Molecular mechanisms highlighting the potential role of COVID-19 in the development of neurodegenerative diseases.

Coronavirus disease 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition to the pulmonary manifestations, COVID-19 patients may present a wide range of neurological disorders as extrapulmonary presentations. In this view, several studies have recently documented the worsening of neurological symptoms within COVID-19 morbidity in patients previously diagnosed with neurodegenerative diseases (NDs). Moreover, several cases have also been reported in which the patients presented parkinsonian features after initial COVID-19 symptoms. These data raise a major concern about the possibility of communication between SARS-CoV-2 infection and the initiation and/or worsening of NDs. In this review, we have collected compelling evidence suggesting SARS-CoV-2, as an environmental factor, may be capable of developing NDs. In this respect, the possible links between SARS-CoV-2 infection and molecular pathways related to most NDs and the pathophysiological mechanisms of the NDs such as Alzheimer's disease, vascular dementia, frontotemporal dementia, Parkinson's disease, and amyotrophic lateral sclerosis will be explained.

The roles of Eph receptors, neuropilin-1, P2X7, and CD147 in COVID-19-associated neurodegenerative diseases: inflammasome and JaK inhibitors as potential promising therapies.

The novel coronavirus disease 2019 (COVID-19) pandemic has spread worldwide, and finding a safe therapeutic strategy and effective vaccine is critical to overcoming severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, elucidation of pathogenesis mechanisms, especially entry routes of SARS-CoV-2 may help propose antiviral drugs and novel vaccines. Several receptors have been demonstrated for the interaction of spike (S) protein of SARS-CoV-2 with host cells, including angiotensin-converting enzyme (ACE2), ephrin ligands and Eph receptors, neuropilin 1 (NRP-1), P2X7, and CD147. The expression of these entry receptors in the central nervous system (CNS) may make the CNS prone to SARS-CoV-2 invasion, leading to neurodegenerative diseases. The present review provides potential pathological mechanisms of SARS-CoV-2 infection in the CNS, including entry receptors and cytokines involved in neuroinflammatory conditions. Moreover, it explains several neurodegenerative disorders associated with COVID-19. Finally, we suggest inflammasome and JaK inhibitors as potential therapeutic strategies for neurodegenerative diseases.

Neurodegenerative disease in association with sexual transmission of human T-cell lymphotropic virus type 2 subtype b in Argentina.

BACKGROUND: The aim of this study is to show that human T-cell lymphotropic virus type 2 (HTLV-2) infection produces symptoms resembling those described for HTLV-1-associated myeloneuropathy and to highlight the role of sexual transmission in the silent dissemination of HTLV-2. METHODS: Patient samples were tested by particle agglutination and indirect immunofluorescence assay. The HTLV type was defined by molecular techniques. Nucleotide sequence analysis of HTLV-2 long terminal repeat region, T cell CD3/CD4 and T cell CD3/CD8 counts and typing of human leucocyte antigen (HLA) alleles A, B, C and DRB1 were also performed. RESULTS: HTLV-2 subtype b infection was confirmed in two blood donors and their sexual partners. Two patients exhibited distinctive signs and symptoms of progressive neurological disease. Three infected patients carried HLA-C*04. Both patients with neurological disease also carried HLA-A*31 and HLA-DRB1*07 alleles. CONCLUSIONS: Herein we describe for the first time sexual transmission of HTLV-2 in a non-endemic region of Argentina, highlighting the relevance of this transmission route in HTLV-2 silent dissemination out of the clusters of endemicity. We also provide evidence that HTLV-2 infection causes symptoms resembling those described for HTLV-1-associated myeloneuropathy. The evidence presented herein points to the critical need for public health strategies to reduce the spread of this neglected infection.

Systems Biology to Understand and Regulate Human Retroviral Proinflammatory Response.

The majority of human genome are non-coding genes. Recent research have revealed that about half of these genome sequences make up of transposable elements (TEs). A branch of these belong to the endogenous retroviruses (ERVs), which are germline viral infection that occurred over millions of years ago. They are generally harmless as evolutionary mutations have made them unable to produce viral agents and are mostly epigenetically silenced. Nevertheless, ERVs are able to express by still unknown mechanisms and recent evidences have shown links between ERVs and major proinflammatory diseases and cancers. The major challenge is to elucidate a detailed mechanistic understanding between them, so that novel therapeutic approaches can be explored. Here, we provide a brief overview of TEs, human ERVs and their links to microbiome, innate immune response, proinflammatory diseases and cancer. Finally, we recommend the employment of systems biology approaches for future HERV research.

Following the Clues: Usefulness of Biomarkers of Neuroinflammation and Neurodegeneration in the Investigation of HTLV-1-Associated Myelopathy Progression.

Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurodegenerative disease due to axonal damage of the corticospinal secondary to an inflammatory response against infected T-cells. In the present work, we aimed to evaluate biomarkers of neurodegeneration and neuroinflammation in the definition of HAM/TSP prognosis. Neurofilament light (NfL) and phosphorylated heavy (pNfH) chains, total Tau protein, cellular prion protein (PrPc), inflammatory chemokines, and neopterin were quantified in paired cerebrospinal fluid (CSF) and serum samples from HAM/TSP patients (n=21), HTLV-1 asymptomatic carriers (AC) (n=13), and HTLV-1 seronegative individuals with non-inflammatory non-degenerative neurological disease (normal-pressure hydrocephalus) (n=9) as a control group. HTLV-1 proviral load in peripheral blood mononuclear cells and the expression of chemokine receptors CCR4, CCR5, and CXCR3 in infected CD4+ T-cells (HTLV-1 Tax+ cells) were also assessed. CSF levels of Tau, NfL, and pNfH were similar between groups, but PrPc and neopterin were elevated in HAM/TSP patients. Most individuals in the control group and all HTLV-1 AC had CSF/serum neopterin ratio < 1.0, and two-thirds of HAM/TSP patients had ratio values > 1.0, which positively correlated with the speed of disease progression and pNfH levels, indicating active neuroinflammation. HAM/TSP patients showed high serum levels of CXCR3-binding chemokines (CXCL9, CXCL10, and CXCL11) and elevated CSF levels of CCL2, CCL3, CCL4, CCL17, CXCL5, CXCL10, and CXCL11. Indeed, CXCL10 concentration in CSF of HAM/TSP patients was 5.8-fold and 8.7-fold higher in than in HTLV-1 AC and controls, respectively, and correlated with CSF cell counts. HAM/TSP patients with typical/rapid disease progression had CSF/serum CXCL10 ratio > 1.0 and a higher frequency of CXCR3+Tax+CD4+ T-cells in blood, which indicated a positive gradient for the migration of infected cells and infiltration into the central nervous system. In conclusion, the slow progression of HAM/TSP abrogates the usefulness of biomarkers of neuronal injury for the disease prognosis. Thus, markers of inflammation provide stronger evidence for HAM/TSP progression, particularly the CSF/serum neopterin ratio, which may contribute to overcome differences between laboratory assays.

The Potential Role of COVID-19 in the Pathogenesis of Multiple Sclerosis-A Preliminary Report.

Coronavirus 2019 (COVID-19) is an infectious respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that mainly affects the lungs. COVID-19 symptoms include the presence of fevers, dry coughs, fatigue, sore throat, headaches, diarrhea, and a loss of taste or smell. However, it is understood that SARS-CoV-2 is neurotoxic and neuro-invasive and could enter the central nervous system (CNS) via the hematogenous route or via the peripheral nerve route and causes encephalitis, encephalopathy, and acute disseminated encephalomyelitis (ADEM) in COVID-19 patients. This review discusses the possibility of SARS-CoV-2-mediated Multiple Sclerosis (MS) development in the future, comparable to the surge in Parkinson's disease cases following the Spanish Flu in 1918. Moreover, the SARS-CoV-2 infection is associated with a cytokine storm. This review highlights the impact of these modulated cytokines on glial cell interactions within the CNS and their role in potentially prompting MS development as a secondary disease by SARS-CoV-2. SARS-CoV-2 is neurotropic and could interfere with various functions of neurons leading to MS development. The influence of neuroinflammation, microglia phagocytotic capabilities, as well as hypoxia-mediated mitochondrial dysfunction and neurodegeneration, are mechanisms that may ultimately trigger MS development.

Dialogue between Neuroinflammation and Neurodegenerative Diseases in COVID-19.

It has now been almost a year since the emergence of the deadly SARS-CoV-2 with millions of people losing their lives due to resultant COVID-19. Apart from the well-known consequences of respiratory illnesses, it has even effortlessly mapped itself into the nervous system through routes like blood, CSF, neurons, and olfactory cells. Interestingly, the interaction of SARS-CoV-2 with the nervous system cells like neurons, microglia, and astrocytes has been a factor to worsen COVID-19 through its neuroinflammatory actions. The release of cytokines due to astrocyte and microglial activation could progress towards the most anticipated cytokine storm proving to be detrimental in the management of COVID-19. Such hyper-inflammatory conditions could make the BBB vulnerable, encouraging excessive viral particles into the CNS, leading to further neurodegenerative pathologies like Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease, and Multiple Sclerosis. Excessive neuroinflammation and neurodegeneration being the anticipated root causes of these multiple conditions, it is also essential to look into other factors that synergistically enhance the worsening of these diseases in COVID-19 patients for which additional studies are essential.

Decoding pathogenesis factors involved in the progression of ATLL or HAM/TSP after infection by HTLV-1 through a systems virology study.

BACKGROUND: Human T-cell Leukemia Virus type-1 (HTLV-1) is a retrovirus that causes two diseases including Adult T-cell Leukemia/Lymphoma (ATLL cancer) and HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP, a neurodegenerative disease) after a long latency period as an asymptomatic carrier (AC). There are no obvious explanations about how each of the mentioned diseases develops in the AC carriers. Finding the discriminative molecular factors and pathways may clarify the destiny of the infection. METHODS: To shed light on the involved molecular players and activated pathways in each state, differentially co-expressed modules (DiffCoEx) algorithm was employed to identify the highly correlated genes which were co-expressed differently between normal and ACs, ACs and ATLL, as well as ACs and HAM/TSP samples. Through differential pathway analysis, the dysregulated pathways and the specific disease-genes-pathways were figured out. Moreover, the common genes between the member of DiffCoEx and differentially expressed genes were found and the specific genes in ATLL and HAM/TSP were introduced as possible biomarkers. RESULTS: The dysregulated genes in the ATLL were mostly enriched in immune and cancer-related pathways while the ones in the HAM/TSP were enriched in immune, inflammation, and neurological pathways. The differential pathway analysis clarified the differences between the gene players in the common activated pathways. Eventually, the final analysis revealed the involvement of specific dysregulated genes including KIRREL2, RAB36, and KANK1 in HAM/TSP as well as LTB4R2, HCN4, FZD9, GRIK5, CREB3L4, TACR2, FRMD1, LHB, FGF3, TEAD3, GRIN2D, GNRH2, PRLH, GPR156, and CRHR2 in ATLL. CONCLUSION: The identified potential prognostic biomarkers and therapeutic targets are proposed as the most important platers in developing ATLL or HAM/TSP. Moreover, the proposed signaling network clarifies the differences between the functional players in the activated pathways in ACs, ATLL, and HAM/TSP.

LAMP2 deficiency attenuates the neurodegeneration markers induced by HSV-1 infection.

Mounting evidence suggests a major role of infectious agents in the pathogenesis of sporadic Alzheimer's disease (AD). Among them, herpes simplex virus type 1 (HSV-1) infection has emerged as a major factor in the etiology of AD. HSV-1 is able to induce some of the main alterations of the disease such as hyperphosphorylation of tau protein and accumulation of amyloid-ß peptide. Functional genomic analysis of a cell model of HSV-1 infection and oxidative stress developed in our laboratory revealed lysosomal system to be the main pathway altered, and the lysosome-associated membrane protein 2 (LAMP2) gene one of the most strongly modulated genes. The aim of this work is to study LAMP2 as an AD candidate gene and to investigate its role in the neurodegeneration induced by HSV-1 using a LAMP2 knockdown cell model. LAMP2 deficiency led to a significant reduction of viral DNA replication and formation of infectious particles. In addition, tau hyperphosphorylation and inhibition of Aß secretion induced by the virus were attenuated by the absence of LAMP2. Finally, genetic association studies revealed LAMP2 genetic variants to be associated with AD risk. In summary, our data indicate that LAMP2 could be a suitable candidate to mediate the AD-like phenotype caused by HSV-1.

The Impact of SARS-CoV-2 Infection on the Development of Neurodegeneration in Multiple Sclerosis.

The novel coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global challenge. Currently, there is some information on the consequences of COVID-19 infection in multiple sclerosis (MS) patients, as it is a newly discovered coronavirus, but its far-reaching effects on participation in neurodegenerative diseases seem to be significant. Recent cases reports showed that SARS-CoV-2 may be responsible for initiating the demyelination process in people who previously had no symptoms associated with any nervous system disorders. It is presently known that infection of SARS-CoV-2 evokes cytokine storm syndrome, which may be one of the factors leading to the acute cerebrovascular disease. One of the substantial problems is the coexistence of cerebrovascular disease and MS in an individual's life span. Epidemiological studies showed an enhanced risk of death rate from vascular disabilities in MS patients of approximately 30%. It has been demonstrated that patients with severe SARS-CoV-2 infection usually show increased levels of D-dimer, fibrinogen, C-reactive protein (CRP), and overactivation of blood platelets, which are essential elements of prothrombotic events. In this review, the latest knowledge gathered during an ongoing pandemic of SARS-CoV-2 infection on the neurodegeneration processes in MS is discussed.

SARS-CoV-2 spike protein interactions with amyloidogenic proteins: Potential clues to neurodegeneration.

The post-infection of COVID-19 includes a myriad of neurologic symptoms including neurodegeneration. Protein aggregation in brain can be considered as one of the important reasons behind the neurodegeneration. SARS-CoV-2 Spike S1 protein receptor binding domain (SARS-CoV-2 S1 RBD) binds to heparin and heparin binding proteins. Moreover, heparin binding accelerates the aggregation of the pathological amyloid proteins present in the brain. In this paper, we have shown that the SARS-CoV-2 S1 RBD binds to a number of aggregation-prone, heparin binding proteins including Aß, α-synuclein, tau, prion, and TDP-43 RRM. These interactions suggests that the heparin-binding site on the S1 protein might assist the binding of amyloid proteins to the viral surface and thus could initiate aggregation of these proteins and finally leads to neurodegeneration in brain. The results will help us to prevent future outcomes of neurodegeneration by targeting this binding and aggregation process.

Clinical Utility of ß-Amyloid PET Imaging in People Living With HIV With Cognitive Symptoms.

BACKGROUND: Imaging with ß-amyloid (Aß) positron emission tomography (PET) has the potential to aid the diagnosis of the cause of cognitive impairment affecting people living with HIV (PLWH) when neurodegenerative disorders are considered. We evaluated the clinical utility of [18F]Florbetaben (FBB) in PLWH with cognitive symptoms. METHODS: Imaging with FBB PET was performed in 20 patients with cognitive concerns about dementia. Neuropsychological testing, plasma neurofilament light protein, plasma Aß40, Aß42, and cerebrospinal fluid Aß42, tau, and HIV RNA were obtained. FBB PET images were assessed visually by 3 readers blinded to the clinical diagnosis and quantitatively by obtaining a composite cortical to cerebellar cortex standardized uptake value ratio (SUVR). FBB SUVR from 10 age-matched healthy controls was compared with SUVR of PLWH. RESULTS: Most participants were men (90%) of white ethnicity (90%) with a median age (interquartile range) of 59 (43-79) years. Median CD4 count was 682 (74-1056). All patients were on combination antiretroviral therapy with plasma and cerebrospinal fluid HIV RNA <40 copies/mL. Fourteen patients had objective cognitive impairment including 2 who met clinical criteria for a diagnosis of dementia. No significant differences in composite SUVRs between PLWH and controls [mean (SD): 1.18 (0.03) vs. 1.16 (0.09); P = 0.37] were observed. Four patients were FBB+ with the highest SUVR in the posterior cingulate, superior temporal, and frontal superior lobe. Amyloid PET results contributed to a change in diagnosis and treatment for 10 patients. CONCLUSION: [18F]Florbetaben PET has potential as an adjunctive tool in the diagnosis of PLWH with cognitive impairment, increasing diagnostic certainty and optimizing management.

Does coronaviruses induce neurodegenerative diseases? A systematic review on the neurotropism and neuroinvasion of SARS-CoV-2.

The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified in 2019 in Wuhan, China. Clinically, respiratory tract symptoms as well as other organs disorders are observed in patients positively diagnosed coronavirus disease 2019 (COVID-19). In addition, neurological symptoms, mainly anosmia, ageusia and headache were observed in many patients. Once in the central nervous system (CNS), the SARS-CoV-2 can reside either in a quiescent latent state, or eventually in actively state leading to severe acute encephalitis, characterized by neuroinflammation and prolonged neuroimmune activation. SRAS-CoV-2 requires angiotensin-converting enzyme 2 (ACE2) as a cell entry receptor. The expression of this receptor in endothelial cells of blood-brain barrier (BBB) shows that SRAS-CoV-2 may have higher neuroinvasive potential compared to known coronaviruses. This review summarizes available information regarding the impact of SRAS-CoV-2 in the brain and tended to identify its potential pathways of neuroinvasion. We offer also an understanding of the long-term impact of latently form of SARS-CoV-2 on the development of neurodegenerative disorders. As a conclusion, the persistent infection of SRAS-CoV-2 in the brain could be involved on human neurodegenerative diseases that evolve a gradual process, perhapes, over several decades.

Modeling neurological disorders using brain organoids.

Neurological disorders are challenging to study given the complexity and species-specific features of the organ system. Brain organoids are three dimensional structured aggregates of neural tissue that are generated by self-organization and differentiation from pluripotent stem cells under optimized culture conditions. These brain organoids exhibit similar features of structural organization and cell type diversity as the developing human brain, creating opportunities to recapitulate disease phenotypes that are not otherwise accessible. Here we review the initial attempt in the field to apply brain organoid models for the study of many different types of human neurological disorders across a wide range of etiologies and pathophysiologies. Forthcoming advancements in both brain organoid technology as well as analytical methods have significant potentials to advance the understanding of neurological disorders and to uncover opportunities for meaningful therapeutic intervention.

TCRD and Pharos 2021: mining the human proteome for disease biology.

In 2014, the National Institutes of Health (NIH) initiated the Illuminating the Druggable Genome (IDG) program to identify and improve our understanding of poorly characterized proteins that can potentially be modulated using small molecules or biologics. Two resources produced from these efforts are: The Target Central Resource Database (TCRD) (http://juniper.health.unm.edu/tcrd/) and Pharos (https://pharos.nih.gov/), a web interface to browse the TCRD. The ultimate goal of these resources is to highlight and facilitate research into currently understudied proteins, by aggregating a multitude of data sources, and ranking targets based on the amount of data available, and presenting data in machine learning ready format. Since the 2017 release, both TCRD and Pharos have produced two major releases, which have incorporated or expanded an additional 25 data sources. Recently incorporated data types include human and viral-human protein-protein interactions, protein-disease and protein-phenotype associations, and drug-induced gene signatures, among others. These aggregated data have enabled us to generate new visualizations and content sections in Pharos, in order to empower users to find new areas of study in the druggable genome.

Análisis de letalidad por COVID-19 en pacientes con demencia neurodegenerativa / Case fatality of COVID-19 in patients with neurodegenerative dementia

INTRODUCTION: The elderly population is the group most threatened by COVID-19, with the highest mortality rates. This study aims to analyse the case fatality of COVID-19 in a cohort of patients with degenerative dementia. METHODS: We conducted a descriptive case-control study of a sample of patients diagnosed with primary neurodegenerative dementia. RESULTS: Twenty-four of the 88 patients with COVID-19 included in the study died: 10/23 (43.4%) patients diagnosed with dementia and 14/65 (21.5%) controls; this difference was statistically significant. DISCUSSION: Our results suggest that case fatality of COVID-19 is significantly higher among patients with primary degenerative dementia than in other patients with similar mean ages and comorbidities

INTRODUCCIÓN: La población anciana es la más amenazada por COVID-19, con mayores tasas de mortalidad. El objetivo de este trabajo es analizar la letalidad en una cohorte de pacientes de COVID-19 con demencia degenerativa. MÉTODOS: Hicimos un estudio descriptivo de casos-control de una muestra de pacientes diagnosticados con demencias neurodegenerativas primarias. RESULTADOS: De los 88 pacientes incluidos en el estudio, 24 pacientes con COVID-19 fallecieron: 10/23 (43,4%) eran pacientes con diagnóstico de demencia y 14/65 (21,5%) pacientes del grupo control, una diferencia estadísticamente significativa. DISCUSIÓN: La letalidad entre los pacientes con demencia degenerativa primaria por COVID-19 es significativamente mayor en comparación con otros pacientes con edades medias y comorbilidades similares, según nuestro estudio

Viral Infection-Induced Gut Dysbiosis, Neuroinflammation, and α-Synuclein Aggregation: Updates and Perspectives on COVID-19 and Neurodegenerative Disorders.

The current pandemic of coronavirus disease 2019 (COVID-19) has gained increased attention in the neuroscience community, especially taking into account the neuroinvasive potential of its causative agent, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the impact of its infection on the structure and function of the brain. Apart from the neurotropic properties of SARS-CoV-2, it is likewise important the observation that virus infection may perturb specific cellular processes that are believed to play an important role in the pathogenesis of diverse neurological disorders, particularly in Parkinson's disease (PD). In this scenario, viral infection-induced colon inflammation, gut microbial imbalance, and α-synuclein upregulation are of particular interest with regard to the interplay between the gastrointestinal tract and the central nervous system (microbiome-gut-brain axis). In this Perspective, we present a critical view on the different hypotheses that are recently being raised by neuroscientists about the relationship between SARS-CoV-2 infection and long-lasting neurodegenerative disorders, opening the question of whether COVID-19 might represent a risk factor for the development of PD.