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1.
Nat Commun ; 12(1): 5739, 2021 10 19.
Article in English | MEDLINE | ID: covidwho-1475293

ABSTRACT

Protein aggregates associated with neurodegenerative diseases have the ability to transmit to unaffected cells, thereby templating their own aberrant conformation onto soluble homotypic proteins. Proteopathic seeds can be released into the extracellular space, secreted in association with extracellular vesicles (EV) or exchanged by direct cell-to-cell contact. The extent to which each of these pathways contribute to the prion-like spreading of protein misfolding is unclear. Exchange of cellular cargo by both direct cell contact or via EV depends on receptor-ligand interactions. We hypothesized that enabling these interactions through viral ligands enhances intercellular proteopathic seed transmission. Using different cellular models propagating prions or pathogenic Tau aggregates, we demonstrate that vesicular stomatitis virus glycoprotein and SARS-CoV-2 spike S increase aggregate induction by cell contact or ligand-decorated EV. Thus, receptor-ligand interactions are important determinants of intercellular aggregate dissemination. Our data raise the possibility that viral infections contribute to proteopathic seed spreading by facilitating intercellular cargo transfer.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Extracellular Vesicles/metabolism , Membrane Glycoproteins/metabolism , Protein Aggregation, Pathological/virology , Spike Glycoprotein, Coronavirus/metabolism , Viral Envelope Proteins/metabolism , Adult , Aged , Brain/pathology , Case-Control Studies , Cell Line , Endocytosis , Female , Humans , Intravital Microscopy , Male , Middle Aged , Prions/metabolism , Protein Aggregation, Pathological/pathology , Protein Folding , tau Proteins/metabolism
2.
Med Sci Monit ; 27: e934077, 2021 Jul 26.
Article in English | MEDLINE | ID: covidwho-1326004

ABSTRACT

Current treatments for patients with Alzheimer's disease aim to improve behavioral, cognitive, and non-cognitive symptoms. There have been no new drug approvals for preventing or treating Alzheimer's disease for more than two decades. Drug development in Alzheimer's disease aims to identify disease-modifying therapies that will delay or slow the clinical course of this disease. More than 50% of the current Alzheimer's disease drug pipeline now involves immunotherapies or oral small molecule agents. The most promising disease-modifying drug targets are amyloid ß and tau protein. In June 2021, aducanumab, a humanized recombinant monoclonal antibody to amyloid ß, was the first potential disease-modifying therapy approved by the US Food and Drug Administration (FDA) to treat Alzheimer's disease and mild cognitive impairment. Accelerated approval of aducanumab was based on the results of only one of two phase 3 clinical trials. Several clinical trials of targeted disease-modifying immunotherapies to the tau protein and amyloid ß that commenced before the current COVID-19 pandemic have been delayed. This Editorial aims to provide an update on past, present, and future disease-modifying therapies in Alzheimer's disease, including targeted therapies for amyloid ß and tau protein.


Subject(s)
Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , tau Proteins/metabolism , Antibodies, Monoclonal, Humanized/therapeutic use , Cognitive Dysfunction/drug therapy , Cognitive Dysfunction/immunology , Humans , Immunotherapy/methods , Immunotherapy/trends , Tauopathies/drug therapy
3.
Biochem Biophys Res Commun ; 554: 94-98, 2021 05 21.
Article in English | MEDLINE | ID: covidwho-1157142

ABSTRACT

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.


Subject(s)
Amyloid/metabolism , COVID-19/metabolism , Heparin/metabolism , Neurodegenerative Diseases/metabolism , Protein Aggregation, Pathological , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/metabolism , Amyloid beta-Peptides/metabolism , Brain/metabolism , Brain/pathology , Brain/virology , COVID-19/virology , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/metabolism , Humans , Molecular Docking Simulation , Neurodegenerative Diseases/virology , Prions/metabolism , Protein Binding , SARS-CoV-2/chemistry , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , alpha-Synuclein/metabolism , tau Proteins/metabolism
4.
EMBO J ; 40(2): e107213, 2021 01 15.
Article in English | MEDLINE | ID: covidwho-1068058

ABSTRACT

COVID-19 is increasingly understood as a systemic disease with pathogenic manifestations beyond the respiratory tract. Recent work by Ramani et al (2020) dissects the cellular and molecular mechanisms of SARS-CoV-2's neurotrophic properties, using viral exposure of human brain organoids. Their findings highlight neurons as primary target of cerebral SARS-CoV-2 infection and uncover its Tau-related neurotoxicity.


Subject(s)
Brain/pathology , Brain/virology , COVID-19/pathology , Organoids/pathology , tau Proteins/metabolism , Humans , Neurons/pathology , Neurons/virology , Organoids/virology , SARS-CoV-2/pathogenicity
6.
EMBO J ; 39(20): e106230, 2020 10 15.
Article in English | MEDLINE | ID: covidwho-740598

ABSTRACT

COVID-19 pandemic caused by SARS-CoV-2 infection is a public health emergency. COVID-19 typically exhibits respiratory illness. Unexpectedly, emerging clinical reports indicate that neurological symptoms continue to rise, suggesting detrimental effects of SARS-CoV-2 on the central nervous system (CNS). Here, we show that a Düsseldorf isolate of SARS-CoV-2 enters 3D human brain organoids within 2 days of exposure. We identified that SARS-CoV-2 preferably targets neurons of brain organoids. Imaging neurons of organoids reveal that SARS-CoV-2 exposure is associated with altered distribution of Tau from axons to soma, hyperphosphorylation, and apparent neuronal death. Our studies, therefore, provide initial insights into the potential neurotoxic effect of SARS-CoV-2 and emphasize that brain organoids could model CNS pathologies of COVID-19.


Subject(s)
Betacoronavirus/physiology , Brain/virology , Neurons/virology , Animals , Cell Death , Chlorocebus aethiops , Humans , Nervous System Diseases/virology , Organoids , SARS-CoV-2 , Vero Cells , tau Proteins/metabolism
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