Biology subjects

Killick, R.

Publications and source records attributed to Killick, R..

8 recordsLinked to original sources

bioRxiv2025

Synaptotoxic forms of amyloid-b and a-synuclein act through a common pathway.

It has been suggested that -synuclein (Syn), a major player in Parkinsons disease (PD), plays a role in Alzheimers disease (AD). Several reports have also concluded that Syn and amyloid-{beta} (A{beta}) are mechanistically linked, although how is unclear. Synapse loss is an early feature in both PD and AD and held to be the driver of both diseases. We have previously uncovered a signalling pathway required for A{beta}-driven dendritic spine loss - a non-canonical branch of Wnt signalling known as the Wnt/Planar Cell Polarity (Wnt/PCP) pathway. We asked if a synaptotoxic form of Syn known to impact dendritic spines, the A53T autosomal dominant PD mutant form of Syn (A53T-Syn), might act on synapses through the same pathway. Here, by blocking all Wnt activity with the porcupine inhibitor IWP2, we show that A53T-Syn-driven spine loss is Wnt-dependent. By silencing Daam1, which is unique to Wnt/PCP, we show that A53T-Syn spine loss is Daam1-dependent. Finally, using the pan-ROCK inhibitor fasudil indicates the mechanism also involves ROCK1/2, which Daam1 signals to via RhoA to modulate actin cytoskeletal dynamics within dendritic spines. Together, these observations indicate that A53T-Syn-driven spine loss involves the Wnt/PCP pathway, the same pathway that mediates A{beta} synaptotoxicity. This indicates that A{beta} and Syn are mechanistically connected and that a common pathway is responsible for synapse loss in AD and PD. It also begins to explain why this group of neurodegenerative diseases have many features in common and suggests that drugs which target Wnt/PCP could be of benefit for both AD and PD.

neuroscience↗

bioRxiv2025

Transcription driven repurposing of cardiotonic steroids for Lithium treatment of severe depression

Lithium is prescribed as a mood stabiliser in bipolar disorder and severe depression. However, the mechanism of action of Lithium is unknown and there are major side effects associated with prolonged medication. This motivates a search for safer alternative drug repurposing candidates. Given that the drug mechanism may be encoded in transcriptional changes we have generated the gene expression profile for acute Lithium treatment of cortical neuronal cultures. We found that the Lithium associated transcription response harbours a significant component that is the reverse of that seen in human brain samples from patients with Major Depression, Bipolar Disorder and a mouse model of depression. Interrogating publicly available drug driven expression data we found that cardiotonic steroids drive gene expression in a correlated manner to our acute Lithium profile. An analysis of the psychiatric medication cohort of the Norwegian Prescription Database showed that cardiotonic prescription is associated with a lower incidence of lithium prescription. Our transcriptional and epidemiological observations point towards cardiotonic steroids as possible repurposing candidates for Lithium. These observations motivate a controlled trial to establish a causal connection and genuine therapeutic benefit in the context of depression.

neuroscience↗

bioRxiv2023

Wnt-7a-positive dendritic cytonemes induce synaptogenesis in cortical neurons.

SummaryNeuronal circuits evolve as a precisely patterned network. In this context, a growing neuron must locate the appropriate target area on a neurite of a neighbouring cell with which to connect. Controlled target selection involves dendritic filopodial contacts and requires the exact apposition of synaptic components. Calcium signalling has been postulated to trigger the transformation from dendritic filopodia into functional synapses. However, calcium is a rather unspecific signalling system, and it needs to be clarified how the exact development of synaptic connections is controlled. Similarly, Wnt/{beta}-catenin signalling promotes synapse formation; however, how secreted Wnts induce and maintain synapses on neuronal dendrites is not well understood. Here, we show that Wnt-7a is tethered to the tips of dynamic dendritic filopodia during spine formation in human cortical neurons. These filopodia can activate Wnt signalling precisely at the contact sites on the dendrites of an adjacent neuron. Subsequently, local calcium transients can be observed at these Wnt-positive contact sites. Depleting either the filopodial-loaded Wnt or the extracellular calcium pool blocks the clustering of pre- and post-synaptic markers, hence the establishment of stable connections. Therefore, we postulate that local Wnt-7a signalling from the tip of the dendritic filopodia, verified by simultaneous calcium signalling, provides an elegant mechanism for orchestrating focal synapse maturation.

neuroscience↗

bioRxiv2022

Neurodegenerative disease associated pathways in brain of the triple transgenic Alzheimer's model are reversed in vivo following two weeks peripheral administration of fasudil

The pan ROCK inhibitor fasudil acts as a vasodilator and has been used as a medication post cerebral stroke for the past 27 years in Japan and China. More recently, on the basis of the involvement of ROCK inhibition on synaptic function, neuronal survival and processes associated with neuroinflammation, it has been suggested that the drug may be repurposed for neurodegenerative diseases. Indeed, fasudil has demonstrated preclinical efficacy in many neurodegenerative disease models. To facilitate an understanding of the wider biological processes at play due to ROCK inhibition in the context of neurodegeneration we performed a global gene expression analysis on the brains of Alzheimers disease model mice treated with fasudil via peripheral i.p injection. Our results show that fasudil tends to drive gene expression in a reverse sense to that seen in postmortem neurodegenerative disease brains. The results are most striking in terms of pathway enrichment analysis where pathways regulated in Alzheimers disease and by fasudil treatment are overwhelmingly regulated in opposite directions. Thus, our results bolster the repurposing potential of fasudil by demonstrating an anti-neurodegenerative phenotype in a disease context and highlight the potential of in vivo transcriptional profiling of drug activity.

neuroscience↗

bioRxiv2021

In vivo multi-parametric manganese-enhanced MRI for detecting senile plaques in rodent models of Alzheimer's disease

Senile plaques are a hallmark of Alzheimers disease (AD) that develop in its earliest stages. Thus, non-invasive detection of these plaques would be invaluable for diagnosis and the development and monitoring of treatments, but this remains a challenge due to their small size. Here, we investigated the utility of manganese-enhanced MRI (MEMRI) for visualizing plaques in transgenic rodent models of AD across two species: 5xFAD mice and TgF344-AD rats. Fourteen mice (eight transgenic, six wild-type) and eight rats (four transgenic, four wild-type) were given subcutaneous injections of MnCl2 and imaged in vivo using a 9.4T Bruker scanner. Susceptibility-weighted images, transverse relaxation rate (R2*) maps, and quantitative susceptibility maps were derived from high-resolution 3D multi-gradient-echo (MGE) data to directly visualize plaques. Longitudinal relaxation rate (R1) maps were derived from MP2RAGE data to measure regional manganese uptake. After scanning, the brains were processed for histology and stained for beta-amyloid (4G8 antibody), iron (Perls), and calcium/manganese (Alizarin Red). MnCl2 improved signal-to-noise ratio (1.55{+/-}0.39-fold increase in MGE images) as expected, although this was not necessary for detection of plaques in the high-resolution images. Plaques were visible in susceptibility-weighted images, R2* maps, and quantitative susceptibility maps, with increased R2* and more positive magnetic susceptibility compared to surrounding tissue. In the 5xFAD mice, most MR-visible plaques were in the hippocampus, though histology confirmed plaques in the cortex and thalamus as well. In the TgF344-AD rats, many more plaques were MR-visible throughout the hippocampus and cortex. Beta-amyloid and iron staining indicate that, in both models, MR visibility was driven by plaque size and iron load. Voxel-wise comparison of R1 maps revealed increased manganese uptake in brain regions of high plaque burden in transgenic animals compared to their wild-type littermates. Interestingly, in contrast to plaque visibility in the high-resolution images, the increased manganese uptake was limited to the rhinencephalon in the TgF344-AD rats (family-wise error (FWE)-corrected p < 0.05) while it was most significantly increased in the cortex of the 5xFAD mice (FWE-corrected p < 0.3). Alizarin Red staining suggests that manganese bound to plaques in 5xFAD mice but not in TgF344-AD rats. Multi-parametric MEMRI is a simple, viable method for detecting senile plaques in rodent models of AD. Manganese-induced signal enhancement can enable higher-resolution imaging, which is key to visualizing these small amyloid deposits. We also present in vivo evidence of manganese as a potential targeted contrast agent for imaging plaques in the 5xFAD model of AD. HighlightsO_LIThis is the first study to use manganese-enhanced MRI (MEMRI) for direct visualization of senile plaques in rodent models of Alzheimers disease, in vivo. C_LIO_LIManganese enhancement is not necessary to detect plaques but improves image contrast and signal-to-noise ratio. C_LIO_LIManganese binds to plaques in 5xFAD mice but not in TgF344-AD rats, demonstrating potential as a targeted contrast agent for imaging plaques in certain models of AD. C_LI

neuroscience↗

bioRxiv2019

Loss of the Alzheimer’s-linked bridging integrator 1 (BIN1) protein affects synaptic structure and disrupts tau localisation and release

BackgroundPost-translational modifications of tau modify its interaction with binding partners and cause tau mislocalisation and altered tau function in Alzheimers disease (AD). The AD risk gene BIN1, is a binding partner for tau, however the mechanism by which BIN1 influences tau function is not fully understood. We hypothesised that BIN1 modulates AD risk by causing damaging tau mis-sorting to the synapse.\n\nMethodsTau and BIN1 levels, distribution and interactions were assessed in post-mortem control and AD brain and in primary neurons. In primary neurons, tau was further examined using structured illumination microscopy and immunoblotting following BIN1 knockdown, BIN1-tau interactions were examined using proximity ligation assays and tau release from neurons was measured by sensitive sandwich ELISA.\n\nResultsProline 216 in tau was identified as critical for tau interaction with the BIN1-SH3 domain, and tau phosphorylation at serine/threonine residues disrupted this interaction. Subcellular fractionation showed that BIN1 is lost from the cytoplasm of AD brain and this correlated with the mislocalisation of phosphorylated tau to synapses. Mimicking BIN1 loss in AD by knockdown of the protein in primary neurons altered the structure of dendritic spines, caused phosphorylated tau to mis-sort to synapses and reduced the physiological release of predominantly dephosphorylated tau.\n\nConclusionsThese data suggest that BIN1 loss in AD allows phosphorylated tau to be mis-sorted to synapses which likely alters the integrity of the post-synapse, alongside reducing the functionally important release of physiological forms of tau.

neuroscience↗

bioRxiv2019

Identifying Novel Candidates for Re-Purposing as Potential Therapeutic Agents for Alzheimer’s disease

The current paper describes the identification of novel candidate compounds for repositioning as treatments for Alzheimers disease (AD) from the CMAP library. Candidate compounds were identified based on inverse correlation with transcriptome signatures developed from meta-analyses of Alzheimer RNA expression studies using the SPIED platform. The 78 compounds with a significant inverse correlation were taken forward into an in vitro programme using 6 well validated screening assays relevant to potential treatment targets in AD. Nineteen pf the compounds were hits in at least 2 of these assays. A description of each of these compounds is presented.

neuroscience↗

bioRxiv2019

Measuring vision using innate behaviours in mice with intact and impairedretina function

Measuring vision in rodents is a critical step for understanding vision, improving models of human disease, and developing therapies. Established behavioural tests for perceptual vision, such as the visual water task, rely on learning. The learning process, while effective for sighted animals, can be laborious and stressful in animals with impaired vision, requiring long periods of training. Current tests that that do not require training are based on sub-conscious, reflex responses (e.g. optokinetic nystagmus) that dont require involvement of visual cortex and higher order thalamic nuclei. A potential alternative for measuring vision relies on using visually guided innate defensive responses, such as escape or freeze, that involve cortical and thalamic circuits. In this study we address this possibility in mice with intact and degenerate retinas. We first develop automatic methods to detect behavioural responses based on high dimensional tracking and changepoint detection of behavioural time series. Using those methods, we show that visually guided innate responses can be elicited using parametisable stimuli, and applied to describing the limits of visual acuity in healthy animals and discriminating degrees of visual dysfunction in mouse models of retinal degeneration.

neuroscience↗