Degeneration
degeneration
Biomolecular condensates as drivers of neuroinflammation
The tubulin code in neuron health and disease : focus on detyrosination
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.
Computational modelling of ocular pharmacokinetics
Pharmacokinetics in the eye is an important factor for the success of ocular drug delivery and treatment. Pharmacokinetic features determine the feasible routes of drug administration, dosing levels and intervals, and it has impact on eventual drug responses. Several physical, biochemical, and flow-related barriers limit drug exposure of anterior and posterior ocular target tissues during treatment during local (topical, subconjunctival, intravitreal) and systemic administration (intravenous, per oral). Mathematical models integrate joint impact of various barriers on ocular pharmacokinetics (PKs) thereby helping drug development. The models are useful in describing (top-down) and predicting (bottom-up) pharmacokinetics of ocular drugs. This is useful also in the design and development of new drug molecules and drug delivery systems. Furthermore, the models can be used for interspecies translation and probing of disease effects on pharmacokinetics. In this lecture, ocular pharmacokinetics and current modelling methods (noncompartmental analyses, compartmental, physiologically based, and finite element models) are introduced. Future challenges are also highlighted (e.g. intra-tissue distribution, prediction of drug responses, active transport).
An inconvenient truth: pathophysiological remodeling of the inner retina in photoreceptor degeneration
Photoreceptor loss is the primary cause behind vision impairment and blindness in diseases such as retinitis pigmentosa and age-related macular degeneration. However, the death of rods and cones allows retinoids to permeate the inner retina, causing retinal ganglion cells to become spontaneously hyperactive, severely reducing the signal-to-noise ratio, and creating interference in the communication between the surviving retina and the brain. Treatments aimed at blocking or reducing hyperactivity improve vision initiated from surviving photoreceptors and could enhance the signal fidelity generated by vision restoration methodologies.
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.
LRRK2 – a master regulator of neurodegeneration: acting on multiple systems including neuroinflammatory signaling, vesicular trafficking, and cell death pathways
The synaptic functions of Alpha Synuclein and Lrrk2
Alpha synuclein and Lrrk2 are key players in Parkinson's disease and related disorders, but their normal role has been confusing and controversial. Data from acute gene-editing based knockdown, followed by functional assays, will be presented.
Why age-related macular degeneration is a mathematically tractable disease
Among all prevalent diseases with a central neurodegeneration, AMD can be considered the most promising in terms of prevention and early intervention, due to several factors surrounding the neural geometry of the foveal singularity. • Steep gradients of cell density, deployed in a radially symmetric fashion, can be modeled with a difference of Gaussian curves. • These steep gradients give rise to huge, spatially aligned biologic effects, summarized as the Center of Cone Resilience, Surround of Rod Vulnerability. • Widely used clinical imaging technology provides cellular and subcellular level information. • Data are now available at all timelines: clinical, lifespan, evolutionary • Snapshots are available from tissues (histology, analytic chemistry, gene expression) • A viable biogenesis model exists for drusen, the largest population-level intraocular risk factor for progression. • The biogenesis model shares molecular commonality with atherosclerotic cardiovascular disease, for which there has been decades of public health success. • Animal and cell model systems are emerging to test these ideas.
The many roles of microglia in the pathogenesis of neurodegeneration
‘Going South!’ Comparative mitochondrial biology in ageing and neurodegeneration
Effects of Presenilin1 FAD mutants on brain angiogenic functions and neuroprotection in Alzheimer’s Disease
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.
Diverse applications of artificial intelligence and mathematical approaches in ophthalmology
Ophthalmology is ideally placed to benefit from recent advances in artificial intelligence. It is a highly image-based specialty and provides unique access to the microvascular circulation and the central nervous system. This talk will demonstrate diverse applications of machine learning and deep learning techniques in ophthalmology, including in age-related macular degeneration (AMD), the leading cause of blindness in industrialized countries, and cataract, the leading cause of blindness worldwide. This will include deep learning approaches to automated diagnosis, quantitative severity classification, and prognostic prediction of disease progression, both from images alone and accompanied by demographic and genetic information. The approaches discussed will include deep feature extraction, label transfer, and multi-modal, multi-task training. Cluster analysis, an unsupervised machine learning approach to data classification, will be demonstrated by its application to geographic atrophy in AMD, including exploration of genotype-phenotype relationships. Finally, mediation analysis will be discussed, with the aim of dissecting complex relationships between AMD disease features, genotype, and progression.
Valentine’s Day for people with multiple sclerosis: promoting brain repair through remyelination
Current disease-modifying therapies in multiple sclerosis are all focused on suppressing the inflammatory phase of the disease. This has been extremely successful, and it is doubtful that significantly more efficacious anti-inflammatory treatments will be found. However, it remains the case that people with relapsing-remitting multiple sclerosis acquire disability on treatment, and enter the secondary progressive phase. I argue that we now need treatments that prevent neuronal degeneration. The most promising approach is to prevent axons degenerating by remyelination. Since the discovery that the adult brain contains stem cells which can remyelinate, the problem now is how to promote endogenous remyelination, and how to know when we have achieved this! We have successfully identified one drug which promotes remyelination but unfortunately it is too toxic for use in the clinic. So the hunt continues.
Programmed axon death: from animal models into human disease
Programmed axon death is a widespread and completely preventable mechanism in injury and disease. Mouse and Drosophila studies define a molecular pathway involving activation of SARM1 NA Dase and its prevention by NAD synthesising enzyme NMNAT2 . Loss of axonal NMNAT2 causes its substrate, NMN , to accumulate and activate SARM1 , driving loss of NAD and changes in ATP , ROS and calcium. Animal models caused by genetic mutation, toxins, viruses or metabolic defects can be alleviated by blocking programmed axon death, for example models of CMT1B , chemotherapy-induced peripheral neuropathy (CIPN), rabies and diabetic peripheral neuropathy (DPN). The perinatal lethality of NMNAT2 null mice is completely rescued, restoring a normal, healthy lifespan. Animal models lack the genetic and environmental diversity present in human populations and this is problematic for modelling gene-environment combinations, for example in CIPN and DPN , and identifying rare, pathogenic mutations. Instead, by testing human gene variants in WGS datasets for loss- and gain-of-function, we identified enrichment of rare SARM1 gain-of-function variants in sporadic ALS , despite previous negative findings in SOD1 transgenic mice. We have shown in mice that heterozygous SARM1 loss-of-function is protective from a range of axonal stresses and that naturally-occurring SARM1 loss-of-function alleles are present in human populations. This enables new approaches to identify disorders where blocking SARM1 may be therapeutically useful, and the existence of two dominant negative human variants in healthy adults is some of the best evidence available that drugs blocking SARM1 are likely to be safe. Further loss- and gain-of-function variants in SARM1 and NMNAT2 are being identified and used to extend and strengthen the evidence of association with neurological disorders. We aim to identify diseases, and specific patients, in whom SARM1 -blocking drugs are most likely to be effective.
Glial and Neuronal Biology of the Aging Brain Symposium, Alana Down Syndrome Center and Aging Brain Initiative at Picower, MIT
The Aging Brain Initiative (ABI) is an interdisciplinary effort by MIT focusing on understanding neurodegeneration and discovery efforts to find hallmarks of aging, both in health and disease." "The Alana Down Syndrome Center (ADSC) aims to deepen knowledge about Down syndrome and to improve health, autonomy and inclusion of people with this genetic condition." "The ABI and the ADSC have joined forces for this year's symposium to highlight how aging-related changes to the brain overlap with neurological aspects of Down syndrome. Our hope is to encourage greater collaboration between the brain aging and Down syndrome research communities.
Glial and Neuronal Biology of the Aging Brain Symposium, Alana Down Syndrome Center and Aging Brain Initiative at Picower, MIT
The Aging Brain Initiative (ABI) is an interdisciplinary effort by MIT focusing on understanding neurodegeneration and discovery efforts to find hallmarks of aging, both in health and disease." "The Alana Down Syndrome Center (ADSC) aims to deepen knowledge about Down syndrome and to improve health, autonomy and inclusion of people with this genetic condition." "The ABI and the ADSC have joined forces for this year's symposium to highlight how aging-related changes to the brain overlap with neurological aspects of Down syndrome. Our hope is to encourage greater collaboration between the brain aging and Down syndrome research communities.
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.
Zebrafish models help untangle genetic interactions in motor neuron degeneration
Due to high homology to the human genome and rapid development, zebrafish have been successfully used to model diseases of the neuromuscular system. In this seminar, I will present current advances in modeling genetic causes of Amyotrophic Lateral Sclerosis (ALS), the most common motor neuron degeneration and show how epistatic interaction studies in zebrafish have helped elucidate synergistic effects of major ALS genes and their cellular targets.
Apathy and impulsivity in neurological disease – cause, effect and treatment
The Synaptome Architecture of the Brain: Lifespan, disease, evolution and behavior
The overall aim of my research is to understand how the organisation of the synapse, with particular reference to the postsynaptic proteome (PSP) of excitatory synapses in the brain, informs the fundamental mechanisms of learning, memory and behaviour and how these mechanisms go awry in neurological dysfunction. The PSP indeed bears a remarkable burden of disease, with components being disrupted in disorders (synaptopathies) including schizophrenia, depression, autism and intellectual disability. Our work has been fundamental in revealing and then characterising the unprecedented complexity (>1000 highly conserved proteins) of the PSP in terms of the subsynaptic architecture of postsynaptic proteins such as PSD95 and how these proteins assemble into complexes and supercomplexes in different neurons and regions of the brain. Characterising the PSPs in multiple species, including human and mouse, has revealed differences in key sets of functionally important proteins, correlates with brain imaging and connectome data, and a differential distribution of disease-relevant proteins and pathways. Such studies have also provided important insight into synapse evolution, establishing that vertebrate behavioural complexity is a product of the evolutionary expansion in synapse proteomes that occurred ~500 million years ago. My lab has identified many mutations causing cognitive impairments in mice before they were found to cause human disorders. Our proteomic studies revealed that >130 brain diseases are caused by mutations affecting postsynaptic proteins. We uncovered mechanisms that explain the polygenic basis and age of onset of schizophrenia, with postsynaptic proteins, including PSD95 supercomplexes, carrying much of the polygenic burden. We discovered the “Genetic Lifespan Calendar”, a genomic programme controlling when genes are regulated. We showed that this could explain how schizophrenia susceptibility genes are timed to exert their effects in young adults. The Genes to Cognition programme is the largest genetic study so far undertaken into the synaptic molecular mechanisms underlying behaviour and physiology. We made important conceptual advances that inform how the repertoire of both innate and learned behaviours is built from unique combinations of postsynaptic proteins that either amplify or attenuate the behavioural response. This constitutes a key advance in understanding how the brain decodes information inherent in patterns of nerve impulses, and provides insight into why the PSP has evolved to be so complex, and consequently why the phenotypes of synaptopathies are so diverse. Our most recent work has opened a new phase, and scale, in understanding synapses with the first synaptome maps of the brain. We have developed next-generation methods (SYNMAP) that enable single-synapse resolution molecular mapping across the whole mouse brain and extensive regions of the human brain, revealing the molecular and morphological features of a billion synapses. This has already uncovered unprecedented spatiotemporal synapse diversity organised into an architecture that correlates with the structural and functional connectomes, and shown how mutations that cause cognitive disorders reorganise these synaptome maps; for example, by detecting vulnerable synapse subtypes and synapse loss in Alzheimer’s disease. This innovative synaptome mapping technology has huge potential to help characterise how the brain changes during normal development, including in specific cell types, and with degeneration, facilitating novel pathways to diagnosis and therapy.
Untitled Seminar
Kaylene Young (Australia) – How does protocadherin 15 direct oligodendrocyte progenitor cell behaviour? Ben Emery (USA) - Loss of oligodendroglial support induces DLK-mediated degeneration of neurons; Carlie Cullen (Australia) – Do myelinating oligodendrocytes help us learn?
ISYNC: International SynAGE Conference on Healthy Ageing
The SynAGE committee members are thrilled to host ISYNC, the International SynAGE conference on healthy ageing, on 28-30 March 2022 in Magdeburg, Germany. This conference has been entirely organised from young scientists of the SynAGE research training group RTG 2413 (www.synage.de) and represents a unique occasion for researchers from all over the world to bring together and join great talks and sessions with us and our guests. A constantly updated list of our speakers can be found on the conference webpage: www.isync-md.de. During the conference, attendees will have access to a range of symposia which will deal with Glia, Biomarkers and Immunoresponses during ageing to neurodegeneration brain integrity and cognitive function in health and diseases. Moreover, the conference will offer social events especially for young researchers and the possibility to network together in a beautiful and suggestive location where our conference will take place: the Johanniskirche. The event will be happening in person, but due to the current pandemic situation and restrictions we are planning the conference as a hybrid event with lots of technical support to ensure that every participant can follow the talks and take part in the scientific discussions. The registration to our ISYNC conference is free of charge. However, the number of people attending the conference in person is restricted to 100. Afterwards, registrations will be accepted for joining virtually only. The registration is open until 15.02.2022. Especially for PhD and MD Students: Check our available Travel Grants, Poster Prize and SynAGE Award Dinner: https://www.isync-md.de/index.php/phd-md-specials/ If you need any further information don’t hesitate to contact us via email: contact@synage.de. We are looking forward to meet you in 2022 in Magdeburg to discuss about our research and ideas and bless together science. Your ISYNC organization Committee
Mutation targeted gene therapy approaches to alter rod degeneration and retain cones
My research uses electrophysiological techniques to evaluate normal retinal function, dysfunction caused by blinding retinal diseases and the restoration of function using a variety of therapeutic strategies. We can use our understanding or normal retinal function and disease-related changes to construct optimal therapeutic strategies and evaluate how they ameliorate the effects of disease. Retinitis pigmentosa (RP) is a family of blinding eye diseases caused by photoreceptor degeneration. The absence of the cells that for this primary signal leads to blindness. My interest in RP involves the evaluation of therapies to restore vision: replacing degenerated photoreceptors either with: (1) new stem or other embryonic cells, manipulated to become photoreceptors or (2) prosthetics devices that replace the photoreceptor signal with an electronic signal to light. Glaucoma is caused by increased intraocular pressure and leads to ganglion cell death, which eliminates the link between the retinal output and central visual processing. We are parsing out of the effects of increased intraocular pressure and aging on ganglion cells. Congenital Stationary Night Blindness (CSNB) is a family of diseases in which signaling is eliminated between rod photoreceptors and their postsynaptic targets, rod bipolar cells. This deafferents the retinal circuit that is responsible for vision under dim lighting. My interest in CSNB involves understanding the basic interplay between excitation and inhibition in the retinal circuit and its normal development. Because of the targeted nature of this disease, we are hopeful that a gene therapy approach can be developed to restore night vision. My work utilizes rodent disease models whose mutations mimic those found in human patients. While molecular manipulation of rodents is a fairly common approach, we have recently developed a mutant NIH miniature swine model of a common form of autosomal dominant RP (Pro23His rhodopsin mutation) in collaboration with the National Swine Resource Research Center at University of Missouri. More genetically modified mini-swine models are in the pipeline to examine other retinal diseases.
The Brain Conference (the Guarantors of Brain)
Join the Brain Conference on 24-25 February 2022 for the opportunity to hear from neurology’s leading scientists and clinicians. The two-day virtual programme features clinical teaching talks and research presentations from expert speakers including neuroscientist Professor Gina Poe, and the winner of the 2021 Brain Prize, neurologist Professor Peter Goadsby." "Tickets for The Brain Conference 2022 cost just £30, but register with promotional code BRAINCONEM20 for a discounted rate of £25.
The Brain Conference (the Guarantors of Brain)
Join the Brain Conference on 24-25 February 2022 for the opportunity to hear from neurology’s leading scientists and clinicians. The two-day virtual programme features clinical teaching talks and research presentations from expert speakers including neuroscientist Professor Gina Poe, and the winner of the 2021 Brain Prize, neurologist Professor Peter Goadsby." "Tickets for The Brain Conference 2022 cost just £30, but register with promotional code BRAINCONEM20 for a discounted rate of £25.
Metabolic spikes: from rogue electrons to Parkinson's
Conventionally, neurons are thought to be cellular units that process synaptic inputs into synaptic spikes. However, it is well known that neurons can also spike spontaneously and display a rich repertoire of firing properties with no apparent functional relevance e.g. in in vitro cortical slice preparations. In this talk, I will propose a hypothesis according to which intrinsic excitability in neurons may be a survival mechanism to minimize toxic byproducts of the cell’s energy metabolism. In neurons, this toxicity can arise when mitochondrial ATP production stalls due to limited ADP. Under these conditions, electrons deviate from the electron transport chain to produce reactive oxygen species, disrupting many cellular processes and challenging cell survival. To mitigate this, neurons may engage in ADP-producing metabolic spikes. I will explore the validity of this hypothesis using computational models that illustrate the implications of synaptic and metabolic spiking, especially in the context of substantia nigra pars compacta dopaminergic neurons and their degeneration in Parkinson's disease.
Effects of pathological Tau on hippocampal neuronal activity and spatial memory in ageing mice
The gradual accumulation of hyperphosphorylated forms of the Tau protein (pTau) in the human brain correlate with cognitive dysfunction and neurodegeneration. I will present our recent findings on the consequences of human pTau aggregation in the hippocampal formation of a mouse tauopathy model. We show that pTau preferentially accumulates in deep-layer pyramidal neurons, leading to their neurodegeneration. In aged but not younger mice, pTau spreads to oligodendrocytes. During ‘goal-directed’ navigation, we detect fewer high-firing pyramidal cells, but coupling to network oscillations is maintained in the remaining cells. The firing patterns of individually recorded and labelled pyramidal and GABAergic neurons are similar in transgenic and non-transgenic mice, as are network oscillations, suggesting intact neuronal coordination. This is consistent with a lack of pTau in subcortical brain areas that provide rhythmic input to the cortex. Spatial memory tests reveal a reduction in short-term familiarity of spatial cues but unimpaired spatial working and reference memory. These results suggest that preserved subcortical network mechanisms compensate for the widespread pTau aggregation in the hippocampal formation. I will also briefly discuss ideas on the subcortical origins of spatial memory and the concept of the cortex as a monitoring device.
Neurocognitive mechanisms of proactive temporal attention: challenging oscillatory and cortico-centered models
To survive in a rapidly dynamic world, the brain predicts the future state of the world and proactively adjusts perception, attention and action. A key to efficient interaction is to predict and prepare to not only “where” and “what” things will happen, but also to “when”. I will present studies in healthy and neurological populations that investigated the cognitive architecture and neural basis of temporal anticipation. First, influential ‘entrainment’ models suggest that anticipation in rhythmic contexts, e.g. music or biological motion, uniquely relies on alignment of attentional oscillations to external rhythms. Using computational modeling and EEG, I will show that cortical neural patterns previously associated with entrainment in fact overlap with interval timing mechanisms that are used in aperiodic contexts. Second, temporal prediction and attention have commonly been associated with cortical circuits. Studying neurological populations with subcortical degeneration, I will present data that point to a double dissociation between rhythm- and interval-based prediction in the cerebellum and basal ganglia, respectively, and will demonstrate a role for the cerebellum in attentional control of perceptual sensitivity in time. Finally, using EEG in neurodegenerative patients, I will demonstrate that the cerebellum controls temporal adjustment of cortico-striatal neural dynamics, and use computational modeling to identify cerebellar-controlled neural parameters. Altogether, these findings reveal functionally and neural context-specificity and subcortical contributions to temporal anticipation, revising our understanding of dynamic cognition.
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.
Keeping axons alive after injury: Inhibiting programmed axon death
Activation of pro-degenerative protein SARM1 in response to diverse physical and disease-relevant injuries triggers programmed axon death. Original studies indicated substantially decreased levels of SARM1 were required for neuroprotection. However, we demonstrate that lowering SARM1 levels by 50% in Sarm1 haploinsufficient mice delays axon degeneration in vivo (after sciatic nerve transection), in vitro (in response to diverse traumatic, neurotoxic, and genetic triggers), and partially prevents neurite outgrowth defects in mice lacking pro-survival factor NMNAT2. We also demonstrate the capacity for Sarm1 antisense oligonucleotides to decrease SARM1 levels by more than 50% which delays or prevents programmed axon degeneration in vitro. Combining Sarm1 haploinsufficiency with antisense oligonucleotides further decreases SARM1 levels and prolongs protection after neurotoxic injuries. These data demonstrate that axon protection occurs in a Sarm1 gene-dose responsive manner and that SARM1 lowering agents have therapeutic potential. Thus, antisense oligonucleotide targeting of Sarm1 is a promising therapeutic strategy against diverse triggers of axon degeneration.
Dysfunction of neurons and circuits in Alzheimer’s disease
Evidence for the role of glymphatic dysfunction in the development of Alzheimer’s disease
Glymphatic perivascular exchange is supported by the astroglial water channel aquaporin-4 (AQP4), which localizes to perivascular astrocytic endfeet surrounding the cerebral vasculature. In aging mice, impairment of glymphatic function is associated with reduced perivascular AQP4 localization, yet whether these changes contribute to the development of neurodegenerative disease, such as Alzheimer’s disease (AD), remains unknown. Using post mortem human tissue, we evaluated perivascular AQP4 localization in the frontal cortical gray matter, white matter, and hippocampus of cognitively normal subjects and those with AD. Loss of perivascular and increasing cellular localization of AQP4 in the frontal gray matter was specifically associated with AD status, amyloid β (Aβ) and tau pathology, and cognitive decline in the early stages of disease. Using AAV-PHP.B to drive expression on non-perivascular AQP4 in wild type and Tg2576 (APPSwe, mouse model of Aβ deposition) mice, increased cellular AQP4 localization did not slow glymphatic function or change Aβ deposition. Using the Snta1 knockout line (which lacks perivascular AQP4 localization), we observed that loss AQP4 from perivascular endfeet slowed glymphatic function in wild type mice and accelerated Aβ plaque deposition in Tg2576 mice. These findings demonstrate that loss of perivascular AQP4 localization, and not increased cellular AQP4 localization, slows glymphatic function and promotes the development of AD pathology. To evaluate whether naturally occurring variation in the human AQP4 gene, or the alpha syntrophin (SNTA1), dystrobrevin (DTNA) or dystroglycan (DAG1) genes (whose products maintain perivascular AQP4 localization) confer risk for or protection from AD pathology or clinical progression, we evaluated 56 tag single nucleotide polymorphisms (SNPs) across these genes for association with CSF AD biomarkers, MRI measures of cortical and hippocampal atrophy, and longitudinal cognitive decline in the Alzheimer’s Disease Neuroimaging Initiative I (ADNI I) cohort. We identify 25 different significant associations between AQP4, SNTA1, DTNA, and DAG1 tag SNPs and phenotypic measures of AD pathology and progression. These findings provide complimentary human genetic evidence for the contribution of perivascular glymphatic dysfunction to the development of AD in human populations.
NAD+ metabolism in axon and neurodegeneration (from a fly’s perspective)
Microbiota in the health of the nervous system and the response to stress
Microbes have shaped the evolution of eukaryotes and contribute significantly to the physiology and behavior of animals. Some of these traits are inherited by the progenies. Despite the vast importance of microbe-host communication, we still do not know how bacteria change short term traits or long-term decisions in individuals or communities. In this seminar I will present our work on how commensal and pathogenic bacteria impact specific neuronal phenotypes and decision making. The traits we specifically study are the degeneration and regeneration of neurons and survival behaviors in animals. We use the nematode Caenorhabditis elegans and its dietary bacteria as model organisms. Both nematode and bacteria are genetically tractable, simplifying the detection of specific molecules and their effect on measurable characteristics. To identify these molecules we analyze their genomes, transcriptomes and metabolomes, followed by functional in vivo validation. We found that specific bacterial RNAs and bacterially produced neurotransmitters are key to trigger a survival behavioral and neuronal protection respectively. While RNAs cause responses that lasts for many generations we are still investigating whether bacterial metabolites are capable of inducing long lasting phenotypic changes.
Synaptic health in Parkinson's Disease
Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting 1% of over 65's; there is currently no effective treatment. Dopaminergic neuronal loss is hallmark in PD and yet despite decades of intensive research there is still no known therapeutic which will completely halt the disorder. As a result, identification of interventive therapies to reverse or prevent PD are essential. Using genetically faithful models (induced pluripotent stem cells and knock-in mice) of familial late onset PD (LRRK2 G2019S and GBA N370S) we have contributed to the literature that neuronal dysfunction precedes degeneration. Specifically, using whole cell patch clamp electrophysiology, biochemical, behavioural and molecular biological techniques, we have begun to investigate the fundamental processes that make neurons specialised i.e., synaptic function and neurotransmission. We illustrate those alterations to spontaneous neurotransmitter release, neuronal firing, and short-term plasticity as well as Ca2+ and energy dyshomeostasis, are some of the earliest observable pathological dysfunctions and are likely precursors to late-stage degeneration. These pathologies represent targets which can be manipulated to address causation, rather than the symptoms of the PD, and represent a marker that, if measurable in patients, could form the basis of early PD detection and intervention.
Understanding the Mechanisms of Epilepsy in mTORopathies
Human stem cell models of neurodegeneration: complex, relevant and robust
Efficient coding and receptive field coordination in the retina
My laboratory studies how the retina processes visual scenes and transmits this information to the brain. We use multi-electrode arrays to record the activity of hundreds of retina neurons simultaneously in conjunction with transgenic mouse lines and chemogenetics to manipulate neural circuit function. We are interested in three major areas. First, we work to understand how neurons in the retina are functionally connected. Second we are studying how light-adaptation and circadian rhythms alter visual processing in the retina. Finally, we are working to understand the mechanisms of retinal degenerative conditions and we are investigating potential treatments in animal models.
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.
Parp mutations protect from mitochondrial toxicity in Alzheimer’s disease
Alzheimer’s disease is the most common age-related neurodegenerative disorder. Familial forms of Alzheimer’s disease associated with the accumulation of a toxic form of amyloid-β (Aβ) peptides are linked to mitochondrial impairment. The coenzyme nicotinamide adenine dinucleotide (NAD+) is essential for both mitochondrial bioenergetics and nuclear DNA repair through NAD+-consuming poly (ADP-ribose) polymerases (PARPs). Here, we analysed the metabolomic changes in flies over-expressing Aβ and showed a decrease of metabolites associated with nicotinate and nicotinamide metabolism, which is critical for mitochondrial function in neurons. We show that increasing the bioavailability of NAD+ protects against Aβ toxicity. Pharmacological supplementation using NAM, a form of vitamin B that acts as a precursor for NAD+ or a genetic mutation of PARP rescues mitochondrial defects, protects neurons against degeneration and reduces behavioural impairments in a fly model of Alzheimer’s disease. Next, we looked at links between PARP polymorphisms and vitamin B intake in patients with Alzheimer’s disease. We show that polymorphisms in the human PARP1 gene or the intake of vitamin B, are associated with a decrease in the risk and severity of Alzheimer’s disease. We suggest that enhancing the availability of NAD+ by either vitamin B supplements or the inhibition of NAD+-dependent enzymes, such as PARPs are potential therapies for Alzheimer’s disease.
Neuronal and Vascular Dysfunction in Optic Neuropathies: New Insights from Live Imaging Studies
Photovoltaic Restoration of Sight in Age-related Macular Degeneration
Regenerative Neuroimmunology - a stem cell perspective
There are currently no approved therapies to slow down the accumulation of neurological disability that occurs independently of relapses in multiple sclerosis (MS). International agencies are engaging to expedite the development of novel strategies capable of modifying disease progression, abrogating persistent CNS inflammation, and support degenerating axons in people with progressive MS. Understanding why regeneration fails in the progressive MS brain and developing new regenerative approaches is a key priority for the Pluchino Lab. In particular, we aim to elucidate how the immune system, in particular its cells called myeloid cells, affects brain structure and function under normal healthy conditions and in disease. Our objective is to find how myeloid cells communicate with the central nervous system and affect tissue healing and functional recovery by stimulating mechanisms of brain plasticity mechanisms such as the generation of new nerve cells and the reduction of scar formation. Applying combination of state-of-the-art omic technologies, and molecular approaches to study murine and human disease models of inflammation and neurodegeneration, we aim to develop experimental molecular medicines, including those with stem cells and gene therapy vectors, which slow down the accumulation of irreversible disabilities and improve functional recovery after progressive multiple sclerosis, stroke and traumatic injuries. By understanding the mechanisms of intercellular (neuro-immune) signalling, diseases of the brain and spinal cord may be treated more effectively, and significant neuroprotection may be achieved with new tailored molecular therapeutics.
Numbing intraneuronal Tau levels to prevent neurodegeneration in tauopathies
Intraneuronal accumulation of the microtubule associated protein Tau is largely recognized as an important toxic factor linked to neuronal cell death in Alzheimer’s disease and tauopathies. While there has been progress uncovering mechanisms leading to the formation of toxic Tau tangles, less is known about how intraneuronal Tau levels are regulated in health and disease. Here, I will discuss our recent work showing that the intracellular trafficking adaptor protein Numb is critical to control intraneuronal Tau levels. Inactivation of Numb in retinal ganglion cells increases monomeric and oligomeric Tau levels and leads to axonal blebbing in optic nerves, followed by significant neuronal cell loss in old mice. Interestingly, overexpression of the long isoform of Numb (Numb-72) decreases intracellular Tau levels by promoting exocytosis of monomeric Tau. In TauP301S and triple transgenic AD mouse models, expression of Numb-72 in RGCs reduces the number of axonal blebs and prevents neurodegeneration. Finally, inactivation of Numb in TauP301S mice accelerates neurodegeneration in both the retina and spinal cord and leads to precocious paralysis. Taken together, these results uncover Numb as a essential regulator of Tau homeostasis in neurons and as a potential therapeutic agent for AD and tauopathies.
A fresh look at the bird retina
I am working on the vertebrate retina, with a main focus on the mouse and bird retina. Currently my work is focused on three major topics: Functional and molecular analysis of electrical synapses in the retina Circuitry and functional role of retinal interneurons: horizontal cells Circuitry for light-dependent magnetoreception in the bird retina Electrical synapses Electrical synapses (gap junctions) permit fast transmission of electrical signals and passage of metabolites by means of channels, which directly connect the cytoplasm of adjoining cells. A functional gap junction channel consists of two hemichannels (one provided by each of the cells), each comprised of a set of six protein subunits, termed connexins. These building blocks exist in a variety of different subtypes, and the connexin composition determines permeability and gating properties of a gap junction channel, thereby enabling electrical synapses to meet a diversity of physiological requirements. In the retina, various connexins are expressed in different cell types. We study the cellular distribution of different connexins as well as the modulation induced by transmitter action or change of ambient light levels, which leads to altered electrical coupling properties. We are also interested in exploiting them as therapeutic avenue for retinal degeneration diseases. Horizontal cells Horizontal cells receive excitatory input from photoreceptors and provide feedback inhibition to photoreceptors and feedforward inhibition to bipolar cells. Because of strong electrical coupling horizontal cells integrate the photoreceptor input over a wide area and are thought to contribute to the antagonistic organization of bipolar cell and ganglion cell receptive fields and to tune the photoreceptor–bipolar cell synapse with respect to the ambient light conditions. However, the extent to which this influence shapes retinal output is unclear, and we aim to elucidate the functional importance of horizontal cells for retinal signal processing by studying various transgenic mouse models. Retinal circuitry for light-dependent magnetoreception in the bird We are studying which neuronal cell types and pathways in the bird retina are involved in the processing of magnetic signals. Likely, magnetic information is detected in cryptochrome-expressing photoreceptors and leaves the retina through ganglion cell axons that project via the thalamofugal pathway to Cluster N, a part of the visual wulst essential for the avian magnetic compass. Thus, we aim to elucidate the synaptic connections and retinal signaling pathways from putatively magnetosensitive photoreceptors to thalamus-projecting ganglion cells in migratory birds using neuroanatomical and electrophysiological techniques.
Can we repair the Parkinsonian brain?
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.
Using human pluripotent stem cells to model obesity in vitro
Obesity and neurodegeneration lead to millions of premature deaths each year and lack broadly effective treatments. Obesity is largely caused by the abnormal function of cell populations in the hypothalamus that regulate appetite. We have developed methods generate human hypothalamic neurons from hPSCs to study how they respond to nutrients and hormones (e.g. leptin) and how disease-associated mutations alter their function. Since human hypothalamic neurons can be produced in large numbers, are functionally responsive, have a human genome that can be readily edited, and are in culture environment that can be readily controlled, there is an unprecedented opportunity to study the genetic and environmental factors underlying obesity. In addition, we are fascinated by the fact that mid-life obesity is a risk factor for dementia later in life, and caloric restriction, exercise, and certain anti-obesity drugs are neuroprotective, suggesting that there are shared mechanisms between obesity and neurodegeneration. Studies of HPSC-derived hypothalamic neurons may help bridge the mechanistic gulf between human genetic data and organismic phenotypes, revealing new therapeutic targets.
Magnetic Resonance Measures of Brain Blood Vessels, Metabolic Activity, and Pathology in Multiple Sclerosis
The normally functioning blood-brain barrier (BBB) regulates the transfer of material between blood and brain. BBB dysfunction has long been recognized in multiple sclerosis (MS), and there is considerable interest in quantifying functional aspects of brain blood vessels and their role in disease progression. Parenchymal water content and its association with volume regulation is important for proper brain function, and is one of the key roles of the BBB. There is convincing evidence that the astrocyte is critical in establishing and maintaining a functional BBB and providing metabolic support to neurons. Increasing evidence suggests that functional interactions between endothelia, pericytes, astrocytes, and neurons, collectively known as the neurovascular unit, contribute to brain water regulation, capillary blood volume and flow, BBB permeability, and are responsive to metabolic demands. Increasing evidence suggests altered metabolism in MS brain which may contribute to reduced neuro-repair and increased neurodegeneration. Metabolically relevant biomarkers may provide sensitive readouts of brain tissue at risk of degeneration, and magnetic resonance offers substantial promise in this regard. Dynamic contrast enhanced MRI combined with appropriate pharmacokinetic modeling allows quantification of distinct features of BBB including permeabilities to contrast agent and water, with rate constants that differ by six orders of magnitude. Mapping of these rate constants provides unique biological aspects of brain vasculature relevant to MS.
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.
Novel mechanisms of neurogenesis and neural repair
In order to re-install neurogenesis after loss of neurons upon injury or neurodegeneration, we need to understand the basic principles of neurogenesis. I will first discuss about our discovery of a novel centrosome protein (Camargo et al., 2019) and discuss unpublished work about the great diversity of interphase centrosome proteomes and their relevance for neurodevelopmental disorders. I would then present work on a master regulator of neural stem cell amplification and brain folding (Stahl et al., 2013; Esgleas et al., 2020) to proceed presenting data on utilizing some of these factors for turning astrocytes into neurons. I will present data on the critical role of mitochondria in this conversion process (Gascon et al., 2016, Russo et al., 2020) and how it regulates the speed of conversion also showing unpublished data. If time permits I may touch on recent progress in in vivo reprogramming (Mattugini et al., 2019). Taken together, these data highlight the surprising specificity and importance of organelle diversity from centrosome, nucleolus and mitochondria as key regulators in development and reprogramming.
Gene Therapy for Neurodegeneration
One of the major challenges in developing therapeutics for the neurodegenerative disorders is the blood-brain barrier, limiting the availability of systemically administered therapies such as recombinant proteins or monoclonal antibodies from reaching the brain. Direct central nervous system (CNS) gene therapy using adeno-associated virus vectors expressing a therapeutic protein, monoclonal antibody or inhibiting RNA-coding sequences has two characteristics ideal for therapy of neurodegenerative disorders: circumventing the blood-brain barrier by directly expressing the therapy in the brain and the ability to provide persistent therapy with only a single administration. There are several critical parameters relevant to successful CNS gene therapy, including choice of vector, design of the gene to be expressed, delivery/route of administration, dose and anti-vector immune responses. The presentation will focus on these issues, the current status of clinical trials of gene therapy for neurodegeneration and specific challenges that will need to be overcome to ensure the success of these therapies.
Untitled Seminar
Understanding how photoreceptor degeneration alters retinal signaling, and how to intervene to rescue vision
Age-related Macular Degeneration (AMD) and Retinitis Pigmentosa (RP) are vision disorders caused by loss of rod and cone photoreceptors, but downstream retinal neurons also show physiological and morphological changes, resulting in the emergence of hyperactivity and rhythmic firing in many retinal ganglion cells (RGC). We recently discovered that retinoic acid (RA) is a key signal that triggers hyperactivity and that blockers of RA unmask light responses in RGCs that would otherwise be obscured. Recent work is revealing where in the retina circuit RA initiates functional changes. Moreover, interfering with the RA signaling pathway with drug or gene therapy can improve spatial vision in a mouse model of RP, providing a new strategy for enhancing low vision in human RP and AMD.
Targeting the synapse in Alzheimer’s Disease
Alzheimer’s Disease is characterised by the accumulation of misfolded proteins, namely amyloid and tau, however it is synapse loss which leads to the cognitive impairments associated with the disease. Many studies have focussed on single time points to determine the effects of pathology on synapses however this does not inform on the plasticity of the synapses, that is how they behave in vivo as the pathology progresses. Here we used in vivo two-photon microscopy to assess the temporal dynamics of axonal boutons and dendritic spines in mouse models of tauopathy[1] (rTg4510) and amyloidopathy[2] (J20). This revealed that pre- and post-synaptic components are differentially affected in both AD models in response to pathology. In the Tg4510 model, differences in the stability and turnover of axonal boutons and dendritic spines immediately prior to neurite degeneration was revealed. Moreover, the dystrophic neurites could be partially rescued by transgene suppression. Understanding the imbalance in the response of pre- and post-synaptic components is crucial for drug discovery studies targeting the synapse in Alzheimer’s Disease. To investigate how sub-types of synapses are affected in human tissue, the Multi-‘omics Atlas Project, a UKDRI initiative to comprehensively map the pathology in human AD, will determine the synaptome changes using imaging and synaptic proteomics in human post mortem AD tissue. The use of multiple brain regions and multiple stages of disease will enable a pseudotemporal profile of pathology and the associated synapse alterations to be determined. These data will be compared to data from preclinical models to determine the functional implications of the human findings, to better inform preclinical drug discovery studies and to develop a therapeutic strategy to target synapses in Alzheimer’s Disease[3].
Phospholipid regulation in cognitive impairment and vascular dementia
An imbalance in lipid metabolism in neurodegeneration is still poorly understood. Phospholipids (PLs) have multifactorial participation in vascular dementia as Alzheimer, post-stroke dementia, CADASIL between others. Which include the hyperactivation of phospholipases, mitochondrial stress, peroxisomal dysfunction and irregular fatty acid composition triggering proinflammation in a very early stage of cognitive impairment. The reestablishment of physiological conditions of cholesterol, sphingolipids, phospholipids and others are an interesting therapeutic target to reduce the progression of AD. We propose the positive effect of BACE1 silencing produces a balance of phospholipid profile in desaturase enzymes-depending mode to reduce the inflammation response, and recover the cognitive function in an Alzheimer´s animal and brain stroke models. Pointing out there is a great need for new well-designed research focused in preventing phospholipids imbalance, and their consequent energy metabolism impairment, pro-inflammation and enzymatic over-processing, which would help to prevent unhealthy aging and AD progression.
Blood phosphorylated tau as biomarkers for Alzheimer’s disease
Alzheimer's disease (AD) is the most common cause of dementia, and its health and socioeconomic burdens are of major concern. Presently, a definite diagnosis of AD is established by examining brain tissue after death. These examinations focus on two major pathological hallmarks of AD in the brain: (i) amyloid plaques consisting of aggregated amyloid beta (Aβ) peptides and (ii) neurofibrillary tangles made of abnormally phosphorylated tau protein. In living individuals, AD diagnosis relies on two main approaches: (i) brain imaging of tau tangles and Aβ plaques using a technique called positron emission tomography (PET) and (ii) measuring biochemical changes in tau (including phosphorylated tau at threonine-181 [p-tau181]) and the Aβ42 peptide metabolized into CSF. Unlike Aβ42, CSF p-tau181 is highly specific for AD but its usability is restricted by the need of a lumbar puncture. Moreover, PET imaging is expensive and only available in specialised medical centres. Due to these shortcomings, a simple blood test that can detect disease-related changes in the brain is a high priority for AD research, clinical care and therapy testing. In this webinar, I will discuss the discovery of p-tau biomarkers in blood and the biochemistry of how these markers differ from those found in CSF. Furthermore, I will critically review the performance of blood p-tau biomarkers across the AD pathological process and how they associate with and predict Aβ and tau pathophysiological and neuropathological changes. Furthermore, I will evaluate the potential advantages, challenges and context of use of blood p-tau in clinical practice, therapeutic trials and population screening.
Neuron-glia interactions in synapse degeneration in Alzheimer's disease
Tara Spires-Jones’ research focuses on the mechanisms and reversibility of neurodegeneration in Alzheimer’s disease, other degenerative brain diseases, and ageing. The objective of her research group is to understand why synapses and neurons become dysfunctional and die in these diseases in order to develop effective therapeutic strategies. Her work has shown that soluble forms of the pathological proteins amyloid beta and tau contribute to synapse degeneration, and that lowering levels of these proteins can prevent and reverse phenotypes in model systems. Further, she has pioneered high-resolution imaging techniques in human post-mortem brain and found evidence that these proteins accumulate in synapses in human disease.
A biophysically detailed model of retinal degeneration
COSYNE 2022
A biophysically detailed model of retinal degeneration
COSYNE 2023
Assessment of Purkinje neuron degeneration in the flocculus vs. medial cerebellum in a mouse model of spinocerebellar ataxia type 13 (SCA13)
FENS Forum 2024
Calcium released by dying neurons mediates Iba-1 dependent polarization of microglial cells in Parkinsonian neurodegeneration
FENS Forum 2024
Cell-specific regulation of neuronal and glial glucose metabolism by neurodegeneration-associated protein TDP-43
FENS Forum 2024
Cerebellar neurodegeneration in phospholipid flippases ATP8A1/ATP8A2 double knock-out mice can be ameliorated by inactivating a microglial PS receptor
FENS Forum 2024
Cerebellar Purkinje cells control movement and their degeneration causes specific gaiting defects
FENS Forum 2024
Characterisation of the neuroprotective effects of the new metabotropic glutamate receptor 3 positive allosteric modulator against dopaminergic degeneration in Parkinson’s disease models
FENS Forum 2024
Degeneration of the ascending vestibular pathway accounts for spatial navigation deficits in aged mice
FENS Forum 2024
Differential metabolism of serine enantiomers in the striatum of MPTP-lesioned monkeys and mice correlates with the severity of dopaminergic midbrain degeneration
FENS Forum 2024
Is dysfunctional neuronal differentiation the link between diet and neurodegeneration?
FENS Forum 2024
Effect of DREAM inhibition on aging and neurodegeneration
FENS Forum 2024
Epigenetic modulation of astrocyte reactivity to prevent neurodegeneration
FENS Forum 2024
Exacerbation of Alzheimer’s neurodegeneration due to Aβ–NETosis cross-talk is rescued by G6PD pharmacological inhibition in neutrophils
FENS Forum 2024
GPR37 processing in neurodegeneration: A potential marker for Parkinson’s disease progression rate
FENS Forum 2024
Hydrogen-sulfide-dependent Schwann cell differentiation during Wallerian degeneration: Multi-omics approach
FENS Forum 2024
An IgLON5 knockout mouse model results in mild behavioral alterations, without neurodegeneration
FENS Forum 2024
The impact of neurodegeneration on the electrical activity of brain tissue: Multielectrode array analysis
FENS Forum 2024
Inhibition of nuclear-retained HDAC5 interactome prevents neurite degeneration induced by α-synuclein overexpression
FENS Forum 2024
Investigation of Spastin-related secondary degenerations in Hereditary Spastic Paraplegia-SPG4
FENS Forum 2024
The interplay between mTORC2 and oxidative stress in neurotoxic models of neurodegeneration
FENS Forum 2024
PML is involved in microglia functions in neuroinflammation and neurodegeneration
FENS Forum 2024
The Janus faces of nanoparticles at the neurovascular unit: A double-edged sword in neurodegeneration
FENS Forum 2024
The knocking-down of the restrictive element 1-silencing transcription factor (REST) improves symptoms and limits motor neuron degeneration in a mouse model of amyotrophic lateral sclerosis
FENS Forum 2024
Longitudinal assessment of neurodegeneration in a mouse model of tauopathy using multiparametric magnetic resonance imaging
FENS Forum 2024
Microglial senescence: Unraveling the link to aging-related neurodegeneration in Alzheimer's disease
FENS Forum 2024
Neurodegeneration risk factors’ interplay: Characterization of APOE3 and APOE4 genotype upon chronic inflammation
FENS Forum 2024
Neuroinflammation precedes photoreceptor distress in induced and inherited degeneration of murine retina
FENS Forum 2024
Neuronal network dysfunction and neurodegeneration mediated by TLR7/8-activated microglia depend on the immunological context
FENS Forum 2024
NF-κB-mediated tolerant phenotype in microglia: Implications for Parkinson’s disease dopaminergic neurodegeneration
FENS Forum 2024
Novel pathways translating astrocyte-derived signalling into cell fate specification of neural progenitor cells: Relevance in neurodevelopment and neurodegeneration
FENS Forum 2024
3D organization of microglia in physiology and neurodegeneration
FENS Forum 2024
P2Y1 receptor participates in dopaminergic neurodegeneration in a rat model of Parkinson’s disease
FENS Forum 2024
A PEDF-derived peptide protects against sodium iodate-induced ferroptosis in retinal pigment epithelial cells and retinal degeneration in rats
FENS Forum 2024
Pharmacological and RNAi-mediated inhibition of class-IIa HDACs both protect against dopaminergic neuronal degeneration in in vivo models of Parkinson’s disease
FENS Forum 2024
The protective role of Alchornea laxiflora (Benth.) Pax & K. Hoffman extract against lead-induced neurodegeneration in cockerel chickens
FENS Forum 2024
Restorative potential of ciliary body cells in a retinal ganglion cell degeneration model
FENS Forum 2024
Rate of neuromelanin accumulation in the locus coeruleus is a critical factor for neurodegeneration
FENS Forum 2024
Regulation of TMEM106b, a gene implicated in neurodegeneration, by neuronal Src kinase
FENS Forum 2024
Retinal dysfunction in Huntington’s disease mouse models is characterized by an early photoreceptor degeneration and a late neuroinflammation
FENS Forum 2024