Neurodegenerative Diseases Research Articles

The role of cellular senescence in neurodegenerative diseases.

Increasing evidence has revealed that cellular senescence drives NDs, including Alzheimer's disease (AD) and Parkinson's disease. Different senescent cell populations secrete senescence-associated secretory phenotypes (SASP), including matrix metalloproteinase-3, interleukin (IL)-1α, IL-6, and IL-8, which can harm adjacent microglia. Moreover, these cells possess high expression levels of senescence hallmarks (p16 and p21) and elevated senescence-associated β-galactosidase activity in in vitro and in vivo ND models. These senescence phenotypes contribute to the deposition of β-amyloid and tau-protein tangles. Selective clearance of senescent cells and SASP regulation by inhibiting p38/mitogen-activated protein kinase and nuclear factor kappa B signaling attenuate β-amyloid load and prevent tau-protein tangle deposition, thereby improving cognitive performance in AD mouse models. In addition, telomere shortening, a cellular senescence biomarker, is associated with increased ND risks. Telomere dysfunction causes cellular senescence, stimulating IL-6, tumor necrosis factor-α, and IL-1β secretions. The forced expression of telomerase activators prevents cellular senescence, yielding considerable neuroprotective effects. This review elucidates the mechanism of cellular senescence in ND pathogenesis, suggesting strategies to eliminate or restore senescent cells to a normal phenotype for treating such diseases.

Medial temporal lobe gray matter microstructure in preclinical Alzheimer's disease.

Typical MRI measures of neurodegeneration have limited sensitivity in early disease stages. Diffusion MRI (dMRI) microstructural measures may allow for detection in preclinical stages. Participants had dMRI and either beta-amyloid PET or plasma biomarkers of Alzheimer's pathology within 18 months of MRI. Microstructure was measured in portions of the medial temporal lobe (MTL) with high neurofibrillary tangle (NFT) burden based on a previously developed post mortem 3D-map. Regressions examined relationships between microstructure and markers of Alzheimer's pathology in preclinical disease and then across disease stages. There was higher isometric volume fraction in amyloid-positive compared to amyloid-negative cognitively unimpaired individuals in high tangle MTL regions. Similarly, plasma biomarkers and 18F-flortaucipir were associated with microstructural changes in preclinical disease. Additional microstructural effects were seen across disease stages. Combining a post mortem atlas of NFT pathology with microstructural measures allows for detection of neurodegeneration in preclinical Alzheimer's disease. Highlights Typical markers of neurodegeneration are not sensitive in preclinical Alzheimer's. dMRI measured microstructure in regions with high NFT. Microstructural changes occur in medial temporal regions in preclinical disease. Microstructural changes occur in other typical Alzheimer's regions in later stages. Combining post mortem pathology atlases with in vivo MRI is a powerful framework.

Circulating Levels of T-Cell Traits and the Risk of Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study.

Amyotrophic lateral sclerosis (ALS) represents a rare and potentially fatal neurodegenerative disease. Diverse T-cell subsets could potentially exert diametrically opposite impacts upon ALS development. A two-sample Mendelian randomization (MR) analysis was performed to investigate the correlation between 244 T-cell subsets and ALS risk. Genetic instrumental variables were procured from a standard genome-wide association study (GWAS) that encompassed 244 T-cell subsets in 3757 individuals of European lineage. ALS-related data were collected from a GWAS comprising 20,806 ALS instances and 59,804 European control participants. Multiple sensitivity analyses were performed to verify the robustness of the significant results. Reverse MR analysis was used for delineating the effects of ALS on the characteristics of T-cells. After multiple comparison corrections, 24 out of the 244 subtypes demonstrated a potential association with ALS risk. Significantly, 75% of these associations encompassed the expression of the CD3 on diverse T-cell subtypes, revealing a highly consistent inverse relation to ALS risk. The proportion of T regulatory cells (Tregs) in CD4+ T cells and secreting Tregs in CD4+ T cells demonstrated negative associations with the risk of ALS. CCR7 expression on naive CD4+ T cells and CCR7 expression on naive CD8+ T cells showed positive associations with ALS risk. Certain T-cell subsets, particularly those identified by CD3 expression on terminally differentiated CD8+ T cells, proportions of Tregs, and CCR7 expression, indicated an association with ALS risk. These findings harmonize with and extend previous observational studies investigating the involvement of T lymphocyte subset-induced immunological processes in ALS.

The effect of social support on the emotional well-being of people with amyotrophic lateral sclerosis: Exploring the mediating role of spirituality.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that, so far, is considered always fatal. Treatments mainly consist in increasing survival and aim to improve the quality of life of people with ALS (pwALS). Social support and spirituality have been shown to play a key role in pwALS' quality of life. Our study explored it in depth by investigating the underlying mechanisms linking social support, spirituality, and emotional well-being. Thirty-six pwALS underwent a battery of tests evaluating emotional well-being (emotional well-being scale of the 40-item Amyotrophic Lateral Sclerosis Assessment Questionnaire), social support (6-item Social Support Questionnaire), and spiritual well-being (12-item Functional Assessment of Chronic Illness Therapy - Spiritual well-being). Our recruitment was web-based through the FILSLAN and the ARSLA websites as well as through Facebook® advertisements (ALS groups). Data were analyzed by Pearson correlation analysis and Process macro was used in an SPSS program to analyze the mediator variable effect. Availability of social support, spiritual well-being, and 2 of its dimensions, i.e., meaning and peace, were positively correlated with emotional well-being. The mediational analyses showed that spiritual well-being, meaning, and peace act as mediators in the association between availability of social support and good emotional well-being. Availability of social support and spirituality are essential for the emotional well-being of pwALS. Spirituality as a mediator between availability of social support and emotional well-being appears as real novel finding which could be explored further. Spiritual well-being, meaning, and peace appear as coping resources for pwALS. We provide practical guidance for professionals working with pwALS.

A mutation in the PRKAR1B gene drives pathological mechanisms of neurodegeneration across species.

Protein Kinase A (PKA) neuronal function is controlled by the interaction of a regulatory (R) subunit dimer to two catalytic (C) subunits. Recently, the L50R variant in the gene encoding the RIβ subunit was identified in individuals with a novel neurodegenerative disease. However, the mechanisms driving the disease phenotype remained unknown. In this study, we generated a mouse model carrying the RIβ-L50R mutation to replicate the human disease phenotype and study its progression with age. We examined postmortem brains of affected individuals as well as live cell cultures. Employing biochemical assays, immunohistochemistry, and behavioral assessments, we investigated the impact of the mutation on PKA complex assembly, protein aggregation and neuronal degeneration. We reveal that RIβ is an aggregation-prone protein that progressively accumulates in wildtype and Alzheimer's mouse models with age, while aggregation is accelerated in the RIβ-L50R mouse model. We define RIβ-L50R as a causal mutation driving an age-dependent behavioral and disease phenotype in human and mouse models. Mechanistically, this mutation disrupts RIβ dimerization, leading to aggregation of its monomers. Intriguingly, interaction with the C-subunit protects the RIβ-L50R from self-aggregating, in a dose-dependent manner. Furthermore, cAMP signaling induces RIβ-L50R aggregation. The pathophysiological mechanism elucidated here for a newly recognized neurodegenerative disease, in which protein aggregation is the result of disrupted homodimerization, sheds light on a remarkably under-appreciated but potentially common mechanism across several neurodegenerative diseases.

Dynamics of cognitive variability with age and its genetic underpinning in NIHR BioResource Genes and Cognition cohort participants.

A leading explanation for translational failure in neurodegenerative disease is that new drugs are evaluated late in the disease course when clinical features have become irreversible. Here, to address this gap, we cognitively profiled 21,051 people aged 17-85 years as part of the Genes and Cognition cohort within the National Institute for Health and Care Research BioResource across England. We describe the cohort, present cognitive trajectories and show the potential utility. Surprisingly, when studied at scale, the APOE genotype had negligible impact on cognitive performance. Different cognitive domains had distinct genetic architectures, with one indicating brain region-specific activation of microglia and another with glycogen metabolism. Thus, the molecular and cellular mechanisms underpinning cognition are distinct from dementia risk loci, presenting different targets to slow down age-related cognitive decline. Participants can now be recalled stratified by genotype and cognitive phenotype for natural history and interventional studies of neurodegenerative and other disorders.

Gustav Oppenheim (1882-1937) and the Discovery of Cerebral Amyloid Angiopathy.

The discovery of cerebral amyloid angiopathy (CAA) is frequently attributed to Dr. Gustav Oppenheim-a man who has been largely passed over in history. Oppenheim's clinical and neuropathologic research covered a variety of disorders, but his name is best known for his work on senile dementia and CAA. Although Oppenheim was in fact not the first to discover CAA, his neuropathologic observations and inferences on neurodegenerative disease proved to be remarkably faithful to our modern understanding of neurodegenerative diseases. As a neurologist, he served in the First World War and was later subjected to religious persecutions in the leadup to the Holocaust but was not fortunate enough to emigrate before his death. The life, social impact, and previously overlooked contributions to science and medicine by Oppenheim are detailed.

P62/sequestosome-1 as a severity-reflecting plasma biomarker in Charcot–Marie–Tooth disease type 1A

Autophagy is a self-degradation system for recycling to maintain homeostasis. p62/sequestosome-1 (p62) is an autophagy receptor that accumulates in neuroglia in neurodegenerative diseases. The objective of this study was to determine the elevation of plasma p62 protein levels in patients with Charcot–Marie–Tooth disease 1A (CMT1A) for its clinical usefulness to assess disease severity. We collected blood samples from 69 CMT1A patients and 59 healthy controls. Plasma concentrations of p62 were analyzed by ELISA, and we compared them with Charcot-Marie-Tooth neuropathy score version 2 (CMTNSv2). A mouse CMT1A model (C22) was employed to determine the source and mechanism of plasma p62 elevation. Plasma p62 was detected in healthy controls with median value of 1978 pg/ml, and the levels were significantly higher in CMT1A (2465 pg/ml, p < 0.001). The elevated plasma p62 levels were correlated with CMTNSv2 (r = 0.621, p < 0.0001), motor nerve conduction velocity (r = − 0.490, p < 0.0001) and disease duration (r = 0.364, p < 0.01). In C22 model, increased p62 expression was observed not only in pathologic Schwann cells but also in plasma. Our findings indicate that plasma p62 measurement could be a valuable tool for evaluating CMT1A severity and Schwann cell pathology.

Mapping protein-protein interactions by mass spectrometry.

Protein-protein interactions (PPIs) are essential for numerous biological activities, including signal transduction, transcription control, and metabolism. They play a pivotal role in the organization and function of the proteome, and their perturbation is associated with various diseases, such as cancer, neurodegeneration, and infectious diseases. Recent advances in mass spectrometry (MS)-based protein interactomics have significantly expanded our understanding of the PPIs in cells, with techniques that continue to improve in terms of sensitivity, and specificity providing new opportunities for the study of PPIs in diverse biological systems. These techniques differ depending on the type of interaction being studied, with each approach having its set of advantages, disadvantages, and applicability. This review highlights recent advances in enrichment methodologies for interactomes before MS analysis and compares their unique features and specifications. It emphasizes prospects for further improvement and their potential applications in advancing our knowledge of PPIs in various biological contexts.

HAP40 modulates mutant Huntingtin aggregation and toxicity in Huntington’s disease mice

Huntington’s disease (HD) is a monogenic neurodegenerative disease, caused by the CAG trinucleotide repeat expansion in exon 1 of the Huntingtin (HTT) gene. The HTT gene encodes a large protein known to interact with many proteins. Huntingtin-associated protein 40 (HAP40) is one that shows high binding affinity with HTT and functions to maintain HTT conformation in vitro. However, the potential role of HAP40 in HD pathogenesis remains unknown. In this study, we found that the expression level of HAP40 is in parallel with HTT but inversely correlates with mutant HTT aggregates in mouse brains. Depletion of endogenous HAP40 in the striatum of HD140Q knock-in (KI) mice leads to enhanced mutant HTT aggregation and neuronal loss. Consistently, overexpression of HAP40 in the striatum of HD140Q KI mice reduced mutant HTT aggregation and ameliorated the behavioral deficits. Mechanistically, HAP40 preferentially binds to mutant HTT and promotes Lysine 48-linked ubiquitination of mutant HTT. Our results revealed that HAP40 is an important regulator of HTT protein homeostasis in vivo and hinted at HAP40 as a therapeutic target in HD treatment.

Rapid classification of a novel ALS-causing I149S variant in superoxide dismutase-1

Variants of the oxygen free radical scavenging enzyme superoxide dismutase-1 (SOD1) are associated with the neurodegenerative disease amyotrophic lateral sclerosis (ALS). These variants occur in roughly 20% of familial ALS cases, and 1% of sporadic ALS cases. Here, we identified a novel SOD1 variant in a patient in their 50s who presented with movement deficiencies and neuropsychiatric features. The variant was heterozygous and resulted in the isoleucine at position 149 being substituted with a serine (I149S). In silico analysis predicted the variant to be destabilizing to the SOD1 protein structure. Expression of the SOD1I149S variant with a C-terminal EGFP tag in neuronal-like NSC-34 cells resulted in extensive inclusion formation and reduced cell viability. Immunoblotting revealed that the intramolecular disulphide between Cys57 and Cys146 was fully reduced for SOD1I149S. Furthermore, SOD1I149S was highly susceptible to proteolytic digestion, suggesting a large degree of instability to the protein fold. Finally, fluorescence correlation spectroscopy and native-PAGE of cell lysates showed that SOD1I149S was monomeric in solution in comparison to the dimeric SOD1WT. This experimental data was obtained within 3 months and resulted in the rapid re-classification of the variant from a variant of unknown significance (VUS) to a clinically actionable likely pathogenic variant.

Sigma Receptor Ligands Are Potent Antiprion Compounds that Act Independently of Sigma Receptor Binding.

Prion diseases are invariably fatal neurodegenerative diseases of humans and other animals for which there are no effective treatment options. Previous work from our laboratory identified phenethylpiperidines as a novel class of anti-prion compounds. While working to identify the molecular target(s) of these molecules, we unexpectedly discovered ten novel antiprion compounds based on their known ability to bind to the sigma receptors, σ1R and σ2R, which are currently being tested as therapeutic or diagnostic targets for cancer and neuropsychiatric disorders. Surprisingly, however, knockout of the respective genes encoding σ1R and σ2R (Sigmar1 and Tmem97) in prion-infected N2a cells did not alter the antiprion activity of these compounds, demonstrating that these receptors are not the direct targets responsible for the antiprion effects of their ligands. Further investigation of the most potent molecules established that they are efficacious against multiple prion strains and protect against downstream prion-mediated synaptotoxicity. While the precise details of the mechanism of action of these molecules remain to be determined, the present work forms the basis for further investigation of these compounds in preclinical studies. Given the therapeutic utility of several of the tested compounds, including rimcazole and haloperidol for neuropsychiatric conditions, (+)-pentazocine for neuropathic pain, and the ongoing clinical trials of SA 4503 and ANAVEX2-73 for ischemic stroke and Alzheimer's disease, respectively, this work has immediate implications for the treatment of human prion disease.

Interleukin-9 protects from microglia- and TNF-mediated synaptotoxicity in experimental multiple sclerosis

BackgroundMultiple sclerosis (MS) is a progressive neurodegenerative disease of the central nervous system characterized by inflammation-driven synaptic abnormalities. Interleukin-9 (IL-9) is emerging as a pleiotropic cytokine involved in MS pathophysiology.MethodsThrough biochemical, immunohistochemical, and electrophysiological experiments, we investigated the effects of both peripheral and central administration of IL-9 on C57/BL6 female mice with experimental autoimmune encephalomyelitis (EAE), a model of MS.ResultsWe demonstrated that both systemic and local administration of IL-9 significantly improved clinical disability, reduced neuroinflammation, and mitigated synaptic damage in EAE. The results unveil an unrecognized central effect of IL-9 against microglia- and TNF-mediated neuronal excitotoxicity. Two main mechanisms emerged: first, IL-9 modulated microglial inflammatory activity by enhancing the expression of the triggering receptor expressed on myeloid cells-2 (TREM2) and reducing TNF release. Second, IL-9 suppressed neuronal TNF signaling, thereby blocking its synaptotoxic effects.ConclusionsThe data presented in this work highlight IL-9 as a critical neuroprotective molecule capable of interfering with inflammatory synaptopathy in EAE. These findings open new avenues for treatments targeting the neurodegenerative damage associated with MS, as well as other inflammatory and neurodegenerative disorders of the central nervous system.

Netrin-1 signaling pathway mechanisms in neurodegenerative diseases

Abstract Netrin-1 and its receptors play crucial roles in inducing axonal growth and neuronal migration during neuronal development. Their profound impacts then extend into adulthood to encompass the maintenance of neuronal survival and synaptic function. Increasing amounts of evidence highlight several key points: (1) Diminished Netrin- 1 levels exacerbate pathological progression in animal models of Alzheimer's disease and Parkinson's disease, and potentially, similar alterations occur in humans. (2) Genetic mutations of Netrin-1 receptors increase an individuals' susceptibility to neurodegenerative disorders. (3) Therapeutic approaches targeting Netrin-1 and its receptors offer the benefits of enhancing memory and motor function. (4) Netrin-1 and its receptors show genetic and epigenetic alterations in a variety of cancers. These findings provide compelling evidence that Netrin-1 and its receptors are crucial targets in neurodegenerative diseases. Through a comprehensive review of Netrin-1 signaling pathways, our objective is to uncover potential therapeutic avenues for neurodegenerative disorders.

Nonpharmacological intervention therapies for dementia: potential break-even intervention price and savings for selected risk factors in the European healthcare system

BackgroundNew effective treatments for dementia are lacking, and early prevention focusing on risk factors of dementia is important. Non-pharmacological intervention therapies aimed at these factors may provide a valuable tool for reducing the incidence of dementia. This study focused on the development of a mathematical model to predict the number of individuals with neurodegenerative diseases, specifically Alzheimer’s disease, Parkinson’s disease, vascular dementia, and amyotrophic lateral sclerosis. Scenarios for non-pharmacological intervention therapies based on risk factor reduction were also assessed. The estimated total costs and potential cost savings from societal were included.MethodsBased on demographic and financial data from the EU, a mathematical model was developed to predict the prevalence and resulting care costs of neurodegenerative diseases in the population. Each disease (Alzheimer’s disease, Parkinson’s disease, vascular dementia, and amyotrophic lateral sclerosis) used parameters that included prevalence, incidence, and death risk ratio, and the simulation is related to the age of the cohort and the disease stage.ResultsA replicable simulation for predicting the prevalence and resulting cost of care for neurodegenerative diseases in the population exhibited an increase in treatment costs from 267 billion EUR in 2021 to 528 billion EUR by 2050 in the EU alone. Scenarios related to the reduction of the prevalence of dementia by up to 20% per decade led to total discounted treatment cost savings of up to 558 billion EUR.ConclusionThe model indicates the magnitude of the financial burden placed on EU healthcare systems due to the growth in the population prevalence of neurodegenerative diseases in the coming decades. Lifestyle interventions based on reducing the most common risk factors could serve as a prevention strategy to reduce the incidence of dementia with substantial cost-savings potential. These findings could support the implementation of public health approaches throughout life to ultimately prevent premature mortality and promote a healthier and more active lifestyle in older individuals.

Context-dependent role of sirtuin 2 in inflammation

Abstract Sirtuin 2 is a member of the sirtuin family nicotinamide adenine dinucleotide (NAD+)- dependent deacetylases, known for its regulatory role in different processes, including inflammation. In this context, sirtuin 2 has been involved in the modulation of key inflammatory signaling pathways and transcription factors by deacetylating specific targets, such as nuclear factor κB and nucleotide-binding oligomerization domain- leucine-rich-repeat and pyrin domain-containing protein 3 (NLRP3). However, whether sirtuin 2-mediated pathways induce a pro- or an anti-inflammatory response remains controversial. Sirtuin 2 has been implicated in promoting inflammation in conditions such as asthma and neurodegenerative diseases, suggesting that its inhibition in these conditions could be a potential therapeutic strategy. Conversely, arthritis and type 2 diabetes mellitus studies suggest that sirtuin 2 is essential at the peripheral level and, thus, its inhibition in these pathologies would not be recommended. Overall, the precise role of sirtuin 2 in inflammation appears to be context-dependent, and further investigation is needed to determine the specific molecular mechanisms and downstream targets through which sirtuin 2 influences inflammatory processes in various tissues and pathological conditions. The present review explores the involvement of sirtuin 2 in the inflammation associated with different pathologies to elucidate whether its pharmacological modulation could serve as an effective strategy for treating this prevalent symptom across various diseases.

Insights into Calpain Activation and Rho-ROCK Signaling in Parkinson’s Disease and Aging

Parkinson’s disease (PD), a progressive neurodegenerative disease, has no cure, and current therapies are not effective at halting disease progression. The disease affects mid-brain dopaminergic neurons and, subsequently, the spinal cord, contributing to many debilitating symptoms associated with PD. The GTP-binding protein, Rho, plays a significant role in the cellular pathology of PD. The downstream effector of Rho, Rho-associated kinase (ROCK), plays multiple functions, including microglial activation and induction of inflammatory responses. Activated microglia have been implicated in the pathology of many neurodegenerative diseases, including PD, that initiate inflammatory responses, leading to neuron death. Calpain expression and activity is increased following glial activation, which triggers the Rho-ROCK pathway and induces inflammatory T cell activation and migration as well as mediates toxic α-synuclein (α-syn) aggregation and neuron death, indicating a pivotal role for calpain in the inflammatory and degenerative processes in PD. Increased calpain activity and Rho-ROCK activation may represent a new mechanism for increased oxidative damage in aging. This review will summarize calpain activation and the role of the Rho-ROCK pathway in oxidative stress and α-syn aggregation, their influence on the neurodegenerative process in PD and aging, and possible strategies and research directions for therapeutic intervention.

Special Issue: “Neurodegenerative Diseases: Recent Advances and Future Perspectives”

Neurodegenerative diseases include a heterogeneous group of conditions that pose a growing challenge to public health and the scientific community [1] [...]

15N Hyperpolarization of Metronidazole Antibiotic in Aqueous Media Using Phase-Separated Signal Amplification by Reversible Exchange with Parahydrogen.

Metronidazole is a prospective hyperpolarized MRI contrast agent with potential hypoxia sensing utility for applications in cancer, stroke, neurodegenerative diseases, etc. We demonstrate a pilot procedure for production of ∼30 mM hyperpolarized [15N3]metronidazole in aqueous media by using a phase-separated SABRE-SHEATH hyperpolarization method, with nitrogen-15 polarization exceeding 2.2% on all three 15N sites achieved in less than 2 min. The 15N polarization T1 of ∼12 min is reported for the 15NO2 group at the clinically relevant field of 1.4 T in the aqueous phase, demonstrating a remarkably long lifetime of the hyperpolarized state. The produced aqueous solution of [15N3]metronidazole that contained only ∼100 μM of residual Ir was deemed biocompatible via validation through the MTT colorimetric test for assessing cell metabolic activity using human embryotic kidney HEK293T cells. This low-cost and ultrafast hyperpolarization procedure represents a major advance for the production of a biocompatible HP [15N3]metronidazole (and potentially other hyperpolarized drugs) formulation for MRI sensing applications.

Spastin and alsin protein interactome analyses begin to reveal key canonical pathways and suggest novel druggable targets

Abstract Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease- causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein-protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration- approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.