and protein networks to synaptic dysfunction is essential to understanding and one day curing this disease. Oligomeric species of Aβ are implicated in synapse loss as is tau, however the interaction between them requires further exploration. The first aim of this thesis was to investigate the interaction of Aβ and tau in a novel mouse model AD. In this model APP/PS1 mice were crossed with mice expressing full length wild type human tau (hTau). Expression of hTau in APP/PS1 mice increased plaque size by~50% and increased plaque-associated dystrophic neurites. However, no increase in neurite curvature, neuron loss, or synapse loss was observed in the hTau APP/PS1 animals compared with APP/PS1 alone. The underlying cause of most cases of AD is not known, however genetic risk factors have been identified, the strongest of which is the APOE ε4 allele. APOE ε4 is associated with increased risk of developing AD and increased rates of cognitive decline compared to the more common APOE ε3 allele. The second aim of this thesis was to detect differences in the AD synaptic proteome compared with controls and to also investigate the effect of an APOE ε4 allele on those changes. Unbiased label free LC-MS/MS based proteomics of synapses isolated from AD and control post-mortem brains of known APOE genotypes was used. Of the 1043 proteins detected in 20 synaptic preparations 17% (173) were found to differ significantly (p1.2) in AD compared with control. A significant sub-set of these proteins were affected by APOE ε4 allele genotype. One of these was Clusterin which was not only increased in the AD synapse but further increased in cases with an APOE ε4 allele. Clusterin is closely related to ApoE has also been genetically linked to AD in genome-wide association studies. Aim three was to further investigate the involvement of Clusterin at the synapse and the interaction of ApoE with Clusterin using array tomography. Array tomography confirmed an increase in Clusterin co-localization with presynapses and postsynapses in AD cases compared with controls and found a further increase in cases with an APOE ε4 allele. Array tomography also found an increase in synapses which co-localized with Clusterin and Aβ together in cases with an APOE ε4 allele. This implies that Clusterin is important in Aβ mediated synapse loss in AD. To further investigate the role of synapse loss in AD aim 4 of this thesis was to develop a novel human based model of Aβ mediated synapse loss. This model uses cortical neurons derived from induced pluripotent stem cells from a control individual that are challenged with Aβ extracted from brains from AD and control individuals. This model shows a significant and concentration dependent reduction in the number of synapses in response Aβ from AD brain but not to control brain extract or AD brain extract immunodepleted of Aβ. The work presented in this thesis has investigated two novel models of AD to assess the effect of known toxic proteins in AD related synapse degeneration. This work also shows that profound protein changes occur at the synapse in AD and that many of these are affected by APOE genotype. Many of these changes potentially cause or contribute to synaptic dysfunction in AD and therefore could be important for therapeutic interventions.Jackson, Rosemary. (2017). An Investigation of Synaptic Dysfunction in Alzheimer’s Disease - Chapter 5 - Matlab Scripts, [dataset]. University of Edinburgh, Deanary of Biomedical Sciences. http://dx.doi.org/10.7488/ds/2136

An Investigation of Synaptic Dysfunction in Alzheimer’s Disease - Chapter 3 - Matlab Scripts

Alzheimer’s disease (AD) is characterized by the presence of aggregates of amyloid beta (Aβ) in senile plaques and tau in neurofibrillary tangles, as well as marked neuron and synapse loss. Of these pathological changes, synapse loss correlates most strongly with cognitive decline. Understanding the contributions of different risk factors, toxic proteins, and protein networks to synaptic dysfunction is essential to understanding and one day curing this disease. Oligomeric species of Aβ are implicated in synapse loss as is tau, however the interaction between them requires further exploration. The first aim of this thesis was to investigate the interaction of Aβ and tau in a novel mouse model AD. In this model APP/PS1 mice were crossed with mice expressing full length wild type human tau (hTau). Expression of hTau in APP/PS1 mice increased plaque size by~50% and increased plaque-associated dystrophic neurites. However, no increase in neurite curvature, neuron loss, or synapse loss was observed in the hTau APP/PS1 animals compared with APP/PS1 alone. The underlying cause of most cases of AD is not known, however genetic risk factors have been identified, the strongest of which is the APOE ε4 allele. APOE ε4 is associated with increased risk of developing AD and increased rates of cognitive decline compared to the more common APOE ε3 allele. The second aim of this thesis was to detect differences in the AD synaptic proteome compared with controls and to also investigate the effect of an APOE ε4 allele on those changes. Unbiased label free LC-MS/MS based proteomics of synapses isolated from AD and control post-mortem brains of known APOE genotypes was used. Of the 1043 proteins detected in 20 synaptic preparations 17% (173) were found to differ significantly (p1.2) in AD compared with control. A significant sub-set of these proteins were affected by APOE ε4 allele genotype. One of these was Clusterin which was not only increased in the AD synapse but further increased in cases with an APOE ε4 allele. Clusterin is closely related to ApoE has also been genetically linked to AD in genome-wide association studies. Aim three was to further investigate the involvement of Clusterin at the synapse and the interaction of ApoE with Clusterin using array tomography. Array tomography confirmed an increase in Clusterin co-localization with presynapses and postsynapses in AD cases compared with controls and found a further increase in cases with an APOE ε4 allele. Array tomography also found an increase in synapses which co-localized with Clusterin and Aβ together in cases with an APOE ε4 allele. This implies that Clusterin is important in Aβ mediated synapse loss in AD. To further investigate the role of synapse loss in AD aim 4 of this thesis was to develop a novel human based model of Aβ mediated synapse loss. This model uses cortical neurons derived from induced pluripotent stem cells from a control individual that are challenged with Aβ extracted from brains from AD and control individuals. This model shows a significant and concentration dependent reduction in the number of synapses in response Aβ from AD brain but not to control brain extract or AD brain extract immunodepleted of Aβ. The work presented in this thesis has investigated two novel models of AD to assess the effect of known toxic proteins in AD related synapse degeneration. This work also shows that profound protein changes occur at the synapse in AD and that many of these are affected by APOE genotype. Many of these changes potentially cause or contribute to synaptic dysfunction in AD and therefore could be important for therapeutic interventions.Jackson, Rosemary. (2017). An Investigation of Synaptic Dysfunction in Alzheimer’s Disease - Chapter 3 - Matlab Scripts, [dataset]. University of Edinburgh, Deanary of Biomedical Sciences. http://dx.doi.org/10.7488/ds/2134