scholarly journals SARS-CoV-2 Spike Protein Induces Cognitive Deficit and Anxiety-like Behavior in Mouse via Non-cell Autonomous Hippocampal Neuronal Death

2022 ◽  
Author(s):  
Sung Joong Lee ◽  
Jun Young Oh ◽  
Woo-Hyun Cho ◽  
Barcelon Ellane ◽  
Kwang Hwan Kim ◽  
...  
Keyword(s):  
Cell Death ◽  
Glial Cell ◽  
Neuronal Death ◽  
Cell Activation ◽  
Cognitive Deficit ◽  
Neuronal Cell ◽  
Neurological Symptoms ◽  
Spike Protein ◽  
Glial Cell Activation ◽  
The Brain

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is accompanied by chronic neurological sequelae such as cognitive decline and mood disorder, but the underlying mechanisms have not yet been elucidated. In this study, we explored the possibility that the brain-infiltrating SARS-CoV-2 spike protein contributes to the development of neurological symptoms observed in COVID-19 patients. Our behavioral study showed that administration of SARS-CoV-2 spike protein S1 subunit (S1 protein) to mouse hippocampus induced cognitive deficit and anxiety-like behavior in vivo. These neurological symptoms were accompanied by neuronal cell death in the dorsal and ventral hippocampus as well as glial cell activation. Interestingly, the S1 protein did not directly induce hippocampal cell death in vitro. Rather, it exerted neurotoxicity via glial cell activation, partially through interleukin-1β induction. In conclusion, our data suggest a novel pathogenic mechanism for the COVID-19-associated neurological symptoms that involves glia activation and non-cell autonomous hippocampal neuronal death by the brain-infiltrating S1 protein.

scholarly journals Neuroimaging of translocator protein in patients with systemic lupus erythematosus: a pilot study using [11C]DPA-713 positron emission tomography

Lupus ◽  
2016 ◽  
Vol 26 (2) ◽  
pp. 170-178 ◽  
Author(s):  
Yuchuan Wang ◽  
Jennifer M Coughlin ◽  
Shuangchao Ma ◽  
Christopher J Endres ◽  
Michael Kassiou ◽  
...  
Keyword(s):  
Glial Cell ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
Translocator Protein ◽  
Emission Tomography ◽  
Cognitively Impaired ◽  
Healthy Controls ◽  
Glial Cell Activation ◽  
Positron Emission ◽  
The Brain

Objective Inflammation secondary to autoantibody-mediated effects occurring in multiple organs is a hallmark of systemic lupus erythematosus (SLE). The inflammatory response to SLE-mediated damage in brain parenchyma has been postulated in both normal and cognitively impaired individuals. Our goal is to use molecular imaging to investigate the distribution within the brain of the mitochondrial translocator protein (TSPO) that is upregulated during glial cell activation, and is considered as a marker of brain injury and repair. Methods We sought to characterize TSPO distribution in the brain of SLE patients using positron emission tomography (PET) and [11C]DPA-713 (DPA), a radiopharmaceutical that targets TSPO. We imaged 11 healthy controls and 10 patients with SLE (years of diagnosis: 13.0 ± 7.7), all between the ages of 22 and 52. Results: Among the nine brain regions studied, no statistically significant increases in DPA binding were observed in SLE. Instead, there was a significant decrease in TSPO distribution in the cerebellum and hippocampus of SLE patients, as compared to healthy controls. Such decreases were most significant in cognitively normal SLE subjects, but showed pseudo-normalization in those with cognitive impairment, due to higher cerebellar and hippocampal DPA binding in the cognitively impaired (versus normal) SLE brain. Conclusions Results from this pilot study suggest a link between diminished regional TSPO expression in the brain of patients with SLE, as well as possible glial cell activation within the cerebellum and hippocampus of cognitively impaired individuals with SLE. Further studies are needed to elucidate how mitochondrial dysfunction and glial cell activation may act together in SLE and SLE-mediated neurocognitive deficits.

Toll-like receptor 2 contributes to glial cell activation and heme oxygenase-1 expression in traumatic brain injury

2008 ◽  
Vol 431 (2) ◽  
pp. 123-128 ◽  
Author(s):  
Chanhee Park ◽  
Ik-Hyun Cho ◽  
Donghoon Kim ◽  
Eun-Kyeong Jo ◽  
Se-Young Choi ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Glial Cell ◽  
Heme Oxygenase ◽  
Cell Activation ◽  
Heme Oxygenase 1 ◽  
Toll Like Receptor ◽  
Glial Cell Activation ◽  
Toll Like Receptor 2

scholarly journals Neuronal apoptosis: signal and cell diversity

1969 ◽  
Vol 40 (1) ◽  
pp. 124-133
Author(s):  
Lina Vanessa Becerra ◽  
Hernán José Pimienta
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Neuronal Response ◽  
Neuronal Cell ◽  
Cell Types ◽  
Point Of View ◽  
Trophic Factors ◽  
Cell Diversity ◽  
Apoptotic Pathways ◽  
The Brain

Programmed cell death occurs as a physiological process during development. In the brain and spinal cord this event determines the number and location of the different cell types. In adulthood, programmed cell death or apoptosis is more restricted but it may play a major role in different acute and chronic pathological entities. However, in contrast to other tissues where apoptosis has been widely documented from a morphological point of view, in the central nervous system complete anatomical evidence of apoptosis is scanty. In spite of this there is consensus about the activation of different signal systems associated to programmed cell death. In the present article we attempt to summarize the main apoptotic pathways so far identified in nervous tissue. Considering that apoptotic pathways are multiple, the neuronal cell types are highly diverse and specialized and that neuronal response to injury and survival depends upon tissue context, (i.e., preservation of connectivity, glial integrity and cell matrix, blood supply and trophic factors availability) what is relevant for the apoptotic process in a sector of the brain may not be important in another.

scholarly journals Induction of the Nrf2 Pathway by Sulforaphane Is Neuroprotective in a Rat Temporal Lobe Epilepsy Model

Antioxidants ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1702
Author(s):  
Sereen Sandouka ◽  
Tawfeeq Shekh-Ahmad
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Status Epilepticus ◽  
Temporal Lobe Epilepsy ◽  
Antioxidant Capacity ◽  
Temporal Lobe ◽  
Epileptiform Activity ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
The Brain

Epilepsy is a chronic disease of the brain that affects over 65 million people worldwide. Acquired epilepsy is initiated by neurological insults, such as status epilepticus, which can result in the generation of ROS and induction of oxidative stress. Suppressing oxidative stress by upregulation of the transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) has been shown to be an effective strategy to increase endogenous antioxidant defences, including in brain diseases, and can ameliorate neuronal damage and seizure occurrence in epilepsy. Here, we aim to test the neuroprotective potential of a naturally occurring Nrf2 activator sulforaphane, in in vitro epileptiform activity model and a temporal lobe epilepsy rat model. Sulforaphane significantly decreased ROS generation during epileptiform activity, restored glutathione levels, and prevented seizure-like activity-induced neuronal cell death. When given to rats after 2 h of kainic acid-induced status epilepticus, sulforaphane significantly increased the expression of Nrf2 and related antioxidant genes, improved oxidative stress markers, and increased the total antioxidant capacity in both the plasma and hippocampus. In addition, sulforaphane significantly decreased status epilepticus-induced neuronal cell death. Our results demonstrate that Nrf2 activation following an insult to the brain exerts a neuroprotective effect by reducing neuronal death, increasing the antioxidant capacity, and thus may also modify epilepsy development.

scholarly journals Investigating the convergent mechanisms between Major Depressive Disorder and Parkinson’s disease

2020 ◽  
Author(s):  
Angela A Tran ◽  
Myra De Smet ◽  
Gary D. Grant ◽  
Tien K. Khoo ◽  
Dean L Pountney
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Cell Activation ◽  
Glutamate Excitotoxicity ◽  
Major Depressive ◽  
Glial Cell Activation ◽  
Underlying Mechanisms ◽  
The Brain

Major depressive disorder (MDD) affects more than cognition, having a temporal relationship with neuroinflammatory pathways of Parkinson’s disease (PD). Although this association is supported by epidemiological and clinical studies, the underlying mechanisms are unclear. Microglia and astrocytes play crucial roles in the pathophysiology of both MDD and PD. In PD, these cells can be activated by misfolded forms of the protein α-synuclein to release cytokines that can interact with multiple different physiological processes to produce depressive symptoms, including monoamine transport and availability, the hypothalamus-pituitary axis, and neurogenesis. In MDD, glial cell activation can be induced by peripheral inflammatory agents that cross the blood brain barrier and/or c-Fos signaling from neurons. The resulting neuroinflammation can cause neurodegeneration due to oxidative stress and glutamate excitotoxicity, contributing to PD pathology. Astrocytes are another major link due to their recognised role in the glymphatic clearance mechanism. Research suggesting that MDD causes astrocytic destruction or structural atrophy highlight the possibility that accumulation of α-synuclein in the brain is facilitated as the brain cannot adequately clear the protein aggregates. This review examines research into the overlapping pathophysiology of MDD and PD with particular focus on the roles of glial cells and neuroinflammation.

scholarly journals Neuroinflammation and glial cell activation in mental disorders

2020 ◽  
Vol 2 ◽  
pp. 100034 ◽  
Author(s):  
Priscila G.C. Almeida ◽  
João Victor Nani ◽  
Jean Pierre Oses ◽  
Elisa Brietzke ◽  
Mirian A.F. Hayashi
Keyword(s):  
Mental Disorders ◽  
Glial Cell ◽  
Cell Activation ◽  
Glial Cell Activation

scholarly journals Proneurotrophins Induce Apoptotic Neuronal Death After Controlled Cortical Impact Injury in Adult Mice

ASN NEURO ◽  
2020 ◽  
Vol 12 ◽  
pp. 175909142093086
Author(s):  
Laura E. Montroull ◽  
Deborah E. Rothbard ◽  
Hur D. Kanal ◽  
Veera D’Mello ◽  
Vincent Dodson ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Cell Death ◽  
Brain Injury ◽  
Neuronal Death ◽  
Apoptotic Cell ◽  
Neuronal Cell ◽  
Adult Brain ◽  
Neurotrophin Receptor ◽  
Cortical Impact ◽  
Impact Injury

The p75 neurotrophin receptor (p75NTR) can regulate multiple cellular functions including proliferation, survival, and apoptotic cell death. The p75NTR is widely expressed in the developing brain and is downregulated as the nervous system matures, with only a few neuronal subpopulations retaining expression into adulthood. However, p75NTR expression is induced following damage to the adult brain, including after traumatic brain injury, which is a leading cause of mortality and disability worldwide. A major consequence of traumatic brain injury is the progressive neuronal loss that continues secondary to the initial trauma, which ultimately contributes to cognitive decline. Understanding mechanisms governing this progressive neuronal death is key to developing targeted therapeutic strategies to provide neuroprotection and salvage cognitive function. In this study, we demonstrate that a cortical impact injury to the sensorimotor cortex elicits p75NTR expression in apoptotic neurons in the injury penumbra, confirming previous studies. To establish whether preventing p75NTR induction or blocking the ligands would reduce the extent of secondary neuronal cell death, we used a noninvasive intranasal strategy to deliver either siRNA to block the induction of p75NTR, or function-blocking antibodies to the ligands pro-nerve growth factor and pro-brain-derived neurotrophic factor. We demonstrate that either preventing the induction of p75NTR or blocking the proneurotrophin ligands provides neuroprotection and preserves sensorimotor function.

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