Tau protein aggregation associated with SARS-CoV-2 main protease (preprint)

The primary function of virus proteases is the proteolytic processing of the viral polyprotein. These enzymes can also cleave host cell proteins, which is important for viral pathogenicity, modulation of cellular processes, viral replication, the defeat of antiviral responses and modulation of the immune response. It is known that COVID-19 can influence multiple tissues or organs and that infection can damage the functionality of the brain in multiple ways. After COVID-19 infections, amyloid-{beta}, neurogranin, tau and phosphorylated tau were detected extracellularly, implicating possible neurodegenerative processes. The present study describes the possible induction of protein aggregation by the SARS-CoV-2 3CL protease (3CLpro) possibly relevant in neuropathology, such as aggregation of tau, alpha-synuclein and TPD-43. Further investigations demonstrated that tau was proteolytically cleaved by the viral protease 3CL and, consequently, generated aggregates. However, more evidence is needed to confirm that COVID-19 is able to trigger neurodegenerative diseases.

Ribosome biogenesis in disease: new players and therapeutic targets.

The ribosome is a multi-unit complex that translates mRNA into protein. Ribosome biogenesis is the process that generates ribosomes and plays an essential role in cell proliferation, differentiation, apoptosis, development, and transformation. The mTORC1, Myc, and noncoding RNA signaling pathways are the primary mediators that work jointly with RNA polymerases and ribosome proteins to control ribosome biogenesis and protein synthesis. Activation of mTORC1 is required for normal fetal growth and development and tissue regeneration after birth. Myc is implicated in cancer development by enhancing RNA Pol II activity, leading to uncontrolled cancer cell growth. The deregulation of noncoding RNAs such as microRNAs, long noncoding RNAs, and circular RNAs is involved in developing blood, neurodegenerative diseases, and atherosclerosis. We review the similarities and differences between eukaryotic and bacterial ribosomes and the molecular mechanism of ribosome-targeting antibiotics and bacterial resistance. We also review the most recent findings of ribosome dysfunction in COVID-19 and other conditions and discuss the consequences of ribosome frameshifting, ribosome-stalling, and ribosome-collision. We summarize the role of ribosome biogenesis in the development of various diseases. Furthermore, we review the current clinical trials, prospective vaccines for COVID-19, and therapies targeting ribosome biogenesis in cancer, cardiovascular disease, aging, and neurodegenerative disease.

COVID-19 and neurodegenerative diseases.

OBJECTIVE: The pandemic of Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues, and SARS-CoV-2 variants continue to emerge. In addition to typical fever and respiratory symptoms, many patients with COVID-19 experience a variety of neurological complications. In this review, we analyzed and reviewed the current status and possible mechanisms between COVID-19 and several typical neurodegenerative diseases, particularly Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, hoping to propose the potential direction of further research and concern. MATERIALS AND METHODS: Electronic literature search of the databases (Medline/PubMed, Web of Science, and Google Scholar). The keywords used were COVID-19, SARS-CoV-2, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The retrieved relevant articles were reviewed and critically analyzed. RESULTS: SARS-CoV-2 is a highly neuroinvasive neurotropic virus that invades cells through angiotensin-converting enzyme 2 (ACE2) receptor-driven pathway. SARS-CoV-2 neuroinvasion, neuroinflammation, and blood-brain barrier (BBB) dysfunction may contribute to the pathogenesis of neurodegenerative diseases. CONCLUSIONS: Some patients with neurodegenerative diseases have already shown more susceptibility to SARS-CoV-2 infection and significantly higher mortality due to the elderly population with underlying diseases. Moreover, SARS-CoV-2 could cause damage to the central nervous system (CNS) that may substantially increase the incidence of neurodegenerative diseases and accelerate the progression of them.

Impact of COVID­19 infection in patients with neurodegenerative diseases with particular focus on Alzheimer's and Parkinson's disease.

Neurodegenerative disorders (NDD) are chronic neurological diseases characterized by loss and/or damage to neurons along with the myelin sheath, and patients are at higher risk of severe infection with the SARS­CoV­2. A comprehensive literature search was performed using relevant terms and inclusion­exclusion criteria. Recent articles, subjects older than 50 years, and articles written in the English language were included, whereas letters to the editor and articles related to pregnant women were excluded from the review study. COVID­19 appears to damage angiotensin­II receptors which cause natural killer cells to lose the ability to clear virus­infected cells, owing to worse outcomes in patients with NDD. COVID­19 can worsen the symptoms of Alzheimer's disease. In addition, COVID­19 worsens drug­responsive motor symptoms in Parkinson's disease (PD) and other symptoms like fatigue and urinary complaints. Vitamin D is essential in decreasing pro­inflammatory and increasing anti­inflammatory cytokines in ongoing COVID­19 infections and reducing angiotensin receptors and, hence, decreasing COVID­19 infection severity. Telemedicine shows promise for patients with NDD but is yet to overcome legal issues and personal barriers. COVID­19 has a significant effect on neurodegenerative conditions, which appears partly to the nature of the NDD and the neuro­invasive capabilities of the SARS­CoV­2. The protective role of vitamin D in patients with NDD further supports this hypothesis. Modifications in current health care, like the telemedicine platform, are required to address the increased risk of serious infection in this population. Further studies will be required to clarify conflicting reports in many fields.

Action of the Purinergic and Cholinergic Anti-inflammatory Pathways on Oxidative Stress in Patients with Alzheimer's Disease in the Context of the COVID-19 Pandemic.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of the 2019 coronavirus disease (COVID-19), has affected more than 20 million people in Brazil and caused a global health emergency. This virus has the potential to affect various parts of the body and compromise metabolic functions. The virus-mediated neural inflammation of the nervous system is due to a storm of cytokines and oxidative stress, which are the clinical features of Alzheimer's disease (AD). This neurodegenerative disease is aggravated in cases involving SARS-CoV-2 and its inflammatory biomarkers, accelerating accumulation of ß-amyloid peptide, hyperphosphorylation of tau protein, and production of reactive oxygen species, which lead to homeostasis imbalance. The cholinergic system, through neurons and the neurotransmitter acetylcholine (ACh), modulates various physiological pathways, such as the response to stress, sleep and wakefulness, sensory information, and the cognitive system. Patients with AD have low concentrations of ACh; hence, therapeutic methods are aimed at adjusting the ACh titers available to the body for maintaining functionality. Herein, we focused on acetylcholinesterase inhibitors, responsible for the degradation of ACh in the synaptic cleft, and muscarinic and nicotinic receptor agonists of the cholinergic system owing to the therapeutic potential of the cholinergic anti-inflammatory pathway in AD associated with SARS-CoV-2 infection.

Identification of the pathogenic relationship between Long COVID and Alzheimer's disease by bioinformatics methods (preprint)

Background The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused an unprecedented global health crisis. Although many Corona Virus Disease 2019 (COVID-19) patients have recovered, the long-term consequences of SARS-CoV-2 infection are unclear. Several independent epidemiological surveys and clinical studies have found that SARS-CoV-2 infection and Long COVID are closely related to Alzheimer's disease (AD). This could lead to long-term medical challenges and social burdens following this health crisis. However, the mechanism between Long COVID and AD is unknown.Methods Genes associated with Long COVID were collected from the database. Two sets of AD-related clinical sample datasets were collected in the Gene Expression Omnibus (GEO) database by limiting screening conditions. After identifying the differentially expressed genes (DEGs) of AD, the significant overlapping genes of AD and Long COVID were obtained by taking the intersection. Then, four kinds of analyses were performed, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis, protein-protein interaction (PPI) analysis, identification of hub genes, hub gene verification and transcription factors (TFs) prediction.Results A total of 197 common genes were selected for subsequent analysis. GO and KEGG enrichment analysis showed that these genes were mainly enriched in multiple neurodegenerative disease related pathways. In addition, 20 important hub genes were identified using cytoHubba. At the same time, these hub genes were verified in another data set, where 19 hub gene expressions were significantly different in the two diseases and 6 hub genes were significantly different in AD patients of different genders. Finally, we collected 9 TFs that may regulate the expression of these hub genes in the Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining (TRUSST) database and verified them in the current data set.Conclusion This work reveals the common pathways and hub genes of AD and Long COVID, providing new ideas for the pathogenic relationship between these two diseases and further mechanism research.

Links between COVID-19 and Parkinson's disease/Alzheimer's disease: reciprocal impacts, medical care strategies and underlying mechanisms.

The impact of coronavirus disease 2019 (COVID-19) pandemic on patients with neurodegenerative diseases and the specific neurological manifestations of COVID-19 have aroused great interest. However, there are still many issues of concern to be clarified. Therefore, we review the current literature on the complex relationship between COVID-19 and neurodegenerative diseases with an emphasis on Parkinson's disease (PD) and Alzheimer's disease (AD). We summarize the impact of COVID-19 infection on symptom severity, disease progression, and mortality rate of PD and AD, and discuss whether COVID-19 infection could trigger PD and AD. In addition, the susceptibility to and the prognosis of COVID-19 in PD patients and AD patients are also included. In order to achieve better management of PD and AD patients, modifications of care strategies, specific drug therapies, and vaccines during the pandemic are also listed. At last, mechanisms underlying the link of COVID-19 with PD and AD are reviewed.

Characteristics and Outcomes of COVID-19 Patients Presumed to be Treated with Sotrovimab in NHS Hospitals in England (preprint)

Introduction: There is limited real-world evidence describing the effectiveness of early treatments for Coronavirus disease 2019 (COVID-19) during the period where Omicron was the dominant variant. Here we describe characteristics and acute clinical outcomes in patients with COVID-19 treated with a monoclonal antibody (mAb; presumed to be sotrovimab) across six distinct periods covering the emergence and subsequent dominance of Omicron subvariants (BA.1, BA.2 and BA.5) in England. Methods: Retrospective cohort study using data from Hospital Episode Statistics database between 1st January - 31st July 2022. Included patients were aged [≥]12 years and received a mAb delivered by a National Health Service (NHS) hospital as a day-case, for which the primary diagnosis was COVID-19. Patients were presumed to have received sotrovimab on the basis of available NHS data showing that 99.98% of individuals who received COVID-19 treatment during the period covered by the study were actually treated with sotrovimab. COVID-19-attributable hospitalisations were reported overall and across six distinct periods of Omicron sub-variant prevalence. A multivariate Poisson regression model was used to estimate incidence rate ratios for each period. Subgroup analyses were conducted in patients with severe renal disease and active cancer. Results: In total, 10,096 patients were included. The most common high-risk comorbidities were Immune-Mediated Inflammatory Disorders (43.0%; n = 4,337), severe renal disease (14.1%; n = 1,422), rare neurological conditions (10.4%; n = 1,053) and active cancer (9.0%; n = 910). The proportions of patients with a COVID-19-attributable hospitalisation was 1.0% (n = 96), or with a hospital visit due to any cause was 4.6% (n = 465) during the acute period. The percentage of patients who died due to any cause during the acute study period was 0.3% (n = 27). COVID-19-attributable hospitalisation rates were consistent among subgroups and no significant differences (p-values ranged from 0.13 to 0.64) were observed across periods of Omicron subvariants. Conclusion: Low levels of COVID-19-attributable hospitalisations and deaths were recorded in mAb-treated patients. Results were consistent for patients with severe renal disease and active cancer. No evidence of differences in hospitalisation rates were observed whilst Omicron BA.1, and BA.2 or BA.5 subvariants were predominant, despite reported reductions in in vitro neutralisation activity of sotrovimab against BA.2 and BA.5.

Natural and Semi-Synthetic Flavonoid Anti-SARS-CoV-2 Agents for the Treatment of Long COVID-19 Disease and Neurodegenerative Disorders of Cognitive Decline.

The aim of this review is to highlight the beneficial attributes of flavonoids, a diverse family of widely-distributed polyphenolic phytochemicals that have beneficial cell and tissue protective properties. Phytochemicals are widely distributed in plants, herbs and shrubs used in traditional complimentary medical formulations for centuries. The bioactive components that convey beneficial medicinal effects in these complex herbal preparations are now being identified using network pharmacology and molecular docking procedures that identify their molecular targets. Flavonoids have anti-oxidant, anti-inflammatory, antiviral, antibacterial and anti-cancer properties that have inspired the development of potent multifunctional derivatised flavonoids of improved efficacy. The antiviral properties of flavonoids and the emergence of the severe acute respiratory syndrome (SARS-CoV-2) pandemic has resulted in a resurgence of interest in phytochemicals in the search for efficacious compounds that can prevent viral infection or replication, with many promising plant compounds identified. Promising semi-synthetic flavonoid derivatives have also been developed that inhibit multiple pathological neurodegenerative processes; these offer considerable promise in the treatment of diseases of cognitive decline. Clinical trials are currently being undertaken to evaluate the efficacy of dietary supplements rich in flavonoids for the treatment of virally-mediated diseases. Such trials are expected to identify flavonoids with cell and tissue protective properties that can be harnessed in biomedical applications that may serve as supportive adjunctive procedures to conventional anti-viral drug therapies against diseases such as COVID-19.

[Olfactory disorders as a multidisciplinary problem]. / Rasstroistva obonyaniya ­ mezhdistsiplinarnaya problema.

Olfactory dysfunction is a serious symptom that requires careful differential diagnosis. The article presents convincing evidence that dysosmia is not only a symptom of rinological pathology, but also a manifestation of various neurodegenerative diseases. Some patients with SARS-CoV-2 have neurological symptoms. Modern studies show that olfactory and gustatory dysfunctions are significant symptoms in the clinical presentation of the COVID-19 infection. The importance of olfactory diagnostics in relatives of patients with hereditary neurodegenerative diseases for the purpose of early detection of pathology is noted. We consider the possibility of introducing new methods for the diagnosis of olfactory dysfunction, which is a promising task both in the field of neurology and otorhinolaryngology, in order to prevent the development of neurodegenerative diseases at an early stage, improve the quality of life and social adaptation of patients.

The relationship between chronic immune response and neurodegenerative damage in long COVID-19.

In the past two years, the world has faced the pandemic caused by the severe acute respiratory syndrome 2 coronavirus (SARS-CoV-2), which by August of 2022 has infected around 619 million people and caused the death of 6.55 million individuals globally. Although SARS-CoV-2 mainly affects the respiratory tract level, there are several reports, indicating that other organs such as the heart, kidney, pancreas, and brain can also be damaged. A characteristic observed in blood serum samples of patients suffering COVID-19 disease in moderate and severe stages, is a significant increase in proinflammatory cytokines such as interferon-α (IFN-α), interleukin-1ß (IL-1ß), interleukin-2 (IL-2), interleukin-6 (IL-6) and interleukin-18 (IL-18), as well as the presence of autoantibodies against interferon-α (IFN-α), interferon-λ (IFN-λ), C-C motif chemokine ligand 26 (CCL26), CXC motif chemokine ligand 12 (CXCL12), family with sequence similarity 19 (chemokine (C-C motif)-like) member A4 (FAM19A4), and C-C motif chemokine ligand 1 (CCL1). Interestingly, it has been described that the chronic cytokinemia is related to alterations of blood-brain barrier (BBB) permeability and induction of neurotoxicity. Furthermore, the generation of autoantibodies affects processes such as neurogenesis, neuronal repair, chemotaxis and the optimal microglia function. These observations support the notion that COVID-19 patients who survived the disease present neurological sequelae and neuropsychiatric disorders. The goal of this review is to explore the relationship between inflammatory and humoral immune markers and the major neurological damage manifested in post-COVID-19 patients.

The contribution of gut-brain axis to development of neurological symptoms in COVID-19 recovered patients: A hypothesis and review of literature.

The gut microbiota undergoes significant alterations in response to viral infections, particularly the novel SARS-CoV-2. As impaired gut microbiota can trigger numerous neurological disorders, we suggest that the long-term neurological symptoms of COVID-19 may be related to intestinal microbiota disorders in these patients. Thus, we have gathered available information on how the virus can affect the microbiota of gastrointestinal systems, both in the acute and the recovery phase of the disease, and described several mechanisms through which this gut dysbiosis can lead to long-term neurological disorders, such as Guillain-Barre syndrome, chronic fatigue, psychiatric disorders such as depression and anxiety, and even neurodegenerative diseases such as Alzheimer's and Parkinson's disease. These mechanisms may be mediated by inflammatory cytokines, as well as certain chemicals such as gastrointestinal hormones (e.g., CCK), neurotransmitters (e.g., 5-HT), etc. (e.g., short-chain fatty acids), and the autonomic nervous system. In addition to the direct influences of the virus, repurposed medications used for COVID-19 patients can also play a role in gut dysbiosis. In conclusion, although there are many dark spots in our current knowledge of the mechanism of COVID-19-related gut-brain axis disturbance, based on available evidence, we can hypothesize that these two phenomena are more than just a coincidence and highly recommend large-scale epidemiologic studies in the future.

Delirium in hospitalized COVID-19 patients: Predictors and implications for patient outcome.

INTRODUCTION: Delirium is recognized as a severe complication of coronavirus-disease-2019 (COVID-19). COVID-19-associated delirium has been linked to worse patient outcomes and is considered to be of multifactorial origin. Here we sought to evaluate the incidence and risk factors of delirium in hospitalized COVID-19 patients, along with its impact on clinical outcome. METHODS: Consecutive adult COVID-19 patients admitted to a tertiary academic referral hospital between March 1st and December 31st, 2020 were included. Potential risk factors for delirium were evaluated, including: age, gender, disease severity (as per the highest WHO grading reached during admission), laboratory parameters for infection and renal function (as per their most extreme values), and presence of comorbidities. To assess the relative strength of risk factors for predicting the occurrence of delirium, we performed a random-forest survival analysis. RESULTS: 347 patients with positive COVID-19 PCR test and median age 68.2 [IQR 55.5, 80.5] years were included. Of those, 79 patients (22.8%) developed delirium, 81 (23.3%) were transferred to ICU, 58 (16.7%) died. 163 (73.8%) patients were discharged home, 13 (5.9%) to another hospital, 32 (14.5%) to nursing homes, 13 (5.9%) to rehabilitation with an overall median admission-to-discharge time of 53 [IQR 14, 195] days. The strongest predictors for the occurrence of delirium were blood urea nitrogen (minimal depth value (MD): 3.33), age (MD: 3.75), disease severity (as captured by WHO grading; MD: 3.93), leukocyte count (MD: 4.22), the presence of a neurodegenerative history (MD: 4.43), ferritin (MD: 4.46) and creatinine (MD: 4.59) levels. CONCLUSION: The risk of delirium in COVID-19 can be stratified based on COVID-19 disease severity and-similar to delirium associated with other respiratory infections-the factors advanced age, neurodegenerative disease history, and presence of elevated infection and renal-retention parameters. Screening for these risk factors may facilitate early identification of patients at high-risk for COVID-19-associated delirium.

Bioinformatics and systems biology approaches to identify the effects of COVID-19 on neurodegenerative diseases: A review.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus disease (COVID-19), has been devastated by COVID-19 in an increasing number of countries and health care systems around the world since its announcement of a global pandemic on 11 March 2020. During the pandemic, emerging novel viral mutant variants have caused multiple outbreaks of COVID-19 around the world and are prone to genetic evolution, causing serious damage to human health. As confirmed cases of COVID-19 spread rapidly, there is evidence that SARS-CoV-2 infection involves the central nervous system (CNS) and peripheral nervous system (PNS), directly or indirectly damaging neurons and further leading to neurodegenerative diseases (ND), but the molecular mechanisms of ND and CVOID-19 are unknown. We employed transcriptomic profiling to detect several major diseases of ND: Alzheimer 's disease (AD), Parkinson' s disease (PD), and multiple sclerosis (MS) common pathways and molecular biomarkers in association with COVID-19, helping to understand the link between ND and COVID-19. There were 14, 30 and 19 differentially expressed genes (DEGs) between COVID-19 and Alzheimer 's disease (AD), Parkinson' s disease (PD) and multiple sclerosis (MS), respectively; enrichment analysis showed that MAPK, IL-17, PI3K-Akt and other signaling pathways were significantly expressed; the hub genes (HGs) of DEGs between ND and COVID-19 were CRH, SST, TAC1, SLC32A1, GAD2, GAD1, VIP and SYP. Analysis of transcriptome data suggests multiple co-morbid mechanisms between COVID-19 and AD, PD, and MS, providing new ideas and therapeutic strategies for clinical prevention and treatment of COVID-19 and ND.

EMAS position statement: Vitamin D and menopausal health.

INTRODUCTION: There is increasing evidence that vitamin D has widespread tissue effects. In addition to osteoporosis, vitamin D deficiency has been associated with cardiovascular disease, diabetes, cancer, infections and neurodegenerative disease. However, the effect of vitamin D supplementation on non-skeletal outcomes requires clarification, especially in postmenopausal women. AIM: This position statement provides an evidence-based overview of the role of vitamin D in the health of postmenopausal women based on observational and interventional studies. MATERIALS AND METHODS: Literature review and consensus of expert opinion. RESULTS AND CONCLUSIONS: Vitamin D status is determined by measuring serum 25-hydroxyvitamin D levels. Concentrations <20 ng/ml (<50 nmol/l) and <10 ng/ml (<25 nmol/l) are considered to constitute vitamin D deficiency and severe deficiency, respectively. Observational data suggest an association between vitamin D deficiency and adverse health outcomes in postmenopausal women, although they cannot establish causality. The evidence from randomized controlled trials concerning vitamin D supplementation is not robust, since many studies did not consider whether people were deficient at baseline. Moreover, high heterogeneity exists in terms of the population studied, vitamin D dosage, calcium co-administration and duration of intervention. Concerning skeletal health, vitamin D deficiency is associated with low bone mass and an increased risk of fractures. Vitamin D supplementation at maintenance doses of 800-2000 IU/day (20-50 µg/day), after repletion of vitamin D status with higher weekly or daily doses, may be of benefit only when co-administered with calcium (1000-1200 mg/day), especially in the elderly populations and those with severe vitamin D deficiency. Concerning cardiovascular disease, vitamin D deficiency is associated with an increased prevalence of cardiovascular risk factors, mainly metabolic syndrome, type 2 diabetes mellitus and dyslipidemia. Vitamin D deficiency, especially its severe form, is associated with an increased risk of cardiovascular events (coronary heart disease, stroke, mortality), independently of traditional risk factors. Vitamin D supplementation may have a modestly beneficial effect on lipid profile and glucose homeostasis, especially in obese individuals or those ≥60 years old and at doses of ≥2000 IU/day (≥50 µg/day). However, it has no effect on the incidence of cardiovascular events. Concerning cancer, vitamin D deficiency is associated with increased incidence of and mortality from several types of cancer, such as colorectal, lung and breast cancer. However, the data on other types of gynecological cancer are inconsistent. Vitamin D supplementation has no effect on cancer incidence, although a modest reduction in cancer-related mortality has been observed. Concerning infections, vitamin D deficiency has been associated with acute respiratory tract infections, including coronavirus disease 2019 (COVID-19). Vitamin D supplementation may decrease the risk of acute respiratory tract infections and the severity of COVID-19 (not the risk of infection). Concerning menopausal symptomatology, vitamin D deficiency may have a negative impact on some aspects, such as sleep disturbances, depression, sexual function and joint pains. However, vitamin D supplementation has no effect on these, except for vulvovaginal atrophy, at relatively high doses, i.e., 40,000-60,000 IU/week (1000-1500 IU/week) orally or 1000 IU/day (25 µg/day) as a vaginal suppository.

Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology. (preprint)

Aging is the primary risk factor for most neurodegenerative diseases, and recently coronavirus disease 2019 (COVID-19) has been associated with severe neurological manifestations that can eventually impact neurodegenerative conditions in the long-term. The progressive accumulation of senescent cells in vivo strongly contributes to brain aging and neurodegenerative co-morbidities but the impact of virus-induced senescence in the aetiology of neuropathologies is unknown. Here, we show that senescent cells accumulate in physiologically aged brain organoids of human origin and that senolytic treatment reduces inflammation and cellular senescence; for which we found that combined treatment with the senolytic drugs dasatinib and quercetin rejuvenates transcriptomic human brain aging clocks. We further interrogated brain frontal cortex regions in postmortem patients who succumbed to severe COVID-19 and observed increased accumulation of senescent cells as compared to age-matched control brains from non-COVID-affected individuals. Moreover, we show that exposure of human brain organoids to SARS-CoV-2 evoked cellular senescence, and that spatial transcriptomic sequencing of virus-induced senescent cells identified a unique SARS-CoV-2 variant-specific inflammatory signature that is different from endogenous naturally-emerging senescent cells. Importantly, following SARS-CoV-2 infection of human brain organoids, treatment with senolytics blocked viral retention and prevented the emergence of senescent corticothalamic and GABAergic neurons. Furthermore, we demonstrate in human ACE2 overexpressing mice that senolytic treatment ameliorates COVID-19 brain pathology following infection with SARS-CoV-2. In vivo treatment with senolytics improved SARS-CoV-2 clinical phenotype and survival, alleviated brain senescence and reactive astrogliosis, promoted survival of dopaminergic neurons, and reduced viral and senescence-associated secretory phenotype gene expression in the brain. Collectively, our findings demonstrate SARS-CoV-2 can trigger cellular senescence in the brain, and that senolytic therapy mitigates senescence-driven brain aging and multiple neuropathological sequelae caused by neurotropic viruses, including SARS-CoV-2.

Glymphatic MRI techniques in sleep and neurodegenerative diseases.

PURPOSE OF REVIEW: The purpose of this review article is to summarize the current in-vivo imaging techniques for the evaluation of the glymphatic function and discuss the factors influencing the glymphatic function and research directions in the future. RECENT FINDINGS: The glymphatic system allows the clearance of metabolic waste from the central nervous system (CNS). The glymphatic pathway has been investigated using intrathecal or intravenous injection of a gadolinium-based contrast agent (GBCA) on MRI, so-called glymphatic MRI. The glymphatic MRI indirectly visualizes the dynamic CSF flow and evaluated the glymphatic function in the animal and human models. Several clinical and preclinical studies using glymphatic MRI have confirmed that the glymphatic function is impaired in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and idiopathic normal pressure hydrocephalus. Furthermore, physiologic process such as sleep facilitates the glymphatic clearance, thus clearing accumulation of protein deposition, such as amyloid or tau, potentially delaying the progression of neurodegenerative diseases. SUMMARY: The glymphatic system plays a crucial role in clearing metabolic wastes in the brain. Glymphatic MR imaging using GBCA administration serves as a functional imaging tool to measure the glymphatic function and investigate various pathophysiologies of neurodegenerative diseases.

Amyloid Protein Cross-Seeding Provides a New Perspective on Multiple Diseases In Vivo.

Amyloid protein cross-seeding is a peculiar phenomenon of cross-spreading among different diseases. Unlike traditional infectious ones, diseases caused by amyloid protein cross-seeding are spread by misfolded proteins instead of pathogens. As a consequence of the interactions among misfolded heterologous proteins or polypeptides, amyloid protein cross-seeding is considered to be the crucial cause of overlapping pathological transmission between various protein misfolding disorders (PMDs) in multiple tissues and cells. Here, we briefly review the phenomenon of cross-seeding among amyloid proteins. As an interesting example worth mentioning, the potential links between the novel coronavirus pneumonia (COVID-19) and some neurodegenerative diseases might be related to the amyloid protein cross-seeding, thus may cause an undesirable trend in the incidence of PMDs around the world. We then summarize the theoretical models as well as the experimental techniques for studying amyloid protein cross-seeding. Finally, we conclude with an outlook on the challenges and opportunities for basic research in this field. Cross-seeding of amyloid opens up a new perspective in our understanding of the process of amyloidogenesis, which is crucial for the development of new treatments for diseases. It is therefore valuable but still challenging to explore the cross-seeding system of amyloid protein as well as to reveal the structural basis and the intricate processes.

CEST MRI and MALDI imaging reveal metabolic alterations in the cervical lymph nodes of EAE mice.

BACKGROUND: Multiple sclerosis (MS) is a neurodegenerative disease, wherein aberrant immune cells target myelin-ensheathed nerves. Conventional magnetic resonance imaging (MRI) can be performed to monitor damage to the central nervous system that results from previous inflammation; however, these imaging biomarkers are not necessarily indicative of active, progressive stages of the disease. The immune cells responsible for MS are first activated and sensitized to myelin in lymph nodes (LNs). Here, we present a new strategy for monitoring active disease activity in MS, chemical exchange saturation transfer (CEST) MRI of LNs. METHODS AND RESULTS: We studied the potential utility of conventional (T2-weighted) and CEST MRI to monitor changes in these LNs during disease progression in an experimental autoimmune encephalomyelitis (EAE) model. We found CEST signal changes corresponded temporally with disease activity. CEST signals at the 3.2 ppm frequency during the active stage of EAE correlated significantly with the cellular (flow cytometry) and metabolic (mass spectrometry imaging) composition of the LNs, as well as immune cell infiltration into brain and spinal cord tissue. Correlating primary metabolites as identified by matrix-assisted laser desorption/ionization (MALDI) imaging included alanine, lactate, leucine, malate, and phenylalanine. CONCLUSIONS: Taken together, we demonstrate the utility of CEST MRI signal changes in superficial cervical LNs as a complementary imaging biomarker for monitoring disease activity in MS. CEST MRI biomarkers corresponded to disease activity, correlated with immune activation (surface markers, antigen-stimulated proliferation), and correlated with LN metabolite levels.

Amyloidogenesis: What Do We Know So Far?

The study of protein aggregation, and amyloidosis in particular, has gained considerable interest in recent times. Several neurodegenerative diseases, such as Alzheimer's (AD) and Parkinson's (PD) show a characteristic buildup of proteinaceous aggregates in several organs, especially the brain. Despite the enormous upsurge in research articles in this arena, it would not be incorrect to say that we still lack a crystal-clear idea surrounding these notorious aggregates. In this review, we attempt to present a holistic picture on protein aggregation and amyloids in particular. Using a chronological order of discoveries, we present the case of amyloids right from the onset of their discovery, various biophysical techniques, including analysis of the structure, the mechanisms and kinetics of the formation of amyloids. We have discussed important questions on whether aggregation and amyloidosis are restricted to a subset of specific proteins or more broadly influenced by the biophysiochemical and cellular environment. The therapeutic strategies and the significant failure rate of drugs in clinical trials pertaining to these neurodegenerative diseases have been also discussed at length. At a time when the COVID-19 pandemic has hit the globe hard, the review also discusses the plausibility of the far-reaching consequences posed by the virus, such as triggering early onset of amyloidosis. Finally, the application(s) of amyloids as useful biomaterials has also been discussed briefly in this review.