Biology subjects

Ballard, C.

Publications and source records attributed to Ballard, C..

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↗

bioRxiv2022

Neuroanatomical substrates in Parkinson's Disease psychosis and their association with serotonergic receptor gene expression: A coordinate-based meta-regression analysis.

BackgroundCommon neural underpinning of Parkinsons Disease (PD) psychosis across different structural magnetic resonance imaging (MRI) studies remains unclear to this day with few studies and even fewer meta-analyses available. ObjectivesOur meta-analysis aimed to identify and summarise studies using MRI approach to identify PD psychosis-specific brain regions and examine the relation between cortical volume loss and dopaminergic and serotonergic receptor density. MethodsPubMed, Web of Science and Embase were searched for MRI studies of PD psychosis (PDP) compared to PD patients without psychosis (PDnP). Seed-based d Mapping with Permutation of Subject Images was applied in the meta-analysis where coordinates were available. Multiple linear regressions to examine the relationship between grey matter volume loss in PDP and receptor gene expression density (extracted from the Allen Human Brain Atlas) were conducted in R. ResultsWe observed lower grey matter volume in parietal-temporo-occipital regions from our meta-analysis (N studies =10, PDP n=211, PDnP, n=298). These results remained significant after adjusting for PD medications and for cognitive scores. Grey matter volume loss in PDP was associated with local expression of 5-HT1a (b=0.109, p=0.012) and 5-HT2a receptors (b=-0.106, p=0.002) also after adjusting for PD medications (5-HT1a, p = 0.005; 5-HT2a, p = 0.001). ConclusionsWidespread cortical volume loss in the parieto-temporo-occipital regions involved in information processing and integration, as well as attention, could result in PD psychosis symptoms. Neurobiological mechanisms implicating serotonergic receptors may also contribute to this condition.

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

Dispersed Sleep Microstates and Associated Structural Changes in GBA1 Mouse: Relevance to Rapid Eye Movement Behavior Disorder

Rapid eye movement (REM) sleep behaviour disorder (RBD) is a rare parasomnia that may predict the later occurrence of alpha-synucleinopathies. Variants in the gene encoding for the lysosomal enzyme glucocerebrosidase, GBA, strongly increase the risk of RBD. In a GBA1-mouse model recently shown to mimic prodromal stages of -synucleinopathy, we now demonstrate striking REM and NREM sleep abnormalities accompanied by distinct structural changes in the more widespread sleep neurocircuitry.

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↗

bioRxiv2020

Whole transcriptome in-silico screening implicates cardiovascular and infectious disease in the mechanism of action underlying atypical antipsychotic side-effects

INTRODUCTIONStroke/thromboembolic events, infections and death are all significantly increased by antipsychotics in dementia but little is known about why they can be harmful. Using a novel application of a drug repurposing paradigm, we aimed to identify potential mechanisms underlying adverse events. METHODWhole transcriptome signatures were generated for SH-SY5Y cells treated with amisulpride, risperidone and volinanserin using RNA-sequencing. Bioinformatic analysis was performed which scored the association between antipsychotic signatures and expression data from 415,252 samples in the NCBI GEO repository. RESULTSAtherosclerosis, venous thromboembolism and influenza NCBI GEO-derived samples scored positively against antipsychotic signatures. Pathways enriched in antipsychotic signatures were linked to the cardiovascular and immune systems (e.g. BDNF, PDGFR-beta, TNF, TGF-beta, selenoamino acid metabolism and influenza infection). CONCLUSIONThese findings for the first time mechanistically link antipsychotics to specific cardiovascular and infectious diseases which are known side effects of their use in dementia, providing new information to explain related adverse events. COMPETING INTERESTSCB has received grants and personal fees from ACADIA Pharmaceuticals and Lundbeck, and personal fees from Heptares, Roche, Lilly, Otsuka, Orion, GlaxoSmithKline and Pfizer. DAC is an employee of Eli Lilly and Company Ltd.

bioinformatics↗

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

Association between schizophrenia polygenic score and psychotic symptoms in Alzheimer disease: meta-analysis of 10 cohort studies

BackgroundPsychosis (delusions and hallucinations) is common in Alzheimers disease (AD) and associated with worse clinical outcomes including accelerated cognitive decline and shorter time to nursing home admission. Atypical antipsychotics have limited efficacy which, along with emerging genomic research, suggests some overlapping mechanisms with other disorders characterized by psychosis, like schizophrenia. In this study, we tested whether polygenic risk score (PRS) for schizophrenia was associated with psychotic symptoms in AD. MethodsSchizophrenia PRS was calculated using Psychiatric Genomics Consortium data at 10 GWAS p-value thresholds (PT) in 3,173 AD cases from 11 cohort studies. Association between PRS and AD psychosis status was tested by logistic regression in each cohort individually and the results meta-analyzed. ResultsThe schizophrenia PRS was associated with psychosis in AD at an optimum PT of The strongest association was for delusions where a one standard deviation increase in PRS was associated with a 1.17-fold increased risk (95% CI: 1.07-1.3; p=0.001). ConclusionThese new findings point towards psychosis in AD - and particularly delusions - sharing some genetic liability with schizophrenia, and support a transdiagnostic view of psychotic symptoms across the lifespan.

genomics↗