Neurodegenerative Diseases
neurodegenerative diseases
Dr Nikolas Nikolaou
Regulation of pre-mRNA splicing plays a significant role in neurons by diversifying the proteome and modulating gene expression during development and in response to physiological cues. Although most pre-mRNA processing reactions are thought to occur in the nucleus, numerous RNA splicing regulators are also found in neurites, however, very little is known about their extra-nuclear functions. We have recently shown that the non-nuclear pool of a major spliceosome component (SNRNP70) modulates the production of alternative spliced mRNA isoforms essential for motor connectivity and protects transcripts from degradation. This project aims to investigate the extra-nuclear activities of SNRNP70 in the context of neuronal connectivity in zebrafish. The ease of genetic manipulations together with the translucency and small size of their offspring allows us to monitor neural cell behaviour and function and observe changes in neuronal connectivity. We will use a range of genetic tools, including transgenic over-expression of cytoplasmic SNRNP70 and nuclear-only SNRNP70 zebrafish knock-in lines to establish developmental functions attributed to the cytoplasmic pool of SNRNP70. The results from this project will contribute to our understanding of how local RNA metabolism in axons contributes to the normal development of neural connections in the brain.
Convergent large-scale network and local vulnerabilities underlie brain atrophy across Parkinson’s disease stages
Cause & Consequences of neuronal Tau protein ‘activation’
Expanding mechanisms and therapeutic targets for neurodegenerative disease
A hallmark pathological feature of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the depletion of RNA-binding protein TDP-43 from the nucleus of neurons in the brain and spinal cord. A major function of TDP-43 is as a repressor of cryptic exon inclusion during RNA splicing. By re-analyzing RNA-sequencing datasets from human FTD/ALS brains, we discovered dozens of novel cryptic splicing events in important neuronal genes. Single nucleotide polymorphisms in UNC13A are among the strongest hits associated with FTD and ALS in human genome-wide association studies, but how those variants increase risk for disease is unknown. We discovered that TDP-43 represses a cryptic exon-splicing event in UNC13A. Loss of TDP-43 from the nucleus in human brain, neuronal cell lines and motor neurons derived from induced pluripotent stem cells resulted in the inclusion of a cryptic exon in UNC13A mRNA and reduced UNC13A protein expression. The top variants associated with FTD or ALS risk in humans are located in the intron harboring the cryptic exon, and we show that they increase UNC13A cryptic exon splicing in the face of TDP-43 dysfunction. Together, our data provide a direct functional link between one of the strongest genetic risk factors for FTD and ALS (UNC13A genetic variants), and loss of TDP-43 function. Recent analyses have revealed even further changes in TDP-43 target genes, including widespread changes in alternative polyadenylation, impacting expression of disease-relevant genes (e.g., ELP1, NEFL, and TMEM106B) and providing evidence that alternative polyadenylation is a new facet of TDP-43 pathology.
Unlocking the Secrets of Microglia in Neurodegenerative diseases: Mechanisms of resilience to AD pathologies
Pharmacological exploitation of neurotrophins and their receptors to develop novel therapeutic approaches against neurodegenerative diseases and brain trauma
Neurotrophins (NGF, BDNF, NT-3) are endogenous growth factors that exert neuroprotective effects by preventing neuronal death and promoting neurogenesis. They act by binding to their respective high-affinity, pro-survival receptors TrkA, TrkB or TrkC, as well as to p75NTR death receptor. While these molecules have been shown to significantly slow or prevent neurodegeneration, their reduced bioavailability and inability to penetrate the blood-brain-barrier limit their use as potential therapeutics. To bypass these limitations, our research team has developed and patented small-sized, lipophilic compounds which selectively resemble neurotrophins’ effects, presenting preferable pharmacological properties and promoting neuroprotection and repair against neurodegeneration. In addition, the combination of these molecules with 3D cultured human neuronal cells, and their targeted delivery in the brain ventricles through soft robotic systems, could offer novel therapeutic approaches against neurodegenerative diseases and brain trauma.
Defining Molecular Mechanisms Underlying Neurodegenerative Diseases
Genetic and epigenetic underpinnings of neurodegenerative disorders
Pluripotent cells, including embryonic stem (ES) and induced pluripotent stem (iPS) cells, are used to investigate the genetic and epigenetic underpinnings of human diseases such as Parkinson’s, Alzheimer’s, autism, and cancer. Mechanisms of somatic cell reprogramming to an embryonic pluripotent state are explored, utilizing patient-specific pluripotent cells to model and analyze neurodegenerative diseases.
Use of human systems for neuroinflammatory/neurodegenerative diseases
Astrocyte reprogramming / activation and brain homeostasis
Astrocytes are multifunctional glial cells, implicated in neurogenesis and synaptogenesis, supporting and fine-tuning neuronal activity and maintaining brain homeostasis by controlling blood-brain barrier permeability. During the last years a number of studies have shown that astrocytes can also be converted into neurons if they force-express neurogenic transcription factors or miRNAs. Direct astrocytic reprogramming to induced-neurons (iNs) is a powerful approach for manipulating cell fate, as it takes advantage of the intrinsic neural stem cell (NSC) potential of brain resident reactive astrocytes. To this end, astrocytic cell fate conversion to iNs has been well-established in vitro and in vivo using combinations of transcription factors (TFs) or chemical cocktails. Challenging the expression of lineage-specific TFs is accompanied by changes in the expression of miRNAs, that post-transcriptionally modulate high numbers of neurogenesis-promoting factors and have therefore been introduced, supplementary or alternatively to TFs, to instruct direct neuronal reprogramming. The neurogenic miRNA miR-124 has been employed in direct reprogramming protocols supplementary to neurogenic TFs and other miRNAs to enhance direct neurogenic conversion by suppressing multiple non-neuronal targets. In our group we aimed to investigate whether miR-124 is sufficient to drive direct reprogramming of astrocytes to induced-neurons (iNs) on its own both in vitro and in vivo and elucidate its independent mechanism of reprogramming action. Our in vitro data indicate that miR-124 is a potent driver of the reprogramming switch of astrocytes towards an immature neuronal fate. Elucidation of the molecular pathways being triggered by miR-124 by RNA-seq analysis revealed that miR-124 is sufficient to instruct reprogramming of cortical astrocytes to immature induced-neurons (iNs) in vitro by down-regulating genes with important regulatory roles in astrocytic function. Among these, the RNA binding protein Zfp36l1, implicated in ARE-mediated mRNA decay, was found to be a direct target of miR-124, that be its turn targets neuronal-specific proteins participating in cortical development, which get de-repressed in miR-124-iNs. Furthermore, miR-124 is potent to guide direct neuronal reprogramming of reactive astrocytes to iNs of cortical identity following cortical trauma, a novel finding confirming its robust reprogramming action within the cortical microenvironment under neuroinflammatory conditions. In parallel to their reprogramming properties, astrocytes also participate in the maintenance of blood-brain barrier integrity, which ensures the physiological functioning of the central nervous system and gets affected contributing to the pathology of several neurodegenerative diseases. To study in real time the dynamic physical interactions of astrocytes with brain vasculature under homeostatic and pathological conditions, we performed 2-photon brain intravital imaging in a mouse model of systemic neuroinflammation, known to trigger astrogliosis and microgliosis and to evoke changes in astrocytic contact with brain vasculature. Our in vivo findings indicate that following neuroinflammation the endfeet of activated perivascular astrocytes lose their close proximity and physiological cross-talk with vasculature, however this event is at compensated by the cross-talk of astrocytes with activated microglia, safeguarding blood vessel coverage and maintenance of blood-brain integrity.
Connectome-based models of neurodegenerative disease
Neurodegenerative diseases involve accumulation of aberrant proteins in the brain, leading to brain damage and progressive cognitive and behavioral dysfunction. Many gaps exist in our understanding of how these diseases initiate and how they progress through the brain. However, evidence has accumulated supporting the hypothesis that aberrant proteins can be transported using the brain’s intrinsic network architecture — in other words, using the brain’s natural communication pathways. This theory forms the basis of connectome-based computational models, which combine real human data and theoretical disease mechanisms to simulate the progression of neurodegenerative diseases through the brain. In this talk, I will first review work leading to the development of connectome-based models, and work from my lab and others that have used these models to test hypothetical modes of disease progression. Second, I will discuss the future and potential of connectome-based models to achieve clinically useful individual-level predictions, as well as to generate novel biological insights into disease progression. Along the way, I will highlight recent work by my lab and others that is already moving the needle toward these lofty goals.
Mathematical and computational modelling of ocular hemodynamics: from theory to applications
Changes in ocular hemodynamics may be indicative of pathological conditions in the eye (e.g. glaucoma, age-related macular degeneration), but also elsewhere in the body (e.g. systemic hypertension, diabetes, neurodegenerative disorders). Thanks to its transparent fluids and structures that allow the light to go through, the eye offers a unique window on the circulation from large to small vessels, and from arteries to veins. Deciphering the causes that lead to changes in ocular hemodynamics in a specific individual could help prevent vision loss as well as aid in the diagnosis and management of diseases beyond the eye. In this talk, we will discuss how mathematical and computational modelling can help in this regard. We will focus on two main factors, namely blood pressure (BP), which drives the blood flow through the vessels, and intraocular pressure (IOP), which compresses the vessels and may impede the flow. Mechanism-driven models translates fundamental principles of physics and physiology into computable equations that allow for identification of cause-to-effect relationships among interplaying factors (e.g. BP, IOP, blood flow). While invaluable for causality, mechanism-driven models are often based on simplifying assumptions to make them tractable for analysis and simulation; however, this often brings into question their relevance beyond theoretical explorations. Data-driven models offer a natural remedy to address these short-comings. Data-driven methods may be supervised (based on labelled training data) or unsupervised (clustering and other data analytics) and they include models based on statistics, machine learning, deep learning and neural networks. Data-driven models naturally thrive on large datasets, making them scalable to a plethora of applications. While invaluable for scalability, data-driven models are often perceived as black- boxes, as their outcomes are difficult to explain in terms of fundamental principles of physics and physiology and this limits the delivery of actionable insights. The combination of mechanism-driven and data-driven models allows us to harness the advantages of both, as mechanism-driven models excel at interpretability but suffer from a lack of scalability, while data-driven models are excellent at scale but suffer in terms of generalizability and insights for hypothesis generation. This combined, integrative approach represents the pillar of the interdisciplinary approach to data science that will be discussed in this talk, with application to ocular hemodynamics and specific examples in glaucoma research.
From the guts to the brain through adaptive immunity in the prevention of Alzheimer’ disease
Dr. Pasinetti is the Saunders Family Chair and Professor of Neurology at Icahn School of medicine at Mount Sinai, New York. His studies allowed him to develop novel therapeutic approaches through investigation of preventable risk factors including mood disorders in the promotion of resilience against neurodegenerative disorder. In his presentation Dr. Pasinetti will discuss novel concepts about the gut-brain axis in mechanisms associated to peripheral adaptive immunity as therapeutic targets to mitigate the onset and the progression of Alzheimer’s disease and other form of dementia.
Establishment and aging of the neuronal DNA methylation landscape in the hippocampus
The hippocampus is a brain region with key roles in memory formation, cognitive flexibility and emotional control. Yet hippocampal function is impaired severely during aging and in neurodegenerative diseases, and impairments in hippocampal function underlie age-related cognitive decline. Accumulating evidence suggests that the deterioration of the neuron-specific epigenetic landscape during aging contributes to their progressive, age-related dysfunction. For instance, we have recently shown that aging is associated with pronounced alterations of neuronal DNA methylation patterns in the hippocampus. Because neurons are generated mostly during development with limited replacement in the adult brain, they are particularly long-lived cells and have to maintain their cell-type specific gene expression programs life-long in order to preserve brain function. Understanding the epigenetic mechanisms that underlie the establishment and long-term maintenance of neuron-specific gene expression programs, will help us to comprehend the sources and consequences of their age-related deterioration. In this talk, I will present our recent work that investigated the role of DNA methylation in the establishment of neuronal gene expression programs and neuronal function, using adult neurogenesis in the hippocampus as a model. I will then describe the effects of aging on the DNA methylation landscape in the hippocampus and discuss the malleability of the aging neuronal methylome to lifestyle and environmental stimulation.
Exploring the Potential of High-Density Data for Neuropsychological Testing with Coregraph
Coregraph is a tool under development that allows us to collect high-density data patterns during the administration of classic neuropsychological tests such as the Trail Making Test and Clock Drawing Test. These tests are widely used to evaluate cognitive function and screen for neurodegenerative disorders, but traditional methods of data collection only yield sparse information, such as test completion time or error types. By contrast, the high-density data collected with Coregraph may contribute to a better understanding of the cognitive processes involved in executing these tests. In addition, Coregraph may potentially revolutionize the field of cognitive evaluation by aiding in the prediction of cognitive deficits and in the identification of early signs of neurodegenerative disorders such as Alzheimer's dementia. By analyzing high-density graphomotor data through techniques like manual feature engineering and machine learning, we can uncover patterns and relationships that would be otherwise hidden with traditional methods of data analysis. We are currently in the process of determining the most effective methods of feature extraction and feature analysis to develop Coregraph to its full potential.
The functional architecture of the human entorhinal-hippocampal circuitry
Cognitive functions like episodic memory require the formation of cohesive representations. Critical for that process is the entorhinal-hippocampal circuitry’s interaction with cortical information streams and the circuitry’s inner communication. With ultra-high field functional imaging we investigated the functional architecture of the human entorhinal-hippocampal circuitry. We identified an organization that is consistent with convergence of information in anterior and lateral entorhinal subregions and the subiculum/CA1 border while keeping a second route specific for scene processing in a posterior-medial entorhinal subregion and the distal subiculum. Our findings agree with information flow along information processing routes which functionally split the entorhinal-hippocampal circuitry along its transversal axis. My talk will demonstrate how ultra-high field imaging in humans can bridge the gap between anatomical and electrophysiological findings in rodents and our understanding of human cognition. Moreover, I will point out the implications that basic research on functional architecture has for cognitive and clinical research perspectives.
The glymphatic system in motor neurone disease
Neurodegenerative diseases are chronic and inexorable conditions characterised by the presence of insoluble aggregates of abnormally ubiquinated and phosphorylated proteins. Recent evidence also suggests that protein misfolding can propagate throughout the body in a prion-like fashion via the interstitial or cerebrospinal fluids (CSF). As protein aggregation occurs well before the onset of brain damage and symptoms, new biomarkers sensitive to early pathology, together with therapeutic strategies that include eliminating seed proteins and blocking cell-to-cell spread, are of vital importance. The glymphatic system, which facilitates the continuous exchange of CSF and interstitial fluid to clear the brain of waste, presents as a potential biomarker of disease severity, therapeutic target, and drug delivery system. In this webinar, Associate Professor David Wright from the Department of Neuroscience, Monash University, will outline recent advances in using MRI to investigate the glymphatic system. He will also present some of his lab’s recent work investigating glymphatic clearance in preclinical models of motor neurone disease. Associate Professor David Wright is an NHMRC Emerging Leadership Fellow and the Director of Preclinical Imaging in the Department of Neuroscience, Monash University and the Alfred Research Alliance, Alfred Health. His research encompasses the development, application and analysis of advanced magnetic resonance imaging techniques for the study of disease, with a particular emphasis on neurodegenerative disorders. Although less than three years post PhD, he has published over 60 peer-reviewed journal articles in leading neuroscience journals such as Nature Medicine, Brain, and Cerebral Cortex.
Pro-regenerative functions of microglia in demyelinating diseases
Our goal is to understand why myelin repair fails in multiple sclerosis and to develop regenerative medicines for the nervous system. A central obstacle for progress in this area has been the complex biology underlying the response to CNS injury. Acute CNS damage is followed by a multicellular response that encompasses different cell types and spans different scales. Currently, we do not understand which factors determines lesion recovery. Failure of inflammation to resolve is a key underlying reason of poor regeneration, and one focus is therefore on the biology of microglia during de- and remyelination, and their cross talk to other cells, in particular oligodendrocytes and the progenitor cells. In addition, we are exploring the link between lipid metabolism and inflammation, and its role in the regulation of regeneration. I will report about our recent progress in our understanding of how microglia promote regeneration in the CNS.
PET imaging in brain diseases
Talk 1. PET based biomarkers of treatment efficacy in temporal lobe epilepsy A critical aspect of drug development involves identifying robust biomarkers of treatment response for use as surrogate endpoints in clinical trials. However, these biomarkers also have the capacity to inform mechanisms of disease pathogenesis and therapeutic efficacy. In this webinar, Dr Bianca Jupp will report on a series of studies using the GABAA PET ligand, [18F]-Flumazenil, to establish biomarkers of treatment response to a novel therapeutic for temporal lobe epilepsy, identifying affinity at this receptor as a key predictor of treatment outcome. Dr Bianca Jupp is a Research Fellow in the Department of Neuroscience, Monash University and Lead PET/CT Scientist at the Alfred Research Alliance–Monash Biomedical Imaging facility. Her research focuses on neuroimaging and its capacity to inform the neurobiology underlying neurological and neuropsychiatric disorders. Talk 2. The development of a PET radiotracer for reparative microglia Imaging of neuroinflammation is currently hindered by the technical limitations associated with TSPO imaging. In this webinar, Dr Lucy Vivash will discuss the development of PET radiotracers that specifically image reparative microglia through targeting the receptor kinase MerTK. This includes medicinal chemistry design and testing, radiochemistry, and in vitro and in vivo testing of lead tracers. Dr Lucy Vivash is a Research Fellow in the Department of Neuroscience, Monash University. Her research focuses on the preclinical development and clinical translation of novel PET radiotracers for the imaging of neurodegenerative diseases.
Systemic regulation and measurement of mammalian aging
Brain aging leads to cognitive decline and is the main risk factor for sporadic forms of neurodegenerative diseases including Alzheimer’s disease. While brain cell- and tissue-intrinsic factors are likely key determinants of the aging process recent studies document a remarkable susceptibility of the brain to circulatory factors. Thus, blood borne factors from young mice or humans are sufficient to slow aspects of brain aging and improve cognitive function in old mice and, vice versa, factors from old mice are detrimental for young mice and impair cognition. We found evidence that the cerebrovasculature is an important target of circulatory factors and that brain endothelial cells show prominent age-related transcriptional changes in response to plasma. Furthermore, plasma proteins are taken up broadly into the young brain through receptor mediated transport which declines with aging. At the same time, brain derived proteins are detectable in plasma allowing us to measure physiological changes linked to brain aging in plasma. We are exploring the relevance of these findings for neurodegeneration and potential applications towards therapies.
MBI Webinar on preclinical research into brain tumours and neurodegenerative disorders
WEBINAR 1 Breaking the barrier: Using focused ultrasound for the development of targeted therapies for brain tumours presented by Dr Ekaterina (Caty) Salimova, Monash Biomedical Imaging Glioblastoma multiforme (GBM) - brain cancer - is aggressive and difficult to treat as systemic therapies are hindered by the blood-brain barrier (BBB). Focused ultrasound (FUS) - a non-invasive technique that can induce targeted temporary disruption of the BBB – is a promising tool to improve GBM treatments. In this webinar, Dr Ekaterina Salimova will discuss the MRI-guided FUS modality at MBI and her research to develop novel targeted therapies for brain tumours. Dr Ekaterina (Caty) Salimova is a Research Fellow in the Preclinical Team at Monash Biomedical Imaging. Her research interests include imaging cardiovascular disease and MRI-guided focused ultrasound for investigating new therapeutic targets in neuro-oncology. - WEBINAR 2 Disposition of the Kv1.3 inhibitory peptide HsTX1[R14A], a novel attenuator of neuroinflammation presented by Sanjeevini Babu Reddiar, Monash Institute of Pharmaceutical Sciences The voltage-gated potassium channel (Kv1.3) in microglia regulates membrane potential and pro-inflammatory functions, and non-selective blockade of Kv1.3 has shown anti-inflammatory and disease improvement in animal models of Alzheimer’s and Parkinson’s diseases. Therefore, specific inhibitors of pro-inflammatory microglial processes with CNS bioavailability are urgently needed, as disease-modifying treatments for neurodegenerative disorders are lacking. In this webinar, PhD candidate Ms Sanju Reddiar will discuss the synthesis and biodistribution of a Kv1.3-inhibitory peptide using a [64Cu]Cu-DOTA labelled conjugate. Sanjeevini Babu Reddiar is a PhD student at the Monash Institute of Pharmaceutical Sciences. She is working on a project identifying the factors governing the brain disposition and blood-brain barrier permeability of a Kv1.3-blocking peptide.
Human stem cell models of Alzheimer’s disease and frontotemporal dementia
The development of human induced pluripotent stem cells (iPSC) and their subsequent differentiation into neurons has provided new opportunities for the generation of physiologically-relevant, in vitro disease models. I will present our work using iPSC to modal familial Alzheimer's Disease (fAD) and Frontotemporal Dementia (FTD). We have investigated the mutation-specific effects of APP and PSEN1 mutations on Abeta generation in neurons generated from individuals with fAD, revealing distinct mechanisms that may contribute to clinical heterogeneity in disease. I will also discuss our work to understand the developmental and pathological changes to tau that occur in iPSC-neurons, particularly the challenges of understanding tau pathology in a developmental system, tau proteostasis and how iPSC-neurons may help us identify early signatures of tau pathology in disease.
2nd In-Vitro 2D & 3D Neuronal Networks Summit
The event is open to everyone interested in Neuroscience, Cell Biology, Drug Discovery, Disease Modeling, and Bio/Neuroengineering! This meeting is a platform bringing scientists from all over the world together and fostering scientific exchange and collaboration.
2nd In-Vitro 2D & 3D Neuronal Networks Summit
The event is open to everyone interested in Neuroscience, Cell Biology, Drug Discovery, Disease Modeling, and Bio/Neuroengineering! This meeting is a platform bringing scientists from all over the world together and fostering scientific exchange and collaboration.
The Role of Cerebrovascular Pathology in Aging and Neurodegenerative Disease Populations
Late-life cognitive impairment and dementia are heterogeneous and multifactorial conditions driven by a combination of genetic, vascular, and lifestyle-related factors. More than 75% of patients with dementia have evidence of cerebrovascular pathology at autopsy. Cerebrovascular disease lesions can be detected on structural MRI and used as biomarkers to determine the extent of cerebrovascular pathology. These biomarkers are associated with cognitive difficulties and increase the risk of dementia for the same level of neurodegenerative pathology. Given that some of the risk factors for cerebrovascular disease are potentially modifiable, identifying the role of cerebrovascular pathology in aging and neurodegenerative disease populations opens a window for prevention of cognitive decline and dementia.
Mechanisms of Axon Growth and Regeneration
Almost everybody that has seen neurons under a microscope for the first time is fascinated by their beauty and their complex shape. Early on during development, however, there are hardly any signs of their future complexity, but the neurons look round and simple. How do neurons develop their sophisticated structure? How do they initially generate domains that later have distinct function within neuronal circuits, such as the axon? And, can a better understanding of the underlying developmental mechanisms help us in pathological conditions, such as a spinal cord injury, to induce axons to regenerate? Here, I will talk about the cytoskeleton as a driving force for neuronal polarization. We will then explore how cytoskeletal changes help to reactivate the growth program of injured CNS axons to elicit axon regeneration after a spinal cord injury. Finally, we will discuss whether axon growth and synapse formation may be processes in neurons that might exclude each other. Following this developmental hypothesis, it will help us to generate a novel perspective on regeneration failure in the adult CNS, and how we can overcome this failure to induce axon regeneration. Thus, this talk will describe how we can exploit developmental mechanisms to induce axon regeneration after a spinal cord injury.
Mechanisms to medicines in neurodegeneration
Dysregulation of protein synthesis both globally and locally in neurons and astrocytes is a key feature of neurodegenerative diseases. Aberrant signalling through the Unfolded Protein Response (UPR) and related Integrated Stress Response (ISR) have become major targets for neuroprotection in these disorders. In addition, other homeostatic mechanisms and stress responses, including the cold shock response, appear to regulate local translation and RNA splicing to control synapse maintenance and regeneration and can also be targeted therapeutically for neuroprotection. We have defined the role of UPR/ISR and the cold-shock response in neurodegenerative disorders and have developed translational strategies targeting them for new treatments for dementia.
Dysfunction of neurons and circuits in Alzheimer’s disease
The Picower Institute Fall 2021 Symposium, Dendrites: Molecules, Structure, and Function
Dendrites play a central role in neuronal computation, and many complex mechanisms shape their structure, function, and connectivity. Dendrites can undergo plastic changes during development and learning, as well as during neurodevelopmental and neurodegenerative disease. We will discuss how the molecular and electrophysiological properties of dendrites enable them to perform complex computations important for sensory-motor processing and higher cognitive function, and how these can go awry.
Introducing YAPiC: An Open Source tool for biologists to perform complex image segmentation with deep learning
Robust detection of biological structures such as neuronal dendrites in brightfield micrographs, tumor tissue in histological slides, or pathological brain regions in MRI scans is a fundamental task in bio-image analysis. Detection of those structures requests complex decision making which is often impossible with current image analysis software, and therefore typically executed by humans in a tedious and time-consuming manual procedure. Supervised pixel classification based on Deep Convolutional Neural Networks (DNNs) is currently emerging as the most promising technique to solve such complex region detection tasks. Here, a self-learning artificial neural network is trained with a small set of manually annotated images to eventually identify the trained structures from large image data sets in a fully automated way. While supervised pixel classification based on faster machine learning algorithms like Random Forests are nowadays part of the standard toolbox of bio-image analysts (e.g. Ilastik), the currently emerging tools based on deep learning are still rarely used. There is also not much experience in the community how much training data has to be collected, to obtain a reasonable prediction result with deep learning based approaches. Our software YAPiC (Yet Another Pixel Classifier) provides an easy-to-use Python- and command line interface and is purely designed for intuitive pixel classification of multidimensional images with DNNs. With the aim to integrate well in the current open source ecosystem, YAPiC utilizes the Ilastik user interface in combination with a high performance GPU server for model training and prediction. Numerous research groups at our institute have already successfully applied YAPiC for a variety of tasks. From our experience, a surprisingly low amount of sparse label data is needed to train a sufficiently working classifier for typical bioimaging applications. Not least because of this, YAPiC has become the "standard weapon” for our core facility to detect objects in hard-to-segement images. We would like to present some use cases like cell classification in high content screening, tissue detection in histological slides, quantification of neural outgrowth in phase contrast time series, or actin filament detection in transmission electron microscopy.
Age-related changes in visual perception – decline or experience?
In Europe, the number of people aged 65 and older is increasing dramatically, and research related to ageing is more crucial than ever. The main research dedicated to age-related changes concentrates on cognitive or sensory deficits. This is also the case in vision research. However, the majority of older adults ages without major cognitive or optical or deficits. These are foremost good news, but even in the absence of neurodegenerative or eye diseases changes in visual perception occur. It has been suggested that age-related changes are due to a general decline of cognitive, perceptual and sensory functions. However, more recent studies reveal large individual differences within the ageing population and whereas some functions show age-related deterioration, others are surprisingly unaffected. Overall, it becomes increasingly apparent that perceptual changes in healthy ageing cannot be attributed to one single underlying factor. I will present studies from various areas of visual perception that challenge the view that age-related changes are primarily related to decline. Instead, our findings suggest that age-related changes are the result of visual experience, such that the brain ages optimally given the input it receives.
Roles of microglia in the pathogenesis of neurodegeneration
Microglia are implicated in a variety of functions in the central nervous system, ranging from shaping neural circuits during early brain development, to surveying the brain parenchyma, and providing trophic support to neurons across the entire lifespan. In neurodegeneration, microglia have been considered for long time mere bystanders, accompanying and worsening neuronal damage. However, recent evidence indicates that microglia can causally contribute to neurodegenerative diseases, and that their dysfunction can even be at the origin of the pathology. In fact, the broad range of physiological roles microglia play in the healthy brain suggest that faulty microglia can initiate neurodegeneration through several possible mechanisms. In particular, in this seminar, we will discuss how dysfunctional microglia can affect synaptic function leading to pathological synapse loss, thus putting microglia center stage in the pathogenesis of brain disorders.
From epigenetics to stratified therapies in neuropsychiatric diseases
The establishment of effective therapies for neurodegenerative and neuropsychiatric diseases is still challenging and one of the reasons is that especially for age-associated neurodegenerative diseases pathology accumulates long before there are any clinical signs of disease. Thus, patients are often only diagnosed at an already advanced state of molecular pathology, when causative therapies fail. Thus, there is an urgent need for molecular biomarkers that could detect individuals at risk for developing a CNS disease and stratify patients. I will address epigenetic processes such as histone-modifications and non-coding RNAs as potential approaches for patient stratification and therapeutic interaction, with a specific focus on RNA-therapies. Here, I plan to cover examples from our recent research on Alzheimer’s disease and Schizophrenia.
AI-guided solutions for early detection of neurodegenerative disorders
Despite the importance of early diagnosis of dementia for prognosis and personalised interventions, we still lack robust tools for predicting individual progression to dementia. We propose a trajectory modelling approach that mines multimodal data from patients at early dementia stages to derive individualised prognostic scores of cognitive decline Our approach has potential to facilitate effective stratification of individuals based on prognostic disease trajectories, reducing patient misclassification with important implications for clinical practice.
Mathematical models of neurodegenerative diseases
Neurodegenerative diseases such as Alzheimer’s or Parkinson’s are devastating conditions with poorly understood mechanisms and no cure. Yet, a striking feature of these conditions is the characteristic pattern of invasion throughout the brain, leading to well-codified disease stages associated with various cognitive deficits and pathologies. How can we use mathematical modelling to gain insight into this process and, doing so, gain understanding about how the brain works? In this talk, I will show that by linking new mathematical theories to recent progress in imaging, we can unravel some of the universal features associated with dementia and, more generally, brain functions.
Fragility of the human connectome across the lifespan
The human brain network architecture can reveal crucial aspects of brain function and dysfunction. The topology of this network (known as the connectome) is shaped by a trade-off between wiring cost and network efficiency, and it has highly connected hub regions playing a prominent role in many brain disorders. By studying a landscape of plausible brain networks that preserve the wiring cost, fragile and resilient hubs can be identified. In this webinar, Dr Leonardo Gollo and Dr James Pang from Monash University will discuss this approach across the lifespan and some of its implications for neurodevelopmental and neurodegenerative diseases. Dr Leonardo Gollo is a Senior Research Fellow at the Turner Institute for Brain and Mental Health, School of Psychological Sciences, Monash University. He holds an ARC Future Fellowship and his research interests include brain modelling, systems neuroscience, and connectomics. Dr James Pang is a Research Fellow at the Turner Institute for Brain and Mental Health, School of Psychological Sciences, Monash University. His research interests are on combining neuroimaging and biophysical modelling to better understand the mechanisms of brain function in health and disease.
Advances and setbacks in prion biology
Transmissible spongiform encephalopathies (TSEs) are neurodegenerative diseases of humans and many animal species caused by prions. The main constituent of prions is PrPSc, an aggregated moiety of the host-derived membrane glycolipoprotein PrPC. Prions were found to encipher many phenotypic, genetically stable TSE variants. The latter is very surprising, since PrPC is encoded by the host genome and all prion strains share the same amino acid sequence. Here I will review what is known about the infectivity, the neurotoxicity, and the neuroinvasiveness of prions. Also, I will explain why I regard the prion strain question as a fascinating challenge – with implications that go well beyond prion science. Finally, I will report some recent results obtained in my laboratory, which is attempting to address the strain question and some other basic issues of prion biology with a “systems” approach that utilizes organic chemistry, photophysics, proteomics, and mouse transgenesis.
Liquid-liquid phase separation out of equilibrium
Living cells contain millions of enzymes and proteins, which carry out multiple reactions simultaneously. To optimize these processes, cells compartmentalize reactions in membraneless liquid condensates. Certain features of cellular condensates can be explained by principles of liquid-liquid phase separation studied in material science. However, biological condensates exist in the inherently out of equilibrium environment of a living cell, being driven by force-generating microscopic processes. These cellular conditions are fundamentally different than the equilibrium conditions of liquid-liquid phase separation studied in materials science and physics. How condensates function in the active riotous environment of a cell is essential for understanding of cellular functions, as well as to the onset of neurodegenerative diseases. Currently, we lack model systems that enable rigorous studies of these processes. Living cells are too complex for quantitative analysis, while reconstituted equilibrium condensates fail to capture the non-equilibrium environment of biological cells. To bridge this gap, we reconstituted a DNA based membraneless condensates in an active environment that mimics the conditions of a living cell. We combine condensates with a reconstituted network of cytoskeletal filaments and molecular motors, and study how the mechanical interactions change the phase behavior and dynamics of membraneless structures. Studying these composite materials elucidates the fundamental physics rules that govern the behavior of liquid-liquid phase separation away from equilibrium while providing insight into the mechanism of condensate phase separation in cellular environments.
Targeting selective autophagy against neurodegenerative diseases
Protein quality control is essential for maintenance of a healthy and functional proteome that can attend the multiplicity of cellular functions. Failure of the systems that contribute to protein homeostasis, the so called proteostasis networks, have been identified in the pathogenesis of multiple neurodegenerative disorders and demonstrated to contribute to disease onset and progression. We are interested in autophagy, one of the components of the proteostasis network, and in the interplay of wo selective types of autophagy, chaperone-mediated autophagy (CMA) and endosomal microautophagy (eMI), with neurodegeneration. We have recently found that pathogenic proteins involved in common neurodegenerative conditions such as tauopathies or Parkinson’s disease, can exert a toxic effect in both types of selective types of autophagy compromising their functioning. We have now used mouse models with compromised CMA that support increased propagation of proteins such as tau and alpha-synuclein and an exacerbation of disease phenotype with aging. Conversely, genetic or chemical upregulation of CMA in this context of proteotoxicity slow down disease progression by facilitating effective intracellular removal of pathogenic proteins. Our findings highlight CMA and eMI as potential novel therapeutic targets against neurodegeneration.
Nr4a1-mediated morphological adaptations in Ventral Pallidal projections to Mediodorsal Thalamus support cocaine intake and relapse-like behaviors
Growing evidence suggests the ventral pallidum (VP) is critical for drug intake and seeking behaviors. Receiving dense projections from the nucleus accumbens as well as dopamine inputs from the midbrain, the VP plays a central role in the control of motivated behaviors. Repeated exposure to cocaine is known to alter VP neuronal firing and neurotransmission. Surprisingly, there is limited information on the molecular adaptations occurring in VP neurons following cocaine intake.To provide insights into cocaine-induced transcriptional alterations we performed RNA-sequencing on VP of mice following cocaine self-administration. Gene Ontology analysis pointed toward alterations in dendrite- and spinerelated genes. Subsequent transcriptional regulator analysis identified the transcription factor Nr4a1 as a common regulator for these sets of morphology-related genes.Consistent with the central role of the VP in reward, its neurons project to several key regions associated with cocaine-mediated behaviors. We thus assessed Nr4a1 expression levels in various projection populations.Following cocaine self-administration, VP neurons projecting to the mediodorsal thalamus (MDT) showed significantly increased Nr4a1 levels. To further investigate the role of Nr4a1 in cocaine intake and relapse, we bidirectionally manipulated its expression levels selectively in VP neurons projecting to the MDT. Increasing Nr4a1 levels resulted in enhanced relapse-like behaviors accompanied by a blockage of cocaine-induced spinogenesis.However, decreasing Nr4a1expression levels completely abolished cocaine intake and consequential relapse-like behaviors. Together, our preliminary findings suggest that drug-induced neuronal remodeling in pallido-thalamic circuits is critical for cocaine intake and relapse-like behaviors.
Genetic therapies for Huntington’s disease, what does the future hold for neurodegenerative disorders?
There are no effective disease-modifying therapies for neurodegenerative diseases such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis or Huntington’s disease. Huntington’s disease (HD) is a devastating autosomal dominantly inherited neurodegenerative disease and the world’s most common genetic dementia. I will present an overview of important approaches in development for targeting mutant HTT DNA and RNA (Tabrizi et al Neuron 2019), the cause of HD pathogenesis, and the translational pathway from bench to clinic for a HTT targeting antisense oligonucleotide (Tabrizi et al New England Journal of Medicine 2019, Tabrizi, Science 2020) which is now in phase 3 studies. In my talk I will also review some of the genetic approaches in development for other CNS diseases. I will talk a bit about my journey as a clinician scientist and share some of my learnings for young scientists on how to survive a career in science.
CURE-ND Neurotechnology Workshop - Innovative models of neurodegenerative diseases
One of the major roadblocks to medical progress in the field of neurodegeneration is the absence of animal models that fully recapitulate features of the human diseases. Unprecedented opportunities to tackle this challenge are emerging e.g. from genome engineering and stem cell technologies, and there are intense efforts to develop models with a high translational value. Simultaneously, single-cell, multi-omics and optogenetics technologies now allow longitudinal, molecular and functional analysis of human disease processes in these models at high resolution. During this workshop, 12 experts will present recent progress in the field and discuss: - What are the most advanced disease models available to date? - Which aspects of the human disease do these accurately models, which ones do they fail to replicate? - How should models be validated? Against which reference, which standards? - What are currently the best methods to analyse these models? - What is the field still missing in terms of modelling, and of technologies to analyse disease models? CURE-ND stands for 'Catalysing a United Response in Europe to Neurodegenerative Diseases'. It is a new alliance between the German Center for Neurodegenerative Diseases (DZNE), the Paris Brain Institute (ICM), Mission Lucidity (ML, a partnership between imec, KU Leuven, UZ Leuven and VIB in Belgium) and the UK Dementia Research Institute (UK DRI). Together, these partners embrace a joint effort to accelerate the pace of scientific discovery and nurture breakthroughs in the field of neurodegenerative diseases. This Neurotechnology Workshop is the first in a series of joint events aiming at exchanging expertise, promoting scientific collaboration and building a strong community of neurodegeneration researchers in Europe and beyond.
Microglia, memories, and the extracellular space
Microglia are the immune cells of the brain, and play increasingly appreciated roles in synapse formation, brain plasticity, and cognition. A growing appreciation that the immune system involved in diseases like schizophrenia, epilepsy, and neurodegenerative diseases has led to renewed interest in how microglia regulate synaptic connectivity. Our group previously identified the IL-1 family cytokine Interleukin-33 (IL-33) as a novel regulator of microglial activation and function. I will discuss a mechanism by which microglia regulate synaptic plasticity and long-term memories by engulfing brain extracellular matrix (ECM) proteins. These studies raise the question of how these pathways may be altered or could be modified in the context of disease.
Lysosomal storage disorders and their unanticipated links to rare and common diseases
Lysosomal storage diseases are a group of over 70 inherited metabolic disorders, many of which have a neurodegenerative clinical course. Treatments have been developed for a subset of these disorders and are now in routine clinical use. We have found that some neurological and neurodegenerative diseases share unanticipated links to lysosomal storage diseases providing insights into disease pathogenesis. These links also suggest treatments developed for lysosomal disorders may have unanticipated utility in other rare and common diseases.
Mapping early brain network changes in neurodegenerative and cerebrovascular disorders: a longitudinal perspective
The spatial patterning of each neurodegenerative disease relates closely to a distinct structural and functional network in the human brain. This talk will mainly describe how brain network-sensitive neuroimaging methods such as resting-state fMRI and diffusion MRI can shed light on brain network dysfunctions associated with pathology and cognitive decline from preclinical to clinical dementia. I will first present our findings from two independent datasets on how amyloid and cerebrovascular pathology influence brain functional networks cross-sectionally and longitudinally in individuals with mild cognitive impairment and dementia. Evidence on longitudinal functional network organizational changes in healthy older adults and the influence of APOE genotype will be presented. In the second part, I will describe our work on how different pathology influences brain structural network and white matter microstructure. I will also touch on some new data on how brain network integrity contributes to behavior and disease progression using multivariate or machine learning approaches. These findings underscore the importance of studying selective brain network vulnerability instead of individual region and longitudinal design. Further developed with machine learning approaches, multimodal network-specific imaging signatures will help reveal disease mechanisms and facilitate early detection, prognosis and treatment search of neuropsychiatric disorders.
Role of Tunneling Nanotubes (TNTs) in the spreading of amyloid proteins in neurodegenerative diseases
Beyond energy - an unconventional role of mitochondria in cone photoreceptors
The long-term goal of my research is to study the mammalian retina as a model for the central nervous system (CNS) -- to understand how it functions in physiological conditions, how it is formed, how it breaks down in pathological conditions, and how it can be repaired. I have focused on two research themes: 1) Photoreceptor structure, synapse, circuits, and development, 2) Hibernation and metabolic adaptations in the retina and beyond. As the first neuron of the visual system, photoreceptors are vital for photoreception and transmission of visual signals. I am particularly interested in cone photoreceptors, as they mediate our daylight vision with high resolution color information. Diseases affecting cone photoreceptors compromise visual functions in the central macular area of the human retina and are thus most detrimental to our vision. However, because cones are much less abundant compared to rods in most mammals, they are less well studied. We have used the ground squirrel (GS) as a model system to study cone vision, taking advantage of their unique cone-dominant retina. In particular, we have focused on short-wavelength sensitive cones (S-cones), which are not only essential for color vision, but are also an important origin of signals for biological rhythm, mood and cognitive functions, and the growth of the eye during development. We are studying critical cone synaptic structures – synaptic ribbons, the synaptic connections of S-cones, and the development of S-cones with regard to their specific connections. These works will provide knowledge of normal retinal development and function, which can also be extended to the rest of CNS; for example, the mechanisms of synaptic targeting during development. In addition, such knowledge will benefit the development of optimal therapeutic strategies for regeneration and repair in cases of retinal degenerative disease. Many neurodegenerative diseases, including retinal diseases, are rooted in metabolic stress in neurons and/or glial cells. Using the same GS model, we aim to learn from this hibernating mammal, which possesses an amazing capability to adapt to the extreme metabolic conditions during hibernation. By exploring the mechanisms of such adaptation, we hope to discover novel therapeutic tactics for neurodegenerative diseases.
The interaction of sensory and motor information to shape neuronal representations in mouse cortical networks
The neurons in our brain never function in isolation; they are organized into complex circuits which perform highly specialized information processing tasks and transfer information through large neuronal networks. The aim of Janelle Pakan's research group is to better understand how neural circuits function during the transformation of information from sensory perception to behavioural output. Importantly, they also aim to further understand the cell-type specific processes that interrupt the flow of information through neural circuits in neurodegenerative disorders with dementia. The Pakan group utilizes innovative neuroanatomical tracing techniques, advanced in vivo two-photon imaging, and genetically targeted manipulations of neuronal activity to investigate the cell-type specific microcircuitry of the cerebral cortex, the macrocircuitry of cortical output to subcortical structures, and the functional circuitry underlying processes of sensory perception and motor behaviour.
Senescencia celular y su impacto en enfermedades neurodegenerativas
Las enfermedades neurodegenerativas como la Enfermedad de Alzheimer, Enfermedad de Parkinson y la Esclerosis Lateral Amiotrófica tienen una prevalencia creciente en nuestra sociedad, de acuerdo con el aumento de la expectativa de vida. Durante el envejecimiento, las células gliales sufren cambios funcionales favoreciendo la “neuroinflamación”, que tiene un reconocido papel patogénico en la progresión de la enfermedad neurodegenerativa. Estudios recientes demuestran que durante el envejecimiento del sistema nervioso se acumulan notablemente células senescentes, tanto de estirpe neuronal como glial. Las células senescentes no proliferan, muchas de ellas exhiben un fenotipo secretor (SASP) con capacidad de inducir inflamación. La eliminación de células senescentes por ablación genética inducida farmacológicamente o por bloqueos de fármacos senolíticos mejoran la neuroinflamación y disminuyen la neurotoxicidad. En la presentación, se realizará una revisión de la bibliografía sobre este tema y se realizará un análisis del potencial terapéutico de fármacos senolíticos como una aproximación terapéutica novedosa de las enfermedades neurodegenerativas.
Development and Application of PET Imaging for Dementia Research
Molecular imaging using Positron Emission Tomography (PET) has become a major biomedical imaging technology. Its application towards characterisation of biochemical processes in disease could enable early detection and diagnosis, development of novel therapies and treatment evaluation. The technology is underpinned by the use of imaging probes radiolabelled with short-lived radioisotopes which can be specific and selective for biological targets in vivo e.g. markers for receptors, protein deposits, enzymes and metabolism. My talk will focus on the increasing development and application of PET imaging to clinical research in neurodegenerative diseases, for which it can be applied to delineate and understand the various pathological components of these disorders.
Untitled Seminar
Neurotoxicity is a major health problem in Africa: focus on Parkinson's / Parkinsonism
Parkinson's disease (PD) is the second most present neurodegenerative disease in the world after Alzheimer's. It is due to the progressive and irreversible loss of dopaminergic neurons of the substantia nigra Pars Compacta. Alpha synuclein deposits and the appearance of Lewi bodies are systematically associated with it. PD is characterized by four cardinal motor symptoms: bradykinesia / akinesia, rigidity, postural instability and tremors at rest. These symptoms appear when 80% of the dopaminergic endings disappear in the striatum. According to Braak's theory, non-motor symptoms appear much earlier and this is particularly the case with anxiety, depression, anhedonia, and sleep disturbances. In 90 to 95% of cases, the causes of the appearance of the disease remain unknown, but polluting toxic molecules are incriminated more and more. In Africa, neurodegenerative diseases of the Parkinson's type are increasingly present and a parallel seems to exist between the increase in cases and the presence of toxic and polluting products such as metals. My Web conference will focus on this aspect, i.e. present experimental arguments which reinforce the hypothesis of the incrimination of these pollutants in the incidence of Parkinson's disease and / or Parkinsonism. Among the lines of research that we have developed in my laboratory in Rabat, Morocco, I have chosen this one knowing that many of our PhD students and IBRO Alumni are working or trying to develop scientific research on neurotoxicity in correlation with pathologies of the brain.
Programmed Axon Death and its Roles in Human Disease
Axons degenerate before the neuronal soma in many neurodegenerative diseases. Programmed axon death (Wallerian degeneration) is a widely-occurring mechanism of axon loss that is well understood and preventable in animals. Its aberrant activation by mutation of the pro-survival gene Nmnat2 directly causes axonopathy in mice with severity ranging from mild polyneuropathy to perinatal lethality. Rare biallelic mutations in the homologous human gene cause related phenotypes in patients. NMNAT2 is a negative regulator of the prodegenerative NADase SARM1. Constitutive activation of SARM1 is cytotoxic and the human SARM1 locus is significantly associated with sporadic ALS. Another negative regulator, STMN2, has also been implicated in ALS, where it is commonly depleted downstream of TDP-43. In mice, programmed axon death can be robustly blocked by deletion of Sarm1, or by overexpression, axonal targeting and/or stabilization of various NMNAT isoforms. This alleviates models of many human disorders including some forms of peripheral neuropathy, motor neuron diseases, glaucoma, Parkinson’s disease and traumatic brain injury, and it confers lifelong rescue on the lethal Nmnat2 null phenotype and other conditions. Drug discovery programs now aim to achieve similar outcomes in human disease. In order to optimize the use of such drugs, we have characterized a range of human NMNAT2 and SARM1 functional variants that underlie a spectrum of axon vulnerability in the human population. Individuals at the vulnerable end of this spectrum are those most likely to benefit from drugs blocking programmed axon death, and disorders associated with these genotypes are promising indications in which to apply them.
Microglia function and dysfunction in Alzheimer’s disease
Emerging genetic studies of late-onset Alzheimer’s Disease implicate the brain’s resident macrophages in the pathogenesis of AD. More than half the risk genes associated with late-onset AD are selectively expressed in microglia and peripheral myeloid cells; yet we know little about the underlying biology or how myeloid cells contribute to AD pathogenesis. Using single-cell RNA sequencing and spatial transcriptomics we identified molecular signatures that can be used to localize and monitor distinct microglia functional states in the human and mouse brain. Our results show that microglia assume diverse functional states in development, aging and injury, including populations corresponding to known microglial functions including proliferation, migration, inflammation, and synaptic phagocytosis. We identified several innate immune pathways by which microglia recognize and prune synapses during development and in models of Alzheimer’s disease, including the classical complement cascade. Illuminating the mechanisms by which developing synaptic circuits are sculpted is providing important insight on understanding how to protect synapses in Alzheimer’s and other neurodegenerative diseases of synaptic dysfunction.
Neuroscience Investigations in the Virgin Lands of African Biodiversity
Africa is blessed with a rich diversity and abundance in rodent and avian populations. This natural endowment on the continent portends research opportunities to study unique anatomical profiles and investigate animal models that may confer better neural architecture to study neurodegenerative diseases, adult neurogenesis, stroke and stem cell therapies. To this end, African researchers are beginning to pay closer attention to some of her indigenous rodents and birds in an attempt to develop spontaneous laboratory models for homegrown neuroscience-based research. For this presentation, I will be showing studies in our lab, involving cellular neuroanatomy of two rodents, the African giant rat (AGR) and Greater cane rat (GCR), Eidolon Bats (EB) and also the Striped Owl (SO). Using histological stains (Cresyl violet and Rapid Golgi) and immunohistochemical biomarkers (GFAP, NeuN, CNPase, Iba-1, Collagen 2, Doublecortin, Ki67, Calbindin, etc), and Electron Microscopy, morphology and functional organizations of neuronal and glial populations of the AGR , GCR, EB and SO brains have been described, with our work ongoing. In addition, the developmental profiles of the prenatal GCR brains have been chronicled across its entire gestational period. Brains of embryos/foetuses were harvested for gross morphological descriptions and then processed using immunofluorescence biomarkers to determine the pattern, onset, duration and peak of neurogenesis (Pax6, Tbr1, Tbr2, NF, HuCD, MAP2) and the onset and peak of glial cell expressions and myelination in the prenatal GCR. The outcome of these research efforts has shown unique neuroanatomical expressions and networks amongst Africa’s rich biodiversity. It is hopeful that continuous effort in this regard will provide sufficient basic research data on neural developments and cellular neuroanatomy with subsequent translational consequences.
Functional characterization of human iPSC-derived neurons at single-cell resolution
Recent developments in induced pluripotent stem cell (iPSC) technology have enabled easier access to human cells in vitro. With increasing availability of human iPSC-derived neurons, both healthy and disease cell lines, screening compounds for neurodegenerative diseases on human cells can potentially be performed in the earlier stages of drug discovery. To accelerate the functional characterization of iPSC-derived neurons and the effect of compounds, reproducible and relevant results are necessary. In this webinar, the speakers will: Introduce high-resolution functional imaging of human iPSC-derived neurons Showcase how to extract functional features of hundreds of cells in a cell culture sample label-free Discuss electrophysiological parameters for characterizing the differences among several human neuronal cell lines
Design and development of nanoliposomes based on soy lecithin for the delivery of molecules to the CNS as strategy for the treatment of neurodegenerative diseases
FENS Forum 2024
Impact of advanced parental age in the susceptibility of offspring to neurodegenerative diseases
FENS Forum 2024
Protective effect of some natural antioxidants on olfactory ensheathing cells exposed to amyloid-β toxicity: A potential therapeutic role in preserving neurodegenerative diseases
FENS Forum 2024
Role of RNA binding proteins in neurodevelopment and neurodegenerative diseases
FENS Forum 2024