Biology subjects

Brandner, S.

Publications and source records attributed to Brandner, S..

18 recordsLinked to original sources

bioRxiv2025

A dividing cell model for stable propagation and curing of bona fide human sporadic Creutzfeldt-Jakob Disease prions

Prions are assemblies of misfolded proteins that cause transmissible, progressive neurodegenerative disease in humans and other mammals. Human prion diseases have particular public health and biological significance, both due to their transmissibility between hosts, and the mechanisms they share with many other neurodegenerative conditions. However, their study has been considerably impeded by the absence of a cell-based system capable of reproducibly propagating and quantifying bona fide human prion infectivity, which has been a goal for several decades. Here, we describe the first robust, cell-based assay of human prion infectivity in dividing cells. We found that CAD5 cells expressing human prion protein instead of the endogenous mouse prion protein, replicate human prion infectivity from brain samples of patients with sporadic Creutzfeldt-Jakob disease (sCJD) expressing valine at codon 129 of the prion protein gene. Moreover, these cells quantify human prion infectivity with similar sensitivity to the current gold standard animal bioassay, at a fraction of the cost and time, maintain persistent infection that can be cured with an anti-prion treatment, and can be adapted for therapeutic screening. This novel system permits direct cell-based quantification and investigation of human prion infectivity for the first time.

neuroscience↗

bioRxiv2025

CANVAS causing AAGGG repeat expansions cause tissue-specific reduction in RFC1 expression and increase sensitivity to DNA damage

Biallelic AAGGG expansions in Replication Factor Complex Subunit 1 (RFC1) are associated with cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and are increasingly recognised as a common cause of adult-onset ataxia and sensory neuropathy. However, the disease-causing mechanisms remain unclear. Here we leveraged in vitro assays, post-mortem brain tissue, patient-derived cell lines and a neuronal Drosophila model to demonstrate that AAGGG expansions are associated with tissue-specific reductions in the expression of RFC1 transcript, along with impaired RFC1 function and increased sensitivity to DNA damage from platinum-based drugs. CRISPR/Cas9 excision of the AAGGG repeat and flanking AluSx3 element normalized RFC1 expression in iPSC-derived neurons and rescued the DNA damage response, providing a framework for future therapeutic strategies. We also show that these biological findings are clinically relevant in heterozygous AAGGG expansion carriers, who display an increased risk and severity of neuropathy with platinum-based chemotherapy.

neuroscience↗

bioRxiv2025

Intracellular Trafficking SNARE Protein, Syntaxin-6, is a Modifier of Prion and Tau Pathogenesis in vivo and in Cellular Models

Syntaxin-6, a SNARE protein involved in intracellular protein trafficking, is a proposed risk factor for sporadic prion disease, progressive supranuclear palsy and Alzheimers disease. However, no study has validated its functional role in these diseases, explored the disease stage at which it is acting nor its mechanism of action. Here, we show that syntaxin-6 acts at early stages of prion disease in experimental mice by increasing disease transmission risk following inoculation with low prion doses. Conversely, syntaxin-6 does not affect prion propagation kinetics or toxicity during established disease. Syntaxin-6 manipulation in cellular models profoundly alters the subcellular distribution and morphologies of disease-related PrP and modifies prion export. Furthermore, syntaxin-6 knockout in a transgenic tauopathy mouse model exerts protective effects on numerous physiological, behavioural and neuropathological outcome measures. Therefore, our studies firmly establish syntaxin-6 as a modifier of prion and tau pathogenesis, providing key insights into a fundamental mechanism of neurodegeneration.

neuroscience↗

bioRxiv2024

Induction and characterisation of Abeta and tau pathology in AppNL-F/NL-F mice following inoculation with Alzheimer's disease brain homogenate

Alzheimers disease (AD) is defined by the accumulation of neurofibrillary tangles containing hyperphosphorylated Tau and plaques containing Amyloid-{beta} (A{beta}). The aggregation of these two proteins is considered central to the disease. The lack of animal models that can recapitulate A{beta} and tau pathologies without overexpressing these proteins has hindered AD research. Accelerating pathology by inoculating A{beta} and tau seeds has helped to understand their prion-like propagation in the brain. Previous studies failed to characterise both A{beta} and tau pathologies in vivo upon inoculating AD brain homogenates. Here we present a longitudinal and systematic study; we inoculated the AppNL-F/NL-F knockin mice, which express humanised A{beta} and murine wild-type tau, with extracts from diseased human brains to analyse the contribution of A{beta} and tau assemblies to AD pathogenesis. We found that mice inoculated with AD brain extracts evinced early and prominent amyloid deposition, while those injected with control brain extracts or vehicle did not. Parenchymal and vascular amyloid accumulated in the same brain regions affected in control-inoculated AppNL-F/NL-F mice. However, the extent of vascular amyloid far exceeded that seen in AppNL-F/NL-Fmice injected with control brain extracts, and parenchymal deposits extended to a previously untargeted brain region - the cerebellum. An end-point titration of an AD brain homogenate in AppNL-F/NL-F mice demonstrated that human A{beta} seeds can be titrated in a prion-like fashion, which is useful for sample comparison, diagnostic and risk studies. Notably, the inoculation of AppNL-F/NL-F mice with AD brain homogenate induced intense tau phosphorylation, and provides more detailed context for the inoculation of AppNL-F/NL-F mice with human samples to study temporal and mechanistic relationships between A{beta} and tau pathology, vascular amyloid deposition and bioactivity of A{beta} seeds.

neuroscience↗

bioRxiv2023

Intricate epileptiform discharges affect memory in an Alzheimer's Disease mouse model

Interictal epileptiform discharges (IEDs) are transient abnormal electrophysiological events commonly observed in epilepsy patients but are also present in other neurological disease, such as Alzheimers Disease (AD). Understanding the role IEDs have on the hippocampal circuit is important for our understanding of the cognitive deficits seen in epilepsy and AD. We characterize and compare the IEDs of human epilepsy patients from microwire hippocampal recording with those of AD transgenic mice with implanted multi-layer hippocampal silicon probes. Both the local field potential features and firing patterns of pyramidal cells and interneurons were similar in mouse and human. We found that as IEDs emerged from the CA3-1 circuits, they recruited pyramidal cells and silenced interneurons, followed by post-IED suppression. IEDs suppressed the incidence and altered the properties of physiological sharp-wave ripples (SPW-Rs), altered their physiological properties, and interfered with the replay of place field sequences in a maze. In addition, IEDs in AD mice inversely correlated with daily memory performance. Together, our work implicates that IEDs may present a common and epilepsy-independent phenomenon in neurodegenerative diseases that perturbs hippocampal-cortical communication and interferes with memory. Significant StatementPrevalence of neurodegenerative diseases and the number of people with dementia is increasing steadily. Therefore, novel treatment strategies for learning and memory disorders are urgently necessary. IEDs, apart from being a surrogate for epileptic brain regions, have also been linked to cognitive decline. Here we report that IEDs in human epilepsy patients and AD mouse models have similar local field potential characteristics and associated firing patterns of pyramidal cells and interneurons. Mice with more IEDs displayed fewer hippocampal SPW-Rs, poorer replay of spatial trajectories, and decreased memory performance. IED suppression is an unexplored target to treat cognitive dysfunction in neurodegenerative diseases.

neuroscience↗

bioRxiv2023

Knockout of Sporadic Creutzfeldt-Jakob Disease Risk Gene Stx6 in Mice Extends Prion Disease Incubation Time

Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is thought to occur when the cellular prion protein (PrPC) spontaneously misfolds and assembles into prion fibrils, culminating in fatal neurodegeneration. In a genome-wide association study of sCJD, we recently identified risk variants in and around the gene STX6, with evidence to suggest a causal increase of STX6 expression in disease-relevant brain regions. STX6 encodes syntaxin-6, a SNARE protein primarily involved in early endosome to trans-Golgi network retrograde transport. Here we developed and characterised a mouse model with genetic depletion of Stx6 and investigated a causal role of Stx6 expression in mouse prion disease through a classical prion transmission study, assessing the impact of homozygous and heterozygous syntaxin-6 knockout on disease incubation periods and prion-related neuropathology. Following inoculation with RML prions, incubation periods in Stx6-/- and Stx6+/- mice differed by 12 days relative to wildtype. Similarly, in Stx6-/- mice, disease incubation periods following inoculation with ME7 prions also differed by 12 days. Histopathological analysis revealed a modest increase in astrogliosis in ME7-inoculated Stx6-/- animals and a variable effect of Stx6 expression on microglia activation, however no differences in neuronal loss, spongiform change or PrP deposition were observed at endpoint. Importantly, Stx6-/- mice are viable and fertile with no gross impairments on a range of neurological, biochemical, histological and skeletal structure tests. Our results provide some support for a pathological role of Stx6 expression in prion disease, which warrants further investigation in the context of prion disease but also other neurodegenerative diseases considering syntaxin-6 appears to have pleiotropic risk effects in progressive supranuclear palsy and Alzheimers disease. Author SummarySporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is an invariably fatal disease with no established disease-modifying treatments. The identification of STX6 as a proposed risk gene for sCJD motivated the generation of a new mouse knockout model, in which we found no grossly deleterious phenotypes. A transmission study in Stx6-/-, Stx6+/- and Stx6+/+ mice challenged with two prion strains showed reduced syntaxin-6 expression is associated with a modest prolongation of prion disease incubation periods, supporting a pathological role of Stx6 expression in prion disease pathogenesis. Syntaxin-6 appears to have pleiotropic risk effects across multiple neurodegenerative diseases including progressive supranuclear palsy and Alzheimers disease. Thus, this work supports further exploration of the STX6 susceptibility mechanism, which likely has relevance across multiple neurodegenerative diseases.

neuroscience↗

bioRxiv2022

Increased mRNA expression of CDKN2A is a transcriptomic marker of clinically aggressive meningiomas

BackgroundHomozygous loss of CDKN2A/B is a genetic alteration found in many cancer types including meningiomas, where it is associated with poor clinical outcome. It is now also a diagnostic criterion for grade 3 meningiomas in the 2021 WHO classification for central nervous system tumors. However, as in other cancers, the relationship between copy number loss of CDKN2A/B and expression of its gene product is unclear and may be either commensurate or paradoxical in nature. Therefore, we aimed to investigate the association of CDKN2A mRNA expression with clinical prognosis, WHO grade, and other molecular biomarkers in meningiomas such as DNA methylation, molecular group, and proteomics. MethodsWe used multidimensional molecular data of 490 meningioma samples from 4 independent cohorts to examine the relationship between mRNA expression of CDKN2A and copy number status, its correlation to clinical outcome, the transcriptomic pathways altered in differential CDKN2A expression, and its relationship with DNA methylation, and proteomics using an integrated molecular approach. ResultsMeningiomas without any copy number loss were dichotomized into high (CDKN2Ahigh) and low (CDKN2Alow) CDKN2A mRNA expression groups. Patients with CDKN2Ahigh meningiomas had poorer progression free survival (PFS) compared to those with CDKN2Alow meningiomas. CDKN2A mRNA expression was increased in more aggressive molecular groups, and in higher WHO grade meningiomas across all cohorts. CDKN2Ahigh meningiomas and meningiomas with CDKN2A copy number loss shared common up-regulated cell cycling pathways. CDK4 mRNA expression was increased in CDKN2Ahigh meningiomas and both p16 and CDK4 protein were more abundant in CDKN2Ahigh meningiomas. CDKN2Ahigh meningiomas were frequently hypermethylated at the gene body and UTR compared to CDKN2Alow meningiomas and found be more commonly Rb-deficient. ConclusionsAn intermediate level of CDKN2A mRNA expression appears to be optimal as significantly low (CDKN2A deleted) or high expression (CDKN2Ahigh) are associated with poorer outcomes clinically. Though CDK4 is elevated in CDKN2Ahigh meningiomas, Rb-deficiency may be more common in this group, leading to lack of response to CDK inhibitors.

cancer biology↗

bioRxiv2022

Farnesoid X Receptor suppresses lipid peroxidation and ferroptosis

ObjectiveFerroptosis is a regulated cell death modality that occurs upon iron-dependent lipid peroxidation. The recent decade of research has uncovered many regulators driving ferroptosis as well as cellular gatekeepers preventing ferroptosis. Yet, many processes and networks remain to be elucidated. Methods and resultsIn this study, we performed a chemical screen using small molecules with known mode of action and identified two agonists (Turofexorate and Fexaramine) of the nuclear receptor Farnesoid X Receptor (FXR), also known as NR1H4, to suppress ferroptosis, but not apoptosis or necroptosis. Further, we demonstrate that in liver cells with high FXR protein levels, inhibition of FXR sensitizes cells to undergo ferroptotic cell death, while activation of FXR inhibits ferroptosis. Importantly, FXR also inhibits ferroptosis in ex vivo primary mouse hepatocytes. Activation of FXR by Turofexorate and Fexaramine significantly reduces lipid peroxidation. Mechanistically, overexpression of FXR or activation of FXR by bile acids upregulates the ferroptosis-inhibitory regulators FSP1, PPAR, GPX4, SCD1, and ACSL3 to reduce peroxidized lipids and to counteract ferroptosis. ConclusionIn this study, we demonstrate that activation of FXR inhibits ferroptotic cell death via upregulation of a number of ferroptosis-inhibitory proteins (FSP1, PPAR, GPX4, SCD1, and ACSL3) to reduce lipid peroxidation. Hence, modulating FXR activity may be beneficial to overcome ferroptosis-mediated degenerative diseases.

cell biology↗

bioRxiv2022

Single-nuclei transcriptomics of mammalian prion diseases identifies dynamic gene signatures shared between species

Mammalian prion diseases are fatal and transmissible neurological conditions caused by the propagation of prions, self-replicating multimeric assemblies of misfolded forms of host cellular prion protein (PrP). The most common human form of the disease, sporadic Creutzfeldt-Jakob disease (sCJD), typically presents as a rapidly progressive dementia and has no effective treatments. Prion diseases are transmissible to laboratory rodents affording unprecedented opportunities to understand neurodegeneration in its evolving stages. Murine models are especially useful in prion research as they develop bona fide prion disease and recapitulate all biochemical and neuropathological hallmarks of human prion disease. Despite extensive studies investigating the changes in transcriptional profiles in prion diseases the mechanisms by which prion diseases induce cellular toxicity, including changes in gene expression profiles are yet to be fully characterized. This is at least in part because confounding effects related to brain cellular heterogeneity have not been resolved. Here, we took advantage of the recent developments in single-cell technologies and performed an unbiased whole-transcriptome single-nucleus transcriptomic analysis in prion disease.

neuroscience↗

bioRxiv2022

Harmonized single-cell landscape, intercellular crosstalk and tumor architecture of glioblastoma

Glioblastoma, isocitrate dehydrogenase (IDH)-wildtype (hereafter, GB), is an aggressive brain malignancy associated with a dismal prognosis and poor quality of life. Single-cell RNA sequencing has helped to grasp the complexity of the cell states and dynamic changes in GB. Large-scale data integration can help to uncover unexplored tumor pathobiology. Here, we resolved the composition of the tumor milieu and created a cellular map of GB ( GBmap), a curated resource that harmonizes 26 datasets gathering 240 patients and spanning over 1.1 million cells. We showcase the applications of our resource for reference mapping, transfer learning, and biological discoveries. Our results uncover the sources of pro-angiogenic signaling and the multifaceted role of mesenchymal-like cancer cells. Reconstructing the tumor architecture using spatially resolved transcriptomics unveiled a high level of well-structured neoplastic niches. The GBmap represents a framework that allows the streamlined integration and interpretation of new data and provides a platform for exploratory analysis, hypothesis generation and testing. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=174 SRC="FIGDIR/small/505439v1_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@7f0d76org.highwire.dtl.DTLVardef@14cbe3borg.highwire.dtl.DTLVardef@15d1e69org.highwire.dtl.DTLVardef@77b16f_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

Global hypo-methylation in a subgroup of glioblastoma enriched for an astrocytic signature is associated with increased invasion and altered immune landscape

We describe a new molecular subgroup of glioblastoma, the most prevalent malignant adult brain tumour, harbouring a bias towards hypomethylation at defined differentially methylated regions. This epigenetic signature correlates with an enrichment for an astrocytic gene signature, which together with the identification of enriched predicted binding sites of transcription factors known to cause demethylation and to be involved in astrocytic/glial lineage specification, point to a shared ontogeny between this glioblastoma subgroup and astroglial progenitors. At functional level, increased invasiveness, at least in part mediated by SRPX2, and macrophage infiltration characterise this glioblastoma subgroup.

cancer biology↗

bioRxiv2021

Mapping prion pathology in mice using quantitative imaging: an MRI study

Human prion diseases are fatal neurodegenerative disorders which cause cognitive impairment and neurological deficits. Additional measures of tissue status are necessary for improving the sensitivity and specificity of clinical diagnosis as in many cases clinical forms of prion disease are commonly mistaken for other forms of dementia. To that effect, we developed a set of quantitative magnetic resonance-based tools, including magnetic resonance spectroscopy (MRS), magnetization transfer ratio (MTR) and quantitative T1 and T2 imaging to study the course of the disease in an animal model of prion disease. Using in vivo MTR, significant changes were detected in the cortex and thalamus of late-stage prion -infected mice as compared to littermates. In addition, we found a significant increase of MTR in thalamus and cortex of 80 dpi healthy mice when compared with 160 dpi healthy mice suggestive of changes occurring during the development of the brain. Using quantitative T2 mapping, significantly higher values were measured in thalamus of prion mice at all stages of the disease (T2=40ms) while T1 was found to be significantly higher in cortex (T1=1.89s) and hippocampus, albeit only in late-stage prion mice as compared to aged-matched controls (T1=1.67s). Using quantitative MRS significant changes were detected in glutamate (Glu) and myo-inositol (Ins) at all stages of prion disease when compared with the control group. NAA, Cr, Lactate and Lipids were only found to be significantly different at early and late stages of the disease while Taurine (Tau) was only significantly increased in the asymptomatic stage without any significant change at early and late stages of the disease. These changes in MRI and MRS signals, which precede clinical signs of disease, could provide insights into the pathogenesis of this disease and may enable early detection of pathology.

biophysics↗

bioRxiv2021

Can Chemical Exchange Saturation Transfer (CEST MRI) be used as biomarker of disease progression in Prion Disease?

Human prion diseases are fatal neurodegenerative disorders that may have prolonged asymptomatic incubation periods. However, the underlying mechanism by which prions cause brain damage remains unclear. In turn, characterization of early pathological aspects would be of benefit for the diagnosis and potential treatment of these progressive neurodegenerative disorders. We investigated chemical exchange saturation transfer (CEST) MRI based on its exquisite sensitivity to cytosol protein content as a surrogate for prion disease pathology. Three groups of prion-infected mice at different stages of the disease underwent conventional magnetic resonance imaging and CEST MRI at 9.4T. For each mouse, chemical exchange contrasts were measured by applying five RF powers at various frequency offsets using magnetization transfer asymmetries. Relayed Nuclear Overhauser effects (NOE*) and amide proton transfer (APT*) were also assessed. For comparison, CEST MRI measurements were also made in healthy control mice brains. Here we show that alterations in CEST signal were detected before structural modifications or any clinical signs of prion disease. The detected CEST signal displayed different patterns at different stages of the disease indicating its potential for use as a longitudinal marker of disease progression. Highly significant correlations were found between CEST metrics and histopathological findings. A decline in NOE signal was positively correlated with abnormal prion protein deposition (R2 = 0.91) in the thalami of prion infected mice. Moreover, the NOE signal was negatively correlated with astrogliosis (R2 = 0.71) in the thalamus. No significant correlations were detected between NOE signals and spongiosis. MTR asymmetry at 3.5 ppm was also correlated with astrogliosis (R2 = 0.59), and prion protein deposition (R2 = 0.63) in thalamus. No significant changes were detected in APT* between prion-infected and control mice at all stages of the disease. Finally, MTR asymmetry between 2.8 and 3.2 ppm was correlated with prion protein deposition (R2 = 0.47) in the thalamus of prion -infected mice. To conclude, CEST MRI has potential utility as a biomarker of neurodegenerative processes in prion disease.

biophysics↗

bioRxiv2021

Recurrent fusions in PLAGL1 define a distinct subset of pediatric-type supratentorial ependymoma

Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of largely ependymoma-like tumors. Immunohistochemically, tumors were GFAP-positive and OLIG2- and SOX10-negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. Consistent with other fusion-positive ependymal groups, all tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Analysis of time to progression or recurrence revealed survival times comparable to those of patients with ZFTA:RELA-fused ependymoma. In summary, our findings suggest the existence of a novel group of supratentorial ependymomas that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients.

cancer biology↗

bioRxiv2021

Acriflavine, a clinically aproved drug, inhibits SARS-CoV-2 and other betacoronaviruses

SO_SCPLOWUMMARYC_SCPLOWThe COVID-19 pandemic caused by SARS-CoV-2 has been socially and economically devastating. Despite an unprecedented research effort, effective therapeutics are still missing to limit severe disease and mortality. Using high-throughput screening, we identified acriflavine as a potent papain-like protease (PLpro) inhibitor. NMR titrations and a co-crystal structure confirm that acriflavine blocks the PLpro catalytic pocket in an unexpected binding mode. We show that the drug inhibits viral replication at nanomolar concentration in cellular models, in vivo in mice and ex vivo in human airway epithelia, with broad range activity against SARS-CoV-2 and other betacoronaviruses. Considering that acriflavine is an inexpensive drug approved in some countries, it may be immediately tested in clinical trials and play an important role during the current pandemic and future outbreaks.

microbiology↗

bioRxiv2020

The white matter is a pro-differentiative microenvironment for glioblastoma

Glioblastomas are hierarchically organised tumours driven by glioma stem cells that retain partial differentiation potential. Glioma stem cells are maintained in specialised microenvironments, but how they undergo lineage progression outside of these niches remains unclear. Here we identify the white matter as a differentiative niche for glioblastomas with oligodendrocyte lineage competency. Tumour cells in contact with white matter acquire pre-oligodendrocyte-like fate, resulting in decreased proliferation and invasion. Differentiation is a response to white matter injury, which is caused by tumour infiltration itself in a tumoursuppressive feedback loop. Mechanistically, tumour cell differentiation is driven by selective white matter upregulation of SOX10, a master regulator of normal oligodendrogenesis. SOX10 overexpression or treatment with myelination-promoting agents that upregulate endogenous SOX10, mimic this response, leading to white matter-independent pre-oligodendrocyte-like differentiation and tumour suppression in vivo. Thus, glioblastoma recapitulates an injury response and exploiting this latent programme may offer treatment opportunities for a subset of patients.

cancer biology↗

bioRxiv2018

Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signalling to pericytes

Vascular compromise occurs early in Alzheimers disease (AD) and other dementias1-3. Amyloid {beta} (A{beta}) reduces cerebral blood flow4-6 and, as most of the cerebral vasculature resistance is in capillaries7, A{beta} might mainly act on contractile pericytes on capillary walls8-10. Employing human tissue to establish disease-relevance, and rodent experiments to define mechanism, we now show that A{beta} constricts brain capillaries at pericyte locations in human subjects with cognitive decline. Applying soluble A{beta}1-42 oligomers to live human cortical tissue constricted capillaries. Using rat cortical slices, this was shown to reflect A{beta} evoking capillary pericyte contraction, with an EC50 of 4.7 nM, via the generation of reactive oxygen species and activation of endothelin ET-A receptors. In freshly-fixed diagnostic biopsies from human patients investigated for cognitive decline, mean capillary diameters were less in subjects showing A{beta} deposition than in subjects without A{beta} deposition. For patients with A{beta} deposition, the capillary diameter was 31% less at pericyte somata than away from somata, predicting a halving of blood flow. Constriction of capillaries by A{beta} will contribute to the energy lack1-3 occurring in AD, which promotes further A{beta} generation11,12. This mechanism reconciles the amyloid hypothesis13-15 with the earliest events in AD being vascular1.

neuroscience↗

bioRxiv2017

Quantitation of brain tumour microstructure response to Temozolomide therapy using non-invasive VERDICT MRI

There has been slow progress in the development of new therapeutic strategies for treating brain tumours, partly because assessment of treatment response is difficult and largely reliant on simple bi-dimensional measurements of MRI contrast-enhancing regions. Hence, there is a clinical need to develop improved imaging techniques for monitoring treatment response. In this study, we evaluate VERDICT (Vascular, Extracellular and Restricted Diffusion for Cytometry in Tumors) MRI in mouse glioblastomas for the quantification of tumour microstructure and assessment of response to Temozolomide (TMZ) chemotherapy, and, we investigate the feasibility of applying VERDICT MRI in a range of human gliomas. VERDICT MRI detected response to TMZ earlier than structural and apparent diffusion coefficient (ADC) measurements. A significant reduction in the cell radius parameter was detected three days earlier than ADC and six days earlier than structural MRI. Histological analysis showed the same trend as VERDICT of decreased intracellular volume fraction in the TMZ-treated mice. Vascular volume fraction was not altered by TMZ, which was consistent with optical projection tomography measurements. In patients, glioblastoma compartmental volume fractions showed good agreement with mouse glioblastoma parameters. The VERDICT parameters varied across the human gliomas, with raised intracellular volume fraction in the oligodendrogliomas and elevated cell radius in both low-grade tumours subtypes. In conclusion, our results suggest that VERDICT MRI is more sensitive at detecting TMZ response than structural or ADC measurements. In patients, VERDICT is feasible within clinical scan times, and performed best at characterising glioblastoma. Further optimisation should improve assessment of different glioma subtypes.

biophysics↗