The Use of Proteomics in Biomarker Discovery in Neurodegenerative Diseases

Biomarkers for neurodegenerative diseases should reflect the central pathogenic processes of the diseases. The field of clinical proteomics is especially well suited for discovery of biomarkers in cerebrospinal fluid (CSF), which reflects the proteins in the brain under healthy conditions as well as in several neurodegenerative diseases. Known proteins involved in the pathology of neurodegenerative diseases are, respectively, normal tau protein,β-amyloid (1-42), synaptic proteins, amyloid precursor protein (APP), apolipoprotein E (apoE), which previously have been studied by protein immunoassays. The objective of this paper was to summarize results from proteomic studies of differential protein patterns in neurodegenerative diseases with focus on Alzheimer's disease (AD). Today, discrimination of AD from controls and from other neurological diseases has been improved by simultaneous analysis of bothβ-amyloid (1-42), total-tau, and phosphorylated tau, where a combination of low levels of CSF-β-amyloid 1-42 and high levels of CSF-tau and CSF-phospho-tau is associated with an AD diagnosis. Detection of new biomarkers will further strengthen diagnosis and provide useful information in drug trials. The combination of immunoassays and proteomic methods show that the CSF proteins express differential protein patterns in AD, FTD, and PD patients, which reflect divergent underlying pathophysiological mechanisms and neuropathological changes in these diseases.

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Molecular mechanisms of cell death in neurological diseases

Cell Death and Differentiation ◽

10.1038/s41418-021-00814-y ◽

2021 ◽

Author(s):

Diane Moujalled ◽

Andreas Strasser ◽

Jeffrey R. Liddell

Keyword(s):

Cell Death ◽

Neurodegenerative Diseases ◽

Molecular Mechanisms ◽

Neuronal Development ◽

Neurological Diseases ◽

Treatment Strategies ◽

Current Treatment ◽

Response To Therapy ◽

Signalling Cascades ◽

The Brain

AbstractTightly orchestrated programmed cell death (PCD) signalling events occur during normal neuronal development in a spatially and temporally restricted manner to establish the neural architecture and shaping the CNS. Abnormalities in PCD signalling cascades, such as apoptosis, necroptosis, pyroptosis, ferroptosis, and cell death associated with autophagy as well as in unprogrammed necrosis can be observed in the pathogenesis of various neurological diseases. These cell deaths can be activated in response to various forms of cellular stress (exerted by intracellular or extracellular stimuli) and inflammatory processes. Aberrant activation of PCD pathways is a common feature in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, resulting in unwanted loss of neuronal cells and function. Conversely, inactivation of PCD is thought to contribute to the development of brain cancers and to impact their response to therapy. For many neurodegenerative diseases and brain cancers current treatment strategies have only modest effect, engendering the need for investigations into the origins of these diseases. With many diseases of the brain displaying aberrations in PCD pathways, it appears that agents that can either inhibit or induce PCD may be critical components of future therapeutic strategies. The development of such therapies will have to be guided by preclinical studies in animal models that faithfully mimic the human disease. In this review, we briefly describe PCD and unprogrammed cell death processes and the roles they play in contributing to neurodegenerative diseases or tumorigenesis in the brain. We also discuss the interplay between distinct cell death signalling cascades and disease pathogenesis and describe pharmacological agents targeting key players in the cell death signalling pathways that have progressed through to clinical trials.

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A Destruction Model of the Vascular and Lymphatic Systems in the Emergence of Psychiatric Symptoms

Biology ◽

10.3390/biology10010034 ◽

2021 ◽

Vol 10 (1) ◽

pp. 34

Author(s):

Kohei Segawa ◽

Yukari Blumenthal ◽

Yuki Yamawaki ◽

Gen Ohtsuki

Keyword(s):

Neurodegenerative Diseases ◽

Lymphatic System ◽

Psychiatric Symptoms ◽

Neurological Diseases ◽

Immune Surveillance ◽

Brain Network ◽

Cellular Mechanisms ◽

Postmortem Brains ◽

New Interpretation ◽

The Brain

The lymphatic system is important for antigen presentation and immune surveillance. The lymphatic system in the brain was originally introduced by Giovanni Mascagni in 1787, while the rediscovery of it by Jonathan Kipnis and Kari Kustaa Alitalo now opens the door for a new interpretation of neurological diseases and therapeutic applications. The glymphatic system for the exchanges of cerebrospinal fluid (CSF) and interstitial fluid (ISF) is associated with the blood-brain barrier (BBB), which is involved in the maintenance of immune privilege and homeostasis in the brain. Recent notions from studies of postmortem brains and clinical studies of neurodegenerative diseases, infection, and cerebral hemorrhage, implied that the breakdown of those barrier systems and infiltration of activated immune cells disrupt the function of both neurons and glia in the parenchyma (e.g., modulation of neurophysiological properties and maturation of myelination), which causes the abnormality in the functional connectivity of the entire brain network. Due to the vulnerability, such dysfunction may occur in developing brains as well as in senile or neurodegenerative diseases and may raise the risk of emergence of psychosis symptoms. Here, we introduce this hypothesis with a series of studies and cellular mechanisms.

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Microglia and Synapse: Interactions in Health and Neurodegeneration

Neural Plasticity ◽

10.1155/2013/425845 ◽

2013 ◽

Vol 2013 ◽

pp. 1-10 ◽

Cited By ~ 42

Author(s):

Zuzana Šišková ◽

Marie-Ève Tremblay

Keyword(s):

Neurodegenerative Diseases ◽

Dendritic Spines ◽

Microglial Cell ◽

Immune Defense ◽

Synaptic Proteins ◽

Neuronal Function ◽

Dynamic Interactions ◽

Main Form ◽

The Brain ◽

Neuronal Compartments

A series of discoveries spanning for the last few years has challenged our view of microglial function, the main form of immune defense in the brain. The surveillance of neuronal circuits executed by each microglial cell overseeing its territory occurs in the form of regular, dynamic interactions. Microglial contacts with individual neuronal compartments, such as dendritic spines and axonal terminals, ensure that redundant or dysfunctional elements are recognized and eliminated from the brain. Microglia take on a new shape that is large and amoeboid when a threat to brain integrity is detected. In this defensive form, they migrate to the endangered sites, where they help to minimize the extent of the brain insult. However, in neurodegenerative diseases that are associated with misfolding and aggregation of synaptic proteins, these vital defensive functions appear to be compromised. Many microglial functions, such as phagocytosis, might be overwhelmed during exposure to the abnormal levels of misfolded proteins in their proximity. This might prevent them from attending to their normal duties, such as the stripping of degenerating synaptic terminals, before neuronal function is irreparably impaired. In these conditions microglia become chronically activated and appear to take on new, destructive roles by direct or indirect inflammatory attack.

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Blood–Brain Barrier and Neurodegenerative Diseases—Modeling with iPSC-Derived Brain Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22147710 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7710

Author(s):

Ying-Chieh Wu ◽

Tuuli-Maria Sonninen ◽

Sanni Peltonen ◽

Jari Koistinaho ◽

Šárka Lehtonen

Keyword(s):

Stem Cell ◽

Neurodegenerative Diseases ◽

Blood Brain Barrier ◽

Current Knowledge ◽

Neurological Diseases ◽

Induced Pluripotent Stem Cell ◽

Brain Barrier ◽

Blood Brain ◽

Induced Pluripotent ◽

The Brain

The blood–brain barrier (BBB) regulates the delivery of oxygen and important nutrients to the brain through active and passive transport and prevents neurotoxins from entering the brain. It also has a clearance function and removes carbon dioxide and toxic metabolites from the central nervous system (CNS). Several drugs are unable to cross the BBB and enter the CNS, adding complexity to drug screens targeting brain disorders. A well-functioning BBB is essential for maintaining healthy brain tissue, and a malfunction of the BBB, linked to its permeability, results in toxins and immune cells entering the CNS. This impairment is associated with a variety of neurological diseases, including Alzheimer’s disease and Parkinson’s disease. Here, we summarize current knowledge about the BBB in neurodegenerative diseases. Furthermore, we focus on recent progress of using human-induced pluripotent stem cell (iPSC)-derived models to study the BBB. We review the potential of novel stem cell-based platforms in modeling the BBB and address advances and key challenges of using stem cell technology in modeling the human BBB. Finally, we highlight future directions in this area.

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Amygdala: Neuroanatomical and Morphophysiological Features in Terms of Neurological and Neurodegenerative Diseases

Brain Sciences ◽

10.3390/brainsci10080502 ◽

2020 ◽

Vol 10 (8) ◽

pp. 502

Author(s):

Vladimir N. Nikolenko ◽

Marine V. Oganesyan ◽

Negoriya A. Rizaeva ◽

Valentina A. Kudryashova ◽

Arina T. Nikitina ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Chronic Traumatic Encephalopathy ◽

Neurological Diseases ◽

Hippocampal Sclerosis ◽

Degenerative Diseases ◽

Behavioral Synthesis ◽

Level Of Activity ◽

Input Signals ◽

The Subject ◽

The Brain

The amygdala is one of the most discussed structures of the brain. Correlations between its level of activity, size, biochemical organization, and various pathologies are the subject of many studies, and can serve as a marker of existing or future disease. It is hypothesized that the amygdala is not just a structural unit, but includes many other regions in the brain. In this review, we present the updated neuroanatomical and physiological aspects of the amygdala, discussing its involvement in neurodegenerative and neurological diseases. The amygdala plays an important role in the processing of input signals and behavioral synthesis. Lesions in the amygdala have been shown to cause neurological disfunction of ranging severity. Abnormality in the amygdala leads to conditions such as depression, anxiety, autism, and also promotes biochemical and physiological imbalance. The amygdala collects pathological proteins, and this fact can be considered to play a big role in the progression and diagnosis of many degenerative diseases, such as Alzheimer’s disease, chronic traumatic encephalopathy, Lewy body diseases, and hippocampal sclerosis. The amygdala has shown to play a crucial role as a central communication system in the brain, therefore understanding its neuroanatomical and physiological features can open a channel for targeted therapy of neurodegenerative diseases.

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From “Clinical Proteomics” to “Clinical Chemistry Proteomics”: considerations using quantitative mass-spectrometry as a model approach

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm.2011.744 ◽

2012 ◽

Vol 50 (2) ◽

Cited By ~ 7

Author(s):

Sylvain Lehmann ◽

Pauline Poinot ◽

Laurent Tiers ◽

Christophe Junot ◽

François Becher ◽

...

Keyword(s):

Mass Spectrometry ◽

Biomarker Discovery ◽

Clinical Chemistry ◽

Biological Fluids ◽

Clinical Proteomics ◽

Detection Methods ◽

Patient Treatment ◽

Quantitative Detection ◽

New Biomarkers

AbstractClinical Proteomics biomarker discovery programs lead to the selection of putative new biomarkers of human pathologies. Following an initial discovery phase, validation of these candidates in larger populations is a major task that recently started relying upon the use of mass spectrometry approaches, especially in cases where classical immune-detection methods were lacking. Thanks to highly sensitive spectrometers, adapted measurement methods like selective reaction monitoring (SRM) and various pre-fractionation methods, the quantitative detection of protein/peptide biomarkers in low concentrations is now feasible from complex biological fluids. This possibility leads to the use of similar methodologies in clinical biology laboratories, within a new proteomic field that we shall name “Clinical Chemistry Proteomics” (CCP). Such evolution of Clinical Proteomics adds important constraints with regards to the in vitro diagnostic (IVD) application. As measured values of analytes will be used to diagnose, follow-up and adapt patient treatment on a routine basis; medical utility, robustness, reference materials and clinical feasibility are among the new issues of CCP to consider.

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Prothrombin/thrombin and the thrombin receptors PAR-1 and PAR-4 in the brain: Localization, expression and participation in neurodegenerative diseases

Thrombosis and Haemostasis ◽

10.1160/th08-03-0131 ◽

2008 ◽

Vol 100 (10) ◽

pp. 576-581 ◽

Cited By ~ 87

Author(s):

Elena Sokolova ◽

Georg Reiser

Keyword(s):

Neurodegenerative Diseases ◽

Neurological Diseases ◽

Active Form ◽

Neural Cells ◽

Protease Activated Receptors ◽

Neuroprotective Effects ◽

Thrombin Receptors ◽

Brain Localization ◽

High Concentrations ◽

The Brain

SummaryEmerging evidence demonstrates that thrombin exerts physiological and pathological functions in the central nervous system. Both prothrombin and its active form thrombin have been detected locally in the brain. The cellular functions of thrombin are mainly regulated by G protein-coupled protease-activated receptors (PARs). Thrombin can signal via PAR-1, PAR-3 and PAR-4. Some neurological diseases (e.g. Alzheimer’s disease or Parkinson’s disease) are characterized by increased levels of both active thrombin and PAR-1. This indicates that thrombin and its receptor may be closely involved in the development of neurodegenerative processes. The role of thrombin in brain injury can be either protective or deleterious, depending on the concentration of thrombin. Thrombin at high concentrations exacerbates brain damage. In contrast, low concentrations of thrombin rescue neural cells from death after brain insults. Also thrombin preconditioning has neuroprotective effects. Therefore, thrombin and thrombin receptors represent novel therapeutic targets for treating neurodegenerative diseases.

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Quest for new genomic and proteomic biomarkers in neurology

Translational Neuroscience ◽

10.2478/s13380-011-0005-6 ◽

2011 ◽

Vol 2 (1) ◽

Author(s):

Kristina Gotovac ◽

Nela Pivac ◽

Sanja Hajnšek ◽

Dorotea Mück-Šeler ◽

Fran Borovečki

Keyword(s):

Neurodegenerative Diseases ◽

Biomarker Discovery ◽

Sample Collection ◽

Disease Etiology ◽

Novel Technologies ◽

Proteomic Data ◽

Genomics And Proteomics ◽

Novel Biomarkers ◽

New Biomarkers ◽

Patient Studies

AbstractThe possibility of identifying novel biomarkers for neurodegenerative diseases has been greatly enhanced with recent advances in genomics and proteomics. Novel technologies have the potential to hasten the development of new biomarkers useful as predictors of disease etiology and outcome, as well as responsiveness to therapy. Disease-modifying new therapies are very much needed in modern approaches to treatment of neurodegenerative diseases. Current progress in the field encounters a degree of skepticism about the reliability of genomic and proteomic data and its relevance for clinical applications. Standard operating procedures covering sample collection, methodology and statistical analysis need to be fully developed and strictly adhered to in order to assure reproducible and clinically relevant results. Previous studies involving patients with neurodegenerative diseases show promise in using genomic and proteomic approaches for development of new biomarkers. Confirmation of any novel biomarker in multiple independent patient cohorts and correlation of the improvement in biomarker endpoint with clinical improvement in longitudinal patient studies remains crucial for future successful application. We propose that a combination of approaches in biomarker discovery may in the end lead to identification of promising candidates at DNA, RNA, protein and small molecule level.

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Ubiquitin-Dependent Proteolysis in Neurons

Physiology ◽

10.1152/nips.01408.2002 ◽

2003 ◽

Vol 18 (1) ◽

pp. 29-33 ◽

Cited By ~ 4

Author(s):

Lars Klimaschewski

Keyword(s):

Neurodegenerative Diseases ◽

Protein Degradation ◽

Current Knowledge ◽

Neurological Diseases ◽

Ubiquitin Proteasome System ◽

Degradation Pathway ◽

Present Review ◽

Major Protein ◽

Ubiquitin Proteasome ◽

The Brain

Various studies identified the ubiquitin-proteasome system as the prime suspect in causing neurodegenerative diseases. The present review summarizes our current knowledge about the expression, regulation, and functions of this major protein degradation pathway in the brain, with particular reference to the pathogenesis of associated neurological diseases.

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Is There a Brain Microbiome?

Neuroscience Insights ◽

10.1177/26331055211018709 ◽

2021 ◽

Vol 16 ◽

pp. 263310552110187

Author(s):

Christopher D Link

Keyword(s):

Animal Models ◽

Human Brain ◽

Neurodegenerative Diseases ◽

Ground Truth ◽

Healthy Human ◽

Strong Motivation ◽

The Many ◽

The Brain

Numerous studies have identified microbial sequences or epitopes in pathological and non-pathological human brain samples. It has not been resolved if these observations are artifactual, or truly represent population of the brain by microbes. Given the tempting speculation that resident microbes could play a role in the many neuropsychiatric and neurodegenerative diseases that currently lack clear etiologies, there is a strong motivation to determine the “ground truth” of microbial existence in living brains. Here I argue that the evidence for the presence of microbes in diseased brains is quite strong, but a compelling demonstration of resident microbes in the healthy human brain remains to be done. Dedicated animal models studies may be required to determine if there is indeed a “brain microbiome.”

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