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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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At least 199 records · Page 11Linked to original sources

bioRxiv2018

An electrochemical biosensor for rapid detection of anti-dsDNA antibodies in absolute scale.

Autoimmune diseases are chronic inflammatory pathologies that are characterized by the presence of antibodies against own epitopes in serum (autoantibodies). Systemic lupus erythematosus (SLE) is a common autoimmune pathology, characterized by the presence of antinuclear antibodies (ANAs). These include anti-dsDNA (-dsDNA) antibodies, which are widely used for diagnosis and disease monitoring. Their determination is carried out by traditional techniques such as Indirect Immunofluorescence (IFI) or Enzyme Linked Immunosorbent Assay (ELISA), which are time consuming, require qualified technicians, and are not compatible with decentralized analysis outside a laboratory facility. Here, we show a sandwich-format electrochemical biosensor-based method for -dsDNA determination in a rapid and simple manner. Total assay time is only 30 minutes and the sensor is capable of detecting 16 ng (8 g / mL) of -dsDNA antibodies. Using the current derived from the detection limit of the method as a cut-off, we could discriminate positive from negative serum samples with 90% sensitivity and 100% specificity. By using monoclonal antibodies for calibration curves, our results are presented in absolute scale (i.e., concentration instead of serum title) what will help to perform comparisons between methods and further improvements of this protocol. In an effort to render the sensor compatible with automation, we minimized manipulation steps without compromise of the analytical performance, even in complex samples such as serum.

bioengineering↗

bioRxiv2018

Spatiotemporally controlled genetic perturbation for efficient large-scale studies of cell non-autonomous effects

Studies in genetic model organisms have revealed much about the development and pathology of complex tissues. Most have focused on cell-intrinsic gene functions and mechanisms. Much less is known about how transformed, or otherwise functionally disrupted, cells interact with healthy ones towards a favorable or pathological outcome. This is largely due to technical limitations. We developed new genetic tools in Drosophila melanogaster that permit efficient multiplexed gain- and loss-of-function genetic perturbations with separable spatial and temporal control. Importantly, our novel tool-set is independent of the commonly used GAL4/UAS system, freeing the latter for additional, non-autonomous, genetic manipulations; and is built into a single strain, allowing one-generation interrogation of non-autonomous effects. Altogether, our design opens up efficient genome-wide screens on any deleterious phenotype. Specifically, we developed tools to study extrinsic effects on neural tumor growth but the strategy presented has endless applications within and beyond neurobiology, and in other model organisms.\n\nImpact statementA novel genetic strategy for induction of reproducible neural tumors (or any other deleterious phenotype) in a single Drosophila stock (applicable to other organisms).

developmental biology↗

bioRxiv2018

The effects of psychiatric history and age on self-regulation of the default mode network

Real-time neurofeedback enables human subjects to learn to regulate their brain activity, effecting behavioral changes and improvements of psychiatric symptomatology. Neurofeedback up-regulation and down-regulation have been assumed to share common neural correlates. Neuropsychiatric pathology and aging incur suboptimal functioning of the default mode network. Despite the exponential increase in real-time neuroimaging studies, the effects of aging, pathology and the direction of regulation on neurofeedback performance remain largely unknown. Using open-access analyses and real-time fMRI data shared through the Rockland Sample Real-Time Neurofeedback project (N=136), we first modeled neurofeedback performance and learning in a group of subjects with psychiatric history (na=74) and a healthy control group (nb=62). Subsequently, we examined the relationship between up-regulation and down-regulation learning, the relationship between age and neurofeedback performance in each group and differences in neurofeedback performance between the two groups. Results show that in an initial session of default mode network neurofeedback with real-time fMRI, up-regulation and down-regulation learning scores are negatively correlated. Moreover, age correlates negatively with default mode network neurofeedback performance, only in absence of psychiatric history. Finally, adults with psychiatric history outperform healthy controls in default mode network up-regulation. Interestingly, the performance difference is related to no up-regulation learning in controls.

neuroscience↗

bioRxiv2018

Microglial and Astrocyte priming in the APP/PS1 model of Alzheimer’s Disease: increased vulnerability to acute inflammation and cognitive deficits

Alzheimers disease (AD) causes devastating cognitive decline and has no disease-modifying therapies. Neuroinflammation is a significant contributor to disease progression but its precise contribution remains unclear. An emerging literature indicates that secondary inflammatory insults including acute trauma and infection alter the trajectory of chronic neurodegenerative diseases and the roles of microglia and astrocytes require elucidation. The current study, using the APP/PS1 mouse model of AD, demonstrates that microglia are primed by {beta}-amyloid pathology to induce exaggerated IL-1{beta} responses to acute stimulation with LPS or IL-1{beta}. Despite disease-associated NLRP3 inflammasome activation, evidenced by ASC speck formation, APP/PS1 microglial cells show neither IL-1{beta} induction nor NF{kappa}B p65 nuclear localisation. Upon secondary stimulation with LPS or IL-1{beta}, NF{kappa}B-p65 nuclear localisation and exaggerated pro-IL-1 induction occur. Microglial priming was also unmasked by secondary stimulation with systemic LPS leading to significant cognitive impairment in APP/PS1 mice compared to WT LPS-treated mice. Astrocytes have also recently emerged as displaying significant phenotypic heterogeneity. Here, by-passing microglial priming, and acutely challenging mice with intra-hippocampal IL-1{beta} we demonstrate that astrocytes proximal to A{beta}-plaques are also primed to produce exaggerated CCL2, CXCL1 and CXCL10 responses. Many astrocytosis-associated genes in APP/PS1 mice share these exaggerated responses to IL-1{beta}, while others are equally induced in both strains. Collectively the data show that the amyloid-laden brain shows multiple vulnerabilities to secondary inflammatory challenge: both microglia and astrocytes are primed to produce exaggerated secondary inflammation and systemic LPS is sufficient to cause cognitive impairments relevant to delirium, selectively in animals with prior amyloid pathology.

neuroscience↗

bioRxiv2018

C. elegans genetic background modifies the core transcriptional response in an α-synuclein model of Parkinson’s disease

Accumulation of protein aggregates is a major cause of Parkinsons disease (PD), a progressive neurodegenerative condition that is one of the most common causes of dementia. Transgenic Caenorhabditis elegans worms expressing the human synaptic protein -synuclein show inclusions of aggregated protein and replicate the defining pathological hallmarks of PD. It is however not known how PD progression and pathology differs among individual genetic backgrounds. Here, we compared gene expression patterns, and investigated the phenotypic consequences of transgenic -synuclein expression in five different C. elegans genetic backgrounds. Transcriptome analysis indicates that the effects of -synuclein expression on pathways associated with nutrient storage, lipid transportation and ion exchange depend on the genetic background. The gene expression changes we observe suggest that a range of phenotypes will be affected by -synuclein expression. We experimentally confirm this, showing that the transgenic lines generally show delayed development, reduced lifespan, and an increased rate of matricidal hatching. These phenotypic effects coincide with the core changes in gene expression, linking developmental arrest, mobility, metabolic and cellular repair mechanisms to -synuclein expression. Together, our results show both genotype-specific effects and core alterations in global gene expression and in phenotype in response to -synuclein. We conclude that the PD effects are substantially modified by the genetic background, illustrating that genetic background mechanisms should be elucidated to understand individual variation in PD.

genomics↗

bioRxiv2018

Nemo-like kinase regulates Progranulin levels in the brain through the microglial endocytosis-lysosomal pathway

Genetic variants in Granulin (GRN), which encodes the secreted glycoprotein Progranulin (PGRN), are associated with several neurodegenerative diseases including frontotemporal lobar degeneration, neuronal ceroid lipofuscinosis, and Alzheimers disease. These genetic alterations manifest in pathological changes due to a reduction of PGRN expression; therefore, identifying a factor that can modulate PGRN levels in vivo would enhance our understanding of PGRN in neurodegeneration, and could reveal novel potential therapeutic targets. Here, we report that Nemo-like kinase (Nlk) regulates Pgrn levels and its associated neuropathophysiology. Genetic interaction studies in mice show that Grn heterozygote mice on an Nlk heterozygote background display pathological and behavioral phenotypes which mimic Grn knockout mice. Furthermore, biochemical and cell biological studies suggest that Nlk reduction promotes Pgrn degradation via the endocytosis-lysosomal pathway, specifically in microglia. Our results reveal a new mechanism for the regulation of Pgrn in the brain and provide insight into the pathophysiology of PGRN-associated diseases.

neuroscience↗

bioRxiv2018

Extreme nuclear branching in healthy epidermal cells of the Xenopus tail fin

Changes in nuclear morphology contribute to regulation of complex cell properties, including differentiation and tissue elasticity. Perturbations of nuclear morphology are associated with pathologies that include, progeria, cancer, and muscular dystrophy. The mechanisms governing nuclear shape changes in healthy cells remain poorly understood, partially because there are few healthy models of nuclear shape variation. Here, we introduce nuclear branching in epidermal fin cells of Xenopus tropicalis as a model for extreme variation of nuclear morphology in a diverse population of healthy cells. We find that nuclear branching arises and elaborates during embryonic development. They contain broadly distributed marks of transcriptionally active chromatin and heterochromatin and have active cell cycles. We find that nuclear branches are disrupted by loss of filamentous actin and depend on epidermal expression of the nuclear lamina protein Lamin B1. Inhibition of nuclear branching disrupts fin morphology, suggesting that nuclear branching may be involved in fin development. This study introduces the nuclei of the fin as a powerful new model for extreme nuclear morphology in healthy cells to complement studies of nuclear shape variation in pathological contexts.\n\nList of abbreviations and symbolsLINC-Linker of Nucleoskeleton and Cytoskeleton, HGPS - Hutchinson-Gilford Progeria Syndrome, TEM - Transmission electron microscopy, PH3 - Phosphorylated Histone 3, Lat B - Latrunculin B, WT-Wild type, Cyto D-Cytochalasin D, Lmnb1 CRISPR - lmnb1 mutants generated by CRISPR/Cas9, E-Lmnb1 CRISPR - epidermal specific lmnb1 mutants generated by CRISPR/Cas9, Scrmbl-tadpoles injected with a scrambled version of the lmnb1 targeted sgRNA, Lmnb1-rod - dominant-negative Lamin B1 containing only the rod domain\n\nSummary StatementNuclei are highly branched throughout the heterogeneous population of healthy epidermal cells that comprise the Xenopus tail fin periphery, and disruption of nuclear branching mechanisms results in improper fin morphology.

cell biology↗

bioRxiv2018

Tau protein aggregation induces cellular senescence in the brain.

Tau protein accumulation is the most common pathology among degenerative brain diseases, including Alzheimers disease (AD), progressive supranuclear palsy (PSP), traumatic brain injury (TBI) and over twenty others1. Tau-containing neurofibrillary tangle (NFT) accumulation is the closest correlate with cognitive decline and cell loss, yet the mechanisms mediating tau toxicity are poorly understood. NFT-containing neurons do not die, which suggests secondary mechanisms are driving toxicity2. We evaluated gene expression patterns of NFT-containing neurons microdissected from AD patient brains3 and found they develop an expression profile consistent with cellular senescence described in dividing cells. This complex stress response induces a near permanent cell cycle arrest, adaptations to maintain survival, cellular remodeling, and metabolic dysfunction4. Moreover, senescent cells induce chronic degeneration of surrounding tissue through the secretion of pro-inflammatory, pro-apoptotic molecules termed the senescence-associated secretory phenotype (SASP)5. Using transgenic mouse models of tau-associated pathogenesis we found that NFTs induced a senescence-like phenotype including DNA damage, karyomegaly, mitochondrial dysfunction and SASP. Cdkn2a transcript level, a hallmark measure of senescence, directly correlated with brain atrophy and NFT load. This relationship extended to postmortem brain tissue from humans with PSP to indicate a phenomenon common to tau toxicity. Tau transgenic mice with late stage pathology were treated with senolytics to remove senescent cells. Despite the advanced age and disease progression, senolytic treatment reduced total NFT burden, neuron loss and ventricular enlargement; and normalized cerebral blood flow to that of non-transgenic control mice. Collectively, these findings indicate that NFTs induce cellular senescence in the brain, which contributes to neurodegeneration and brain dysfunction. Moreover, given the prevalence of tau protein deposition among neurodegenerative diseases, these findings have broad implications for understanding, and potentially treating, dozens of brain diseases.

neuroscience↗

bioRxiv2018

Single molecule analysis of lamin dynamics

The nuclear envelope (NE) is an essential cellular structure that contributes to nuclear stability, organization, and function. Mutations in NE-associated proteins result in a myriad of pathologies with widely diverse clinical manifestations, ages of onsets, and affected tissues. Notably, several hundred disease-causing mutations have been mapped to the LMNA gene, which encodes the intermediate filament proteins lamin A and C, two of the major architectural components of the nuclear envelope. However, how NE dysfunction leads to the highly variable pathologies observed in patient cells and tissues remains poorly understood. One model suggests alterations in the dynamic properties of the nuclear lamina and its associated proteins contribute to disease phenotype. Here, we describe the application of single molecule tracking (SMT) methodology to characterize the behavior of nuclear envelope transmembrane proteins (NETs) and nuclear lamins in their native cellular environment at the single molecule level. As proof-of-concept, we demonstrate by SMT that Halo-tagged lamin B1, Samp1, lamin A, and lamin A {Delta}50 have distinct binding and kinetic properties, and we identify several disease-relevant mutants which exhibit altered binding dynamics. SMT is also able to separately probe the dynamics of the peripheral and the nucleoplasmic populations of lamin A mutants. We suggest that SMT is a robust and sensitive method to investigate how pathogenic mutations or cellular processes affect protein dynamics at the NE.

cell biology↗

bioRxiv2018

CHD8 Regulates Cellular Homeostasis and Neuronal Function Genes Across Multiple Models of CHD8 Haploinsufficiency

The packaging of DNA into chromatin determines the transcriptional potential of cells and is central to eukaryotic gene regulation. Recent sequencing of patient mutations has linked de novo loss-of-function mutations to chromatin remodeling factors with specific, causal roles in neurodevelopmental disorders. Characterizing cellular and molecular phenotypes arising from haploinsufficiency of chromatin remodeling factors could reveal convergent mechanisms of pathology. Chromodomain helicase DNA binding protein 8 (CHD8) encodes a chromatin remodeling factor gene and has among the highest de novo loss-of-function mutations rates in patients with autism spectrum disorder (ASD). Mutations to CHD8 are expected to drive neurodevelopmental pathology through global disruptions to gene expression and chromatin state, however, mechanisms associated with CHD8 function have yet to be fully elucidated. We analyzed published transcriptomic and epigenomic data across CHD8 in vitro and in vivo knockdown and knockout models to identify convergent mechanisms of gene regulation by CHD8. We found reproducible high-affinity interactions of CHD8 near promoters of genes necessary for basic cell functions and gene regulation, especially chromatin organization and RNA processing genes. Overlap between CHD8 interaction and differential expression suggests that reduced dosage of CHD8 directly relates to decreased expression of these genes. In addition, genes important for neuronal development and function showed consistent dysregulation, though there was a reduced rate and decreased affinity for CHD8 interactions near these genes. This meta-analysis verifies CHD8 as a critical regulator of gene expression and reveals a consistent set of high affinity CHD8 interaction targets observed across human and mouse in vivo and in vitro studies. Our findings highlight novel core functions of CHD8 and indicate direct and downstream gene regulatory impacts that are likely to be associated with neuropathology underlying CHD8-associated neurodevelopmental disorder.

neuroscience↗

bioRxiv2018

3D-Printed Biodegradable Microswimmer for Drug Delivery and Targeted Cell Labeling

Miniaturization of interventional medical devices can leverage minimally invasive technologies by enabling operational resolution at cellular length scales with high precision and repeatability. Untethered micron-scale mobile robots can realize this by navigating and performing in hard-to-reach, confined and delicate inner body sites. However, such a complex task requires an integrated design and engineering strategy, where powering, control, environmental sensing, medical functionality and biodegradability need to be considered altogether. The present study reports a hydrogel-based, biodegradable microrobotic swimmer, which is responsive to the changes in its microenvironment for theranostic cargo delivery and release tasks. We design a double-helical magnetic microswimmer of 20 m length, which is 3D-printed with complex geometrical and compositional features. At normal physiological concentrations, matrix metalloproteinase-2 (MMP-2) enzyme can entirely degrade the microswimmer body in 118 h to solubilized non-toxic products. The microswimmer can respond to the pathological concentrations of MMP-2 by swelling and thereby accelerating the release kinetics of the drug payload. Anti-ErbB 2 antibody-tagged magnetic nanoparticles released from the degraded microswimmers serve for targeted labeling of SKBR3 breast cancer cells to realize the potential of medical imaging of local tissue sites following the therapeutic intervention. These results represent a leap forward toward clinical medical microrobots that are capable of sensing, responding to the local pathological information, and performing specific therapeutic and diagnostic tasks as orderly executed operations using their smart composite material architectures.

bioengineering↗

bioRxiv2018

A theoretical approach for discriminating accurately intrinsic pattern of biological systems and recognizing three kind soybean proteomes

proteomics is able to reveal plentiful information related to different physiological and pathological states of biology. Further, the determination of accurately proteomic pattern is the essential platform for deeply proteomic research. While this has been somewhat ignored so far. In this article the quantitative standard Pg=61%, a biological similarity constant for discriminating accurately intrinsic proteomic patterns was established depending on biological common heredity and variation information equation in symmetric variation state. On the other hand, a novel theoretical method was proposed for linearly dividing nonlinear data sequence into linear segments. The proteomes of three kind soybeans were precisely distinguished from one another by analyzing their infrared fingerprint spectra relying on this theoretically systemic approach. Additionally, methods employed in this paper enable us to quickly, accurately and quantitatively determine the proteomic patterns without using any prior knowledge and learning samples, and without using electrophoresis, high performance liquid chromatography-mass spectrometry techniques, which are high cost, time-consuming. This approach provide us with an excellent one for quickly accurate determining biological species, physiological states and diagnosing pathological states based on proteomes.

bioinformatics↗

bioRxiv2018

Motor cortical beta transients delay movement initiation and track errors

Motor cortical activity in the beta range (13-30 Hz) is a hallmark signature of healthy and pathological movement, but its behavioural relevance remains unclear. Recent work in primates and human sensory cortex suggests that sustained oscillatory beta activity observed on average, may arise from the summation of underlying short-lasting, high-amplitude bursts of activity. Classical human movement-related event-related beta desynchronisation (ERD) and synchronization (ERS) may thus provide insufficient, non-dynamic, summaries of underlying focal spatio-temporal burst activity, limiting insight into their functional role during healthy and pathological movement.\n\nHere we directly investigate this transient beta burst activity and its putative behavioural relevance for movement control, using high-precision magnetoencephalography (MEG). We quantified the subject-specific (n=8), trial-wise (n>12,000) dynamics of beta bursts, before and after movement. We show that beta activity on individual trials is dominated by high amplitude, short lasting bursts. While average beta changes generally manifest as bilaterally distributed activity (FWHM = 25mm), individual bursts are spatially more focal (FWHM = 6 mm), sporadic (1.3 -1.5/s), and transient (mean: 96 ms).\n\nPrior to movement (the period of the classical ERD), the timing of the last pre-movement burst predicts movement onset, suggesting a role in the specification of the goal of movement. After movement (the period of the classical ERS), the first beta burst is delayed by ~100ms after a response error occurs, intimating a role in error monitoring and evaluation.\n\nMovement-related beta activity is therefore dominated by a spatially dispersed summation of short lasting, sporadic and focal bursts. Movement-related beta bursts coordinate the retrieval and updating of movement goals in the pre- and post-movement periods, respectively.

neuroscience↗

bioRxiv2018

A bispecific immunotweezer prevents soluble PrP oligomers and abolishes prion toxicity

Antibodies to the prion protein, PrP, represent a promising therapeutic approach against prion diseases but the neurotoxicity of certain anti-PrP antibodies has caused concern. Here we describe scPOM-bi, a bispecific antibody designed to function as a molecular prion tweezer. scPOM-bi combines the complementarity-determining regions of the neurotoxic antibody POM1 and the neuroprotective POM2, which bind the globular domain (GD) and flexible tail (FT) respectively. We found that scPOM-bi confers protection to prion-infected organotypic cerebellar slices even when prion pathology is already conspicuous. Moreover, scPOM-bi prevents the formation of soluble oligomers that correlate with neurotoxic PrP species. Simultaneous targeting of both GD and FT was more effective than concomitant treatment with the individual molecules or targeting the tail alone, possibly by preventing the GD from entering a toxic-prone state. We conclude that simultaneous binding of the GD and flexible tail of PrP results in strong protection from prion neurotoxicity and may represent a promising strategy for anti-prion immunotherapy.\n\nAuthor summaryAntibody immunotherapy is considered a viable strategy against prion disease. We previously showed that antibodies against the so-called globular domain of Prion Protein (PrP) can cause PrP dependent neurotoxicity; this does not happen for antibodies against the flexible tail of PrP, which therefore ought to be preferred for therapy.\n\nHere we show that simultaneous targeting of both globular domain and flexible tail by a bispecific, combination of a toxic and a non-toxic antibody, results in stronger protection against prion toxicity, even if the bispecific is administered when prion pathology is already conspicuous.\n\nWe hypothesize that neurotoxicity arises from binding to specific \"toxicity triggering sites\" in the globular domain. We designed our bispecific with two aims: i) occupying one such site and preventing prion or other factors from docking to it and ii) binding to the flexible tail to engage the region of PrP necessary for neurotoxicity.\n\nWe also show that neurotoxic antibodies cause the formation of soluble PrP oligomers that cause toxicity on PrP expressing cell lines; these are not formed in the presence of prion protective antibodies. We suggest that these soluble species might play a role in prion toxicity, similarly to what is generally agreed to happen in other neurodegenerative disorders.

molecular biology↗

bioRxiv2018

Three-dimensional nanostructure of an intact microglia cell

Microglia are non-neuronal cells of the myeloid lineage that invade and take up long-term residence in the brain during development (Ginhoux et al. 2010) and are increasingly implicated in neuronal maturation, homeostasis, and pathology (Bessis et al. 2007; Paolicelli et al. 2011; Li et al. 2012; Aguzzi et al. 2013, Cunningham 2013, Cunningham et al. 2013). Since the early twentieth century several methods for staining and visualizing microglia have been developed. Scientists in Ramon y Cajals group (Achucarro 1913, Rio-Hortega 1919) pioneered these methods and their work led to the christening of microglia as the third element of the nervous system, distinct from astrocytes and neurons. More recently, a combination of imaging, genetic, and immunological tools has been used to visualize microglia in living brain (Davalos et al. 2005; Nimmerjahn et al. 2005). It was found that microglia are highly motile under resting conditions and rapidly respond to injuries (Kettenmann et al. 2011) suggesting a role for microglia in both brain homeostasis and pathology. Transmission Electron microscopy (TEM) has provided crucial complementary information on microglia morphology and physiology but until recently EM analyses have been limited to single or limited serial section studies (Tremblay et al. 2010; Paolicelli et al. 2011; Schafer et al. 2012; Tremblay et al. 2012; Sipe et al. 2016). TEM studies were successful in defining a set of morphological criteria for microglia: a polygonal nucleus with peripheral condensed chromatin, a relatively small cytoplasm with abundant presence of rough endoplasmic reticulum (RER), and a large volume of lysosomes and inclusions in the perikaryon. Recent advances in volumetric electron microscopy techniques allow for 3D reconstruction of large samples at nanometer-resolution, thus opening up new avenues for the understanding of cell biology and architecture in intact tissues. At the same time, correlative light and electron microscopy (CLEM) techniques have been extended to 3D brain samples to help navigate and identify critical molecular landmarks within large EM volumes (Briggman and Denk 2006; Maco et al. 2013; Blazquez-Llorca et al. 2015, Bosch et al. 2015). Here we present the first volumetric ultrastructural reconstruction of an entire mouse hippocampal microglia using serial block face scanning electron microscopy (SBEM). Using CLEM we have ensured the inclusion of both large, small, and filopodial microglia processes. Segmentation of the dataset allowed us to carry out a comprehensive inventory of microglia cell structures, including vesicles, organelles, membrane protrusions, and processes. This study provides a reference that can serve as a data mining resource for investigating microglia cell biology.

neuroscience↗

bioRxiv2018

A Framework for Cortical Layer Composition Analysis using Low Resolution T1 MRI Images

The layer composition of the cerebral cortex represents a unique anatomical fingerprint of brain development, function, connectivity and pathology. Historically the cortical layers were investigated solely ex-vivo using histological means, but recent magnetic resonance imaging (MRI) studies suggest that T1 relaxation images can be utilized to separate the layers. Despite technological advancements in the field of high resolution MRI, accurate estimation of whole brain layer composition has remained limited due to partial volume effects, leaving some layers far beyond the image resolution. In this study we offer a simple and accurate method for layer composition analysis, resolving partial volume effects and cortical curvature heterogeneity. We use a low resolution echo planar imaging inversion recovery (EPI IR) MRI scan protocol that provides fast acquisition (~12 minutes) and enables extraction of multiple T1 relaxation time components per voxel, which are assigned to types of brain tissue and utilized to extract the subvoxel composition of each T1 layer. While previous investigation of the layers required the estimation of cortical normals or smoothing of layer widths (similar to VBM), here we developed a sphere-based approach to explore the inner mesoscale architecture of the cortex. Our novel algorithm conducts spatial analysis using volumetric sampling of a system of virtual spheres dispersed throughout the entire cortical space. The methodology offers a robust and powerful framework for quantification and visualization of the layers on the cortical surface, providing a basis for quantitative investigation of their role in cognition, physiology and pathology.

neuroscience↗

bioRxiv2018

Large Fatty Acid-derived Aβ42 oligomers Form Ring-like Assemblies

As the primary toxic species in the etiology of Alzheimer disease (AD) are low molecular weight oligomers of A{beta}, it is crucial to understand the structure of A{beta} oligomers for gaining molecular insights into AD pathology. We have earlier demonstrated that in the presence of fatty acids A{beta}42 peptides assemble as 12-24mer oligomers. These Large Fatty Acid-derived Oligomers (LFAOs) exist predominantly as 12mers at low, and as 24mers at high concentrations. The 12mers are more neurotoxic than the 24mers and undergo self-replication, while the latter propagate to morphologically distinct fibrils with succinct pathological consequences. In order to glean into their functional differences and similarities, we have determined their structures in greater detail by combining molecular dynamic simulations with biophysical measurements. We conjecture that the LFAO are made of A{beta} units in an S-shaped conformation, with the 12mers forming a double-layered hexamer ring (6 x 2) while the structure of 24mers is a double-layered dodecamer ring (12 x 2). A closer inspection of the (6 x 2) and (12 x 2) structures reveals a concentration and pH dependent molecular reorganization in the assembly of 12 to 24mers, that seems to be the underlying mechanism for the observed biophysical and cellular properties of LFAOs.

biophysics↗

bioRxiv2018

Reducing tau ameliorates behavioural and transcriptional deficits in a novel model of Alzheimer’s disease

SummaryOne of the key knowledge gaps blocking development of effective therapeutics for Alzheimers disease (AD) is the lack of understanding of how amyloid beta (A{beta}) and tau cooperate in causing disease phenotypes. Within a mouse tau deficient background, we probed the molecular, cellular and behavioural disruption triggered by wild-type human taus influence on human A{beta}-induced pathology. We find that A{beta} and tau work cooperatively to cause a hyperactivity phenotype and to cause downregulation of gene transcription including many involved in synaptic function. In both our mouse model and in human post-mortem tissue, we observe accumulation of pathological tau in synapses, supporting the potential importance of synaptic tau. Importantly, tau depletion in the mice, initiated after behavioural deficits emerge, was found to correct behavioural deficits, reduce synaptic tau levels, and substantially reverse transcriptional perturbations, suggesting that lowering tau levels, particularly at the synapse, may be beneficial in AD.\n\nHighlights- Expression of human familial Alzheimers associated mutant amyloid precursor protein and presenillin 1 with wild-type human tau in the absence of endogenous tau in a novel MAPT-AD mouse model results in behavioural deficits and downregulation of genes involved in synaptic function.\n- Tau is present in pre and postsynaptic terminals in MAPT-AD mice and human AD brain. In mice, lowering synaptic tau levels was associated with improved cognition and recovered gene expression.\n- These data suggest that A{beta} and tau act cooperatively in impairing synaptic function and that lowering tau at synapses could be a beneficial therapeutic approach in AD.

neuroscience↗