Neurodegenerative Disease Research Research Articles

MiR-29a modulates neuronal differentiation through targeting REST in mesenchymal stem cells.

ObjectiveTo investigate the modulation of microRNAs (miRNAs) upon the neuronal differentiation of mesenchymal stem cells (MSCs) through targeting RE-1 Silencing Factor (REST), a mature neuronal gene suppressor in neuronal and un-neuronal cells.MethodsRat bone marrow derived–MSCs were induced into neuron-like cells (MSC-NCs) by DMSO and BHA in vitro. The expression of neuron specific enolase (NSE), microtubule-associated protein tau (Tau), REST and its target genes, including synaptosomal-associated protein 25 (SNAP25) and L1 cell adhesion molecular (L1CAM), were detected in MSCs and MSC-NCs. miRNA array analysis was conducted to screen for the upregulated miRNAs after neuronal differentiation. TargetScan was used to predict the relationship between these miRNAs and REST gene, and dual luciferase reporter assay was applied to validate it. Gain and loss of function experiments were used to study the role of miR-29a upon neuronal differentiation of MSCs. The knockdown of REST was conducted to show that miR-29a affected this process through targeting REST.ResultsMSCs were induced into neuron-like cells which presented neuronal cell shape and expressed NSE and Tau. The expression of REST declined and the expression of SNAP25 and L1CAM increased upon the neuronal differentiation of MSCs. Among 14 upregulated miRNAs, miR-29a was validated to target REST gene. During the neuronal differentiation of MSCs, miR-29a inhibition blocked the downregulation of REST, as well as the upregulation of SNAP25, L1CAM, NSE and Tau. REST knockdown rescued the effect of miR-29a inhibition on the expression of NSE and Tau. Meanwhile, miR-29a knockin significantly decreased the expression of REST and increased the expression of SNAP25 and L1CMA in MSCs, but did not significantly affect the expression of NSE and Tau.ConclusionmiR-29a regulates neurogenic markers through targeting REST in mesenchymal stem cells, which provides advances in neuronal differentiation research and stem cell therapy for neurodegenerative diseases.

Isolation and characterization of microglia from adult mouse brain: selected applications for ex vivo evaluation of immunotoxicological alterations following in vivo xenobiotic exposure.

Microglia play a dual role in neuroprotection as well as in neurodegeneration and thus occupy the focal interest in neurodegenerative disease research. In vitro studies either by using cell lines or neonatal mouse primary microglia correlated xenobiotic induced microglial activation and neuronal death. However, these in vitro studies cannot portray the in vivo scenario. Therefore, environmental pollutant induced in vivo alteration in microglial function can be best assessed by ex vivo analysis, which is not in use because of limitations in the isolation procedure. Therefore, in the first part of the study we describe an optimized isolation procedure and characterization of isolated cells. The second part of the study demonstrates the utility of the isolated cells in evaluation of immunotoxicological alterations following arsenic, as a model xenobiotic, exposure. Purity of the isolated microglia was checked by immunostaining of microglial (CD11b and CD68) and nonmicroglial (GFAP) markers. Immunostaining of activation marker Iba1 proves that cells were not activated during the isolation procedure. Microglia yield and viability from the treated group shows no significant alterations compared to that of the control group. Proinflammatory cytokines (IL-6 and TNF-α) were upregulated following arsenic treatment as in the case of the LPS stimulated group without alterations in anti-inflammatory IL-10. Phagocytic potential was affected significantly following arsenic exposure without alteration in viability. Thus, our protocol can be proficiently used for quick isolation of primary microglia from adult mouse brain without altering their activation status, and most importantly, the isolated cells can be of aid to the ex vivo evaluation of immunotoxicological alterations.

Enabling research in care homes: an evaluation of a national network of research ready care homes

BackgroundIn the UK care homes are one of the main providers of long term care for older people with dementia. Despite the recent increase in care home research, residents with dementia are often excluded from studies. Care home research networks have been recommended by the Ministerial Advisory Group on Dementia Research (MAGDR) as a way of increasing research opportunities for residents with dementia. This paper reports on an evaluation of the feasibility and early impact of an initiative to increase care home participation in research.MethodsA two phase, mixed methods approach was used; phase 1 established a baseline of current and recent studies including the National Institute for Health Research portfolio. To explore the experiences of recruiting care homes and research participation, interviews were conducted with researchers working for the Dementia and Neurodegenerative Diseases Research Network (DeNDRoN) and care home managers. In phase 2, four DeNDRoN area offices recruited care homes to a care home network for their region. The care home networks were separate from the DeNDRoN research network. Diaries were used to document and cost recruitment; DeNDRoN staff were interviewed to understand the barriers, facilitators and impact of the care home networks.ResultsThirty three current or recent studies were identified as involving care homes as care home specific studies or those which included residents. Further details of care home recruitment were obtained on 20 studies by contacting study teams. Care home managers were keen to be involved in research that provided staff support, benefits for residents and with minimal disruption. In phase 2, 141 care homes were recruited to the care home research networks, through corporate engagement and individual invitation. Pre-existing relationships with care homes facilitated recruitment. Sites with minimal experience of working with care homes identified the need for care home training for researchers.ConclusionsPhase 1 review revealed a small but increasing number of studies involving care homes. Phase 2 demonstrated the feasibility of care home research networks, their potential to increase recruitment to research and develop partnerships between health services and care homes, but highlighted the need for care home training for researchers.

Gene Expression Profiling of Mitochondrial Oxidative Phosphorylation (OXPHOS) Complex I in Friedreich Ataxia (FRDA) Patients

Friedreich ataxia (FRDA) is the most frequent progressive autosomal recessive disorder associated with unstable expansion of GAA trinucleotide repeats in the first intron of the FXN gene, which encodes for the mitochondrial frataxin protein. The number of repeats correlates with disease severity, where impaired transcription of the FXN gene results in reduced expression of the frataxin protein. Gene expression studies provide insights into disease pathogenicity and identify potential biomarkers, an important goal of translational research in neurodegenerative diseases. Here, using real-time PCR (RT-PCR), the expression profiles of mitochondrial (mtDNA) and nuclear DNA (nDNA) genes that encode for the mitochondrial subunits of respiratory oxidative phosphorylation (OXPHOS) complex I in the blood panels of 21 FRDA patients and 24 healthy controls were investigated. Here, the expression pattern of mtDNA-encoded complex I subunits was distinctly different from the expression pattern of nDNA-encoded complex I subunits, where significant (p<0.05) down-regulation of the mitochondrial ND2, ND4L, and ND6 complex I genes, compared to controls, were observed. In addition, the expression pattern of one nDNA-encoded gene, NDUFA1, was significantly (p<0.05) down-regulated compared to control. These findings suggest, for the first time, that the regulation of complex I subunit expression in FRDA is complex, rather than merely being a reflection of global co-regulation, and may provide important clues toward novel therapeutic strategies for FRDA and mitochondrial complex I deficiency.

Advances of mass spectrometry based proteomics in biomarker research in neurodegenerative diseases

Proteomics is the research focused on the composition and expression changes of proteins in cells, tissues or organisms at a large scale. Compared to the traditional biological research, proteomics possesses the advantages of fastness, high sensitivity and high throughput. Neurodegenerative diseases are a kind of disorders characterized by the progressive impairment or loss of specific neuronal cells that eventually leads to neurological dysfunctions. In recent years, mass spectrometry based proteomic technologies have been widely applied in the research of neurodegenerative diseases. In this review, we briefly summarize the technological development of proteomic technologies including sample separation, peptide quantification, mass spectrum detection and clinical validation of biomarkers, accompanied by examples to demonstrate the research advances of mass spectrometry based proteomics in biomarker discovery and validation in neurodegenerative diseases.

Zebrafish as a model for investigating developmental lead (Pb) neurotoxicity as a risk factor in adult neurodegenerative disease: A mini-review

Lead (Pb) exposure has long been recognized to cause neurological alterations in both adults and children. While most of the studies in adults are related to higher dose exposure, epidemiological studies indicate cognitive decline and neurobehavioral alterations in children associated with lower dose environmental Pb exposure (a blood Pb level of 10μg/dL and below). Recent animal studies also now report that an early-life Pb exposure results in pathological hallmarks of Alzheimer's disease later in life. While previous studies evaluating higher Pb exposures in adult animal models and higher occupational Pb exposures in humans have suggested a link between higher dose Pb exposure during adulthood and neurodegenerative disease, these newer studies now indicate a link between an early-life Pb exposure and adult neurodegenerative disease. These studies are supporting the “fetal/developmental origin of adult disease” hypothesis and present a new challenge in our understanding of Pb neurotoxicity. There is a need to expand research in this area and additional model systems are needed. The zebrafish presents as a complementary vertebrate model system with numerous strengths including high genetic homology. Several zebrafish genes orthologous to human genes associated with neurodegenerative diseases including Alzheimer's and Parkinson's diseases are identified and this model is starting to be applied in neurodegenerative disease research. Moreover, the zebrafish is being used in developmental Pb neurotoxicity studies to define genetic mechanisms of toxicity and associated neurobehavioral alterations. While these studies are in their infancy, the genetic and functional conservation of genes associated with neurodegenerative diseases and application in developmental Pb neurotoxicity studies supports the potential for this in vivo model to further investigate the link between developmental Pb exposure and adult neurodegenerative disease pathogenesis. In this review, the major factors influencing the pathogenesis of neurodegenerative diseases, Pb neurotoxicity, the developmental origin of adult disease paradigm, and the zebrafish as a model system to investigate the developmental origin of low-dose Pb-induced neurodegenerative diseases is discussed.

200th ENMC International Workshop “European Reference Networks: Recommendations and Criteria in the Neuromuscular field”, 18–20 October 2013, Naarden, the Netherlands

200th ENMC International Workshop “European Reference Networks: Recommendations and Criteria in the Neuromuscular field”, 18–20 October 2013, Naarden, the Netherlands

Biobanking of CSF: International standardization to optimize biomarker development

Cerebrospinal fluid (CSF) reflects pathophysiological aspects of neurological diseases, where neuroprotective strategies and biomarkers are urgently needed. Therefore, biobanking is very relevant for biomarker discovery and evaluation of neurological diseases. Important and unique features of CSF biobanking are intensive collaboration in international networks and the tight application of standardized protocols. The current adoption of standardized protocols for CSF and blood collection as presented in this review enables biomarker studies in large cohorts of patients and controls. Another topic of this review is the selection of control groups, which influences the outcome of biomarker investigations. Control groups in CSF biobanks mainly consist of different disease controls. This is in part due to the fact that lumbar punctures are mostly performed for clinical indications and rarely for research purposes only, as it is a relatively invasive procedure. Moreover, there is a lack of homogenous criteria and definition of control groups. We therefore propose uniform consensus definitions for such control groups in biomarker research, i.e. Healthy controls (HC), Spinal anesthesia subjects (SAS), Symptomatic controls (SC), Inflammatory Neurological Disease Controls (CINDC), Peripheral Inflammatory Neurological Disease Controls (PINDC) and Non-inflammatory Neurological Disease Controls (NINDC). Another important aspect of CSF biobanking is quality control. Systematic studies to address effects of pre-analytical and storage variation on a broad range of CSF proteins are needed.In conclusion, biomarker research in neurodegenerative diseases has entered a new era due to the collaborative and multicenter efforts of many groups. The streamlining of biobanking procedures, including quality control, and the selection of optimal control groups for investigating biomarkers are important improvements to perform high quality biomarker studies.

Recent advances in mass spectrometry-based glycoproteomics.

Protein glycosylation plays fundamental roles in many biological processes as one of the most common, and the most complex, posttranslational modification. Alterations in glycosylation profile are now known to be associated with many diseases. As a result, the discovery and detailed characterization of glycoprotein disease biomarkers is a primary interest of biomedical research. Advances in mass spectrometry (MS)-based glycoproteomics and glycomics are increasingly enabling qualitative and quantitative approaches for site-specific structural analysis of protein glycosylation. While the complexity presented by glycan heterogeneity and the wide dynamic range of clinically relevant samples like plasma, serum, cerebrospinal fluid, and tissue make comprehensive analyses of the glycoproteome a challenging task, the ongoing efforts into the development of glycoprotein enrichment, enzymatic digestion, and separation strategies combined with novel quantitative MS methodologies have greatly improved analytical sensitivity, specificity, and throughput. This review summarizes current MS-based glycoproteomics approaches and highlights recent advances in its application to cancer biomarker and neurodegenerative disease research.

Trem2 Variants and Risk of Alzheimer’s Disease

Object: Alzheimer’s disease (AD) is the most common form of dementia in the elderly. The genetic basis of lateonset AD (LOAD) is not well known. However, since 1993 the relationship with APOE gene is known, recently it has established a new relationship with the TREM2 gene. This review aims to show the implications of mutations in TREM2 gene in AD. Background: Mutations in TREM2 have been involved in Nasu-Hakola disease that causes frontotemporal dementia like (FTD-like) phenotype. Recently it has been involved in AD with an odds ratio as strong as previously reported with APOEe4. Methods and results: We review relevant papers concerning to TREM2 gene, not only its implication in neurodegenerative disease, but also those focused on Alzheimer´s Disease. Conclusion: There is an increased frequency of rare heterozygous TREM2 variations in AD and FTD, and TREM2 variants may play a role in neurodegenerative diseases in general. However, the relationship between TREM2 gene and neurodegenerative diseases is complex and ambiguous results. Surely the TREM2 variants have great interest in future research of neurodegenerative diseases.

Structural analysis and mapping of individual protein complexes by infrared nanospectroscopy

Mid-infrared spectroscopy is a widely used tool for material identification and secondary structure analysis in chemistry, biology and biochemistry. However, the diffraction limit prevents nanoscale protein studies. Here we introduce mapping of protein structure with 30 nm lateral resolution and sensitivity to individual protein complexes by Fourier transform infrared nanospectroscopy (nano-FTIR). We present local broadband spectra of one virus, ferritin complexes, purple membranes and insulin aggregates, which can be interpreted in terms of their α-helical and/or β-sheet structure. Applying nano-FTIR for studying insulin fibrils—a model system widely used in neurodegenerative disease research—we find clear evidence that 3-nm-thin amyloid-like fibrils contain a large amount of α-helical structure. This reveals the surprisingly high level of protein organization in the fibril’s periphery, which might explain why fibrils associate. We envision a wide application potential of nano-FTIR, including cellular receptor in vitro mapping and analysis of proteins within quaternary structures.

Personalized Medicine in Neurodegenerative Diseases: How Far Away?

Neurodegenerative diseases are characterized by progressive dysfunction of the nervous system as a result of neuronal loss in the brain and spinal cord. Despite extensive research efforts aimed at development of new disease-modifying therapeutics, there is still no effective treatment to halt neurodegenerative processes. Thus, modification of current therapeutic and diagnostic research strategies is a goal of increasing urgency. The biggest limitation in neurodegenerative disease research is the lack of appropriate biomarkers. Discovery of universal biomarkers capable of diagnosing patients with neurodegenerative diseases, monitoring their response to therapy, and predicting disease progression seems to be a tall order. Instead, a combination of different methodologies in the discovery of biomarkers specific for each described aspect of the disease seems to be a more viable approach. Although application of personalized medicine in diagnosis and treatment of neurodegenerative diseases may seem far off, some recent developments, such as utilizing specific biological therapies in multiple sclerosis, microRNA profiling as a source of novel biomarkers in Parkinson’s disease, or combination of neuroimaging and proteomic analyses in diagnosis of Alzheimer’s disease patients, already point to the way clinical neurology may integrate new achievements in everyday practice. Combination of genomic, proteomic, glycomic, and metabolomic approaches may yield novel insights into molecular mechanisms of disease pathophysiology, which could then be integrated and translated into clinical neurology. Based on the developments during the past decade, it is feasible to predict that a personalized approach to treating neurological disorders will become more widely applicable in the coming years.

A platform for discovery: The University of Pennsylvania Integrated Neurodegenerative Disease Biobank

Neurodegenerative diseases (NDs) are defined by the accumulation of abnormal protein deposits in the central nervous system (CNS), and only neuropathological examination enables a definitive diagnosis. Brain banks and their associated scientific programs have shaped the actual knowledge of NDs, identifying and characterizing the CNS deposits that define new diseases, formulating staging schemes, and establishing correlations between neuropathological changes and clinical features. However, brain banks have evolved to accommodate the banking of biofluids as well as DNA and RNA samples. Moreover, the value of biobanks is greatly enhanced if they link all the multidimensional clinical and laboratory information of each case, which is accomplished, optimally, using systematic and standardized operating procedures, and in the framework of multidisciplinary teams with the support of a flexible and user-friendly database system that facilitates the sharing of information of all the teams in the network. We describe a biobanking system that is a platform for discovery research at the Center for Neurodegenerative Disease Research at the University of Pennsylvania.

Microglia: A new frontier for synaptic plasticity, learning and memory, and neurodegenerative disease research

We focus on emerging roles for microglia in synaptic plasticity, cognition and disease. We outline evidence that ramified microglia, traditionally thought to be functionally “resting” (i.e. quiescent) in the normal brain, in fact are highly dynamic and plastic. Ramified microglia continually and rapidly extend processes, contact synapses in an activity and experience dependent manner, and play a functionally dynamic role in synaptic plasticity, possibly through release of cytokines and growth factors. Ramified microglial also contribute to structural plasticity through the elimination of synapses via phagocytic mechanisms, which is necessary for normal cognition. Microglia have numerous mechanisms to monitor neuronal activity and numerous mechanisms also exist to prevent them transitioning to an activated state, which involves retraction of their surveying processes. Based on the evidence, we suggest that maintaining the ramified state of microglia is essential for normal synaptic and structural plasticity that supports cognition. Further, we propose that change of their ramified morphology and function, as occurs in inflammation associated with numerous neurological disorders such as Alzheimer’s and Parkinson’s disease, disrupts their intricate and essential synaptic functions. In turn altered microglia function could cause synaptic dysfunction and excess synapse loss early in disease, initiating a range of pathologies that follow. We conclude that the future of learning and memory research depends on an understanding of the role of non-neuronal cells and that this should include using sophisticated molecular, cellular, physiological and behavioural approaches combined with imaging to causally link the role of microglia to brain function and disease including Alzheimer’s and Parkinson’s disease and other neuropsychiatric disorders.

Antioxidant properties and neuroprotective effects of isocampneoside II on hydrogen peroxide-induced oxidative injury in PC12 cells

Oxidative stress has been considered as a major cause of cell damage in various neurodegenerative disorders. One of the reasonable strategies for delaying the disease's progression is to prevent reactive oxygen species (ROS) mediated cellular injury by dietary or pharmaceutical augmentation of free radical scavengers. Isocampneoside II (ICD) is an active phenylethanoid glycoside isolated from the medicinal hardwood genus Paulownia. This study was designed to explore free radical scavenging potential of ICD in different in vitro systems and its protective role in hydrogen peroxide (H₂O₂)-induced oxidative stress and apoptotic death in cultured rat pheochromocytoma (PC12) cells. The results showed ICD eliminated approximately 80.75% superoxide radical at the concentration of 0.1mg/ml and inhibited metal chelating by 22.07% at 8 mg/ml. Additionally, ICD showed a strong ability on reducing power and provided protection against oxidative protein damage induced by hydroxyl radicals. Pretreatment of PC12 cells with ICD prior to H₂O₂ exposure elevated cell viability, enhanced activity of superoxide dismutase and catalase, and decreased levels of malondialdehyde and intracellular ROS. Furthermore, ICD inhibited cell apoptosis and Bax/Bcl-2 ratio induced by H₂O₂. These findings suggested ICD may be considered as a potential antioxidant agent and should encourage for further research in neurodegenerative diseases.

C9orf72 Hexanucleotide Repeat Expansion and Guam Amyotrophic Lateral Sclerosis–Parkinsonism-Dementia Complex

High-prevalence foci of amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC) exist in Japanese on the Kii Peninsula of Japan and in the Chamorros of Guam. Clinical and neuropathologic similarities suggest that the disease in these 2 populations may be related. Recent findings showed that some of the Kii Peninsula ALS cases had pathogenic C9orf72 repeat expansions, a genotype that causes ALS in Western populations. To perform genotyping among Guam residents to determine if the C9orf72 expanded repeat allele contributes to ALS-PDC in this population and to evaluate LRRK2 for mutations in the same population. Case-control series from neurodegenerative disease research programs on Guam that screened residents for ALS, PDC, and dementia. Study participants included 24 with ALS and 22 with PDC and 43 older control subjects with normal cognition ascertained between 1956 and 2006. All but one participant were Chamorro, the indigenous people of Guam. A single individual of white race/ethnicity with ALS was ascertained on Guam during the study. Participants were screened for C9orf72 hexanucleotide repeat length. Participants with repeat numbers in great excess of 30 were considered to have pathogenic repeat expansions. LRRK2 was screened for point mutations by DNA sequencing. We found a single individual with an expanded pathogenic hexanucleotide repeat. This individual of white race/ethnicity with ALS was living on Guam at the time of ascertainment but had been born in the United States. All Chamorro participants with ALS and PDC and control subjects had normal repeats, ranging from 2 to 17 copies. No pathogenic LRRK2 mutations were found. Unlike participants with ALS from the Kii Peninsula, C9orf72 expansions do not cause ALS-PDC in Chamorros. Likewise, LRRK2 mutations do not cause Guam ALS-PDC.

The Journey From Metabolic Profiling to Biomarkers: The Potential of NMR Spectroscopy Based Metabolomics in Neurodegenerative Disease Research

Neurodegenerative diseases have become a “hot” topic in recent years. A major factor for this is that as life expectancy of the population in developed countries increases, so does the probability of developing neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), to name the two most well-known. In many cases, however, neurological and mental diseases are poorly understood. In particular, there is a lack of specific biomarkers which would allow early unambiguous identification of a neurodegenerative disease, distinguishing between e.g. AD; PD; PD with dementia; and Dementia with Lewy bodies, or indicating therapeutic effects. Ultimately, this complicates the search for effective treatments. Thus, there is a high demand for preclinical work to elucidate underlying disease mechanisms and pave the way for disease management. In terms of biomarker research, hope has been set on small molecules that participate in metabolism, since they provide a closer link between cellular mechanisms (with genetic as well as environmental inputs) and the disease phenotype. More specifically, it is expected that not one but a combination of several metabolites may serve as an indicator for disease onset and progression, given that neurodegenerative diseases, whilst often described as “idiopathic”, are understood to arise from complex pathologies expressing themselves with a broad spectrum of phenotypes. Therefore, non-targeted metabolic profiling appears to offer great potential for biomarker discovery in this area. One of the major technical platforms for non-targeted metabolic profiling is high resolution nuclear magnetic resonance (NMR) spectroscopy, a technique that is also available for the non-invasive application in vivo. Hence, in theory, biomarker discovery research using NMR spectroscopy based metabolomics provides a promising means for translation from in vitro/ex vivo research to eventual clinical use. This review will therefore discuss the potential for NMR spectroscopy based metabolomics to be applied to biomarker discovery in the field of neurodegenerative disease. Keywords: Brain, metabolites, metabolomics, metabonomics, metabolic profiling, NMR spectroscopy, neurodegenerative diseases.

Conversion of rat embryonic stem cells into neural precursors in chemical-defined medium

Rat embryonic stem (ES) cells hold great interest for the research of neurodevelopment and neurodegenerative diseases. However, neural conversion of rat ES cells in vitro has proven to be a challenge owing to the proliferation arrest and apoptosis. Here we report that rat ES cells can commit efficiently to a neural fate in the presence of CHIR99021 and Y-27632 (CY medium). In addition, CHIR99021 is crucial for maintaining the metabolic activity of differentiated rat ES cells, while Y-27632 facilitates the neural differentiation of rat ES cells by inhibiting bone morphogenetic protein expression. The chemical-defined CY medium also provides a platform for exploring the mechanism of neural commitment and optimizing the production efficiency of neural precursor from rat ES cells.

Robotherapy with Dementia Patients

Humanoids have increasingly become the focus of attention in robotics research in recent years, especially in service and personal assistance robotics. This paper presents the application developed for humanoid robots in the therapy of dementia patients as a cognitive stimulation tool. The behaviour of the robot during the therapy sessions is visually programmed in a session script that allows music to play, physical movements (dancing, exercises, etc.), speech synthesis and interaction with the human monitor. The application includes the control software on board the robot and some tools like the visual script generator or a monitor to supervise the robot behaviour during the sessions. The robot application's impact on the patient's health has been studied. Experiments with real patients have been performed in collaboration with a centre of research in neurodegenerative diseases. Initial results show a slight or mild improvement in neuropsychiatric symptoms over other traditional therapy methods.

Is it all about Contact? Neurodegeneration as a “Protein Freeze Tag Game” Inside the Central Nervous System

Is it all about Contact? Neurodegeneration as a “Protein Freeze Tag Game” Inside the Central Nervous System