An Enzyme Made by the COVID-19 Virus Can Destroy Brain Blood Vessels

Post by D. Chloe Chung

The takeaway

The COVID-19 virus produces a protein enzyme. This enzyme can damage blood vessels in the brain by  NEMO, a protein essential for the survival of brain endothelial cells (i.e. cells lining blood vessels).

What's the science?

Many COVID-19 patients report experiencing a wide range of neurological and psychiatric symptoms. Several studies have found that blood vessels and the blood-brain barrier can be disrupted in the brain of COVID-19 patients. Yet, it was unclear how blood vessels in the brain can be damaged due to infection with SARS-CoV-2, the virus that causes COVID-19. Recently in Nature Neuroscience, Wenzel and colleagues demonstrated how a major enzyme produced by the COVID-19 virus can kill endothelial cells and destroy blood vessels in the brain.

How did they do it?

The authors first determined the degree of brain blood vessel pathology induced by COVID-19 by staining brain tissue of people who passed away from COVID-19 with antibodies against endothelial cell markers and collagen. They defined thin tubes of collagen without the endothelial cell marker as damaged blood vessels. The authors performed a similar analysis using brain samples of mouse and hamster models infected with the COVID-19 virus. To determine whether protein-cleaving enzymes made by the COVID-19 virus can be the culprit of blood vessel damage, the authors incubated the purified enzyme with a protein called NEMO that is essential for host cell immune response. They also tested whether the enzyme can subsequently affect the brain endothelial cell survival as well as inflammatory pathways downstream of NEMO. Using a conditional knockout mouse model, the author directly manipulated NEMO in the brain’s endothelial cells to examine if it is sufficient to induce vascular pathology in the brain. The authors also used this mouse model to further investigate potential therapeutic strategies against the vascular pathology in COVID-19 by genetically deleting or pharmacologically inhibiting kinases important in cell survival.

What did they find?

First, the authors found that the brain tissue from COVID-19 patients contained more “string vessels,” which are capillaries remaining after the death of blood vessels, compared to control brain tissue. String vessels were also increased in animal models of COVID-19, suggesting that COVID-19 can induce microvascular pathology in the brain. Next, the authors found that the enzyme (termed Mpro) made by the COVID-19 virus can cleave NEMO, a protein critical for the survival of brain endothelial cells. Mpro was found to not only chop off NEMO but also impair inflammatory responses downstream of NEMO. Interestingly, the authors learned that endothelial cells expressing this enzyme are more likely to die than cells without it, which suggests that Mpro can indeed induce endothelial cell death. Importantly, this effect was absent when Mpro was mutated to lose its protein-cleaving ability.  These findings show that the enzymatic activity of Mpro is critical for cell death and vascular pathology. 

What's the impact?

This study has suggested one of the potential mechanisms through which the COVID-19 virus can damage the brain — which could potentially contribute to the neurological symptoms seen in COVID-19 patients. Notably, this work is the first to evaluate vascular pathology in the brain based on the presence of string vessels. Future investigation into ways to protect brain blood vessels may help alleviate or prevent neurological issues in COVID-19 patients.

The Brain Adjusts Coding Precision To Save Energy

Post by Leanna Kalinowski

The takeaway

During times in which access to food is limited, the brain must conserve energy by reducing information processing. Neurons in the visual cortex conserve energy following food restriction by decreasing the coding precision of visual information.

What's the science?

The brain uses considerable energy when processing information from the world around us. In general, it consumes 20% of the body’s total caloric intake while only constituting around 2% of the body’s total mass. Given the high energy cost of neural processing, coupled with limited energy resources, the brain is thought to have evolved an energy-efficient strategy that maximizes the amount of information transmission per unit of energy used (i.e., ATP, the main source of energy for cells). During times of food scarcity, it is believed that neuronal networks in the brain conserve energy by reducing information processing. While there is evidence that suggests this is likely the case in invertebrates, it is unclear how the mammalian brain regulates information processing and energy use when access to food is limited. This week in Neuron, Padamsey and colleagues used the mouse primary visual cortex as a model system to examine how food restriction affects information processing and energy consumption in neuronal networks.

How did they do it?

Adult male mice were separated into one of two groups: a control group, where they were given unrestricted access to food, and a food-restricted group, where they were given limited access to food that led to a 15% reduction in body weight over 2-3 weeks. First, the researchers examined ATP use in the primary visual cortex by taking whole-cell voltage-clamp recordings of neurons in this brain region while exposing mice to videos of the outdoors (i.e., a natural setting). These recordings measured excitatory currents, (indicative of neural activity in the visual cortex), which pose the greatest ATP burden on the cortex. Next, the researchers measured visual cortex activity using two-photon calcium imaging during a coding precision task. In this environment, mice were shown videos of the outdoors or their home cage, and the researchers applied a maximum likelihood decoder to record neuronal activity to determine how well distinct visual stimuli were encoded in the brain of food-restricted mice. The authors also tested visual discrimination behaviourally using a two-alternative, forced-choice task. Finally, the researchers examined the role of the hormone leptin in information processing and energy use. They did this by (1) measuring serum leptin levels in control vs food-restricted mice and (2) delivering synthetic leptin for 10 days and re-assessing the coding precision task.

What did they find?

First, the researchers found that mouse visual cortex neurons save ATP use by decreasing excitatory postsynaptic currents through a reduction in AMPA receptor conductance. The ATP use associated with these currents was reduced by 29% in food-restricted mice compared to controls, while the rate of neuronal spiking remained similar between the two groups owing to compensatory changes in neuronal input resistance and resting potential. Next, they found that ATP savings were accompanied by a reduction in decoding accuracy and visual discrimination ability in the food-restricted mice, decoding of similar scenes from the same environment was impaired in the food-restricted mice. Taken together, these results demonstrate that when food is scarce, neurons reduce ATP utilization on synaptic currents at the expense of coding precision. Finally, they found that this reduction in coding precision was associated with reduced levels of the hormone leptin, and was reversed following administration of synthetic leptin.

What's the impact?

This study is the first to show that, in times of food scarcity, coding precision in the mammalian visual cortex is reduced in order to save energy. This suggests that the brain is able to dynamically adapt coding precision and energy use in a context-dependent manner, which is overall beneficial to survival. Further work is needed to understand the full impact of food restriction on total brain energy use and information processing, particularly in other cell types and brain regions.

The Role of the Immune System in Neurodegeneration

Post by Andrew Vo

The takeaway

The immune system plays a potential role in neurodegenerative diseases, such as Lewy body dementia. The mechanism by which an inflammatory response is trafficked to the brains of these patients might be a potential therapeutic target.

What's the science?

Lewy body dementia (LBD) is distinguished by the abnormal accumulation of α-synuclein protein in the brain, leading to changes in the memory and behavior of these patients. Animal studies have suggested a role of the immune system in LBD, although the mechanism by which T cells (specialized cells in our bodies that identify and attack substances with foreign “antigens” or markers) migrate and function in the brain remains unknown. This week in Science, Gate et al. examine biological samples collected from living and postmortem patients to investigate the relationship between immunity-related T cells and LBD pathology. 

How did they do it?

The authors first compared cognitive function and cerebrospinal fluid (CSF) levels of neurofilament light chain (a protein marker of neurodegeneration) in LBD patients and healthy controls. To directly test if the immune system interacted with LDB pathology, they then examined postmortem brains of LBD patients for T cell localization with α-synuclein accumulation. Next, they used sequencing analyses to measure T cell binding molecules, namely CXCR4 and CXCL12, in the CSF and meninges (protective membranes inside the skull and surrounding the brain) of LBD patients. Finally, they measured T cell immune activation in CSF samples from LBD patients through stimulation with a pool of peptide proteins derived from α-synuclein.

What did they find?

DLB patients were found to have reduced cognitive function and increased neurofilament light chain levels in their CSF. Examining postmortem brains, T cells were observed to be localized next to α-synuclein deposits and were mostly concentrated near the substantia nigra (a brain region containing dopamine neurons that degenerate in Parkinson’s disease) in LBD patients. This demonstrated a link between the immune system and brain pathology in LBD.

Sequencing of T cells in the CSF revealed greater expression of CXCR4 and CXCL12 markers in LBD patients compared to controls. A similar pattern was found in the meninges of LBD patients and specifically localized to the brain’s vasculature (or blood supply). Increased CXCL12 levels measured in CSF were related to lower cognitive function and higher neurofilament light chain levels. Together, these results show that increased CXCR4-CXCL12 signaling is associated with neurodegeneration in LBD.

Before stimulation with a peptide pool containing proteins derived from α-synuclein, T cells in the CSF showed greater baseline activation in LBD patients versus controls. This immune activation was further enhanced following peptide stimulation. Sequencing of these stimulated cells showed increased expression of interleukin 17A, which is related to inflammatory responses mediated by TH17 cells. Examining postmortem brains, they found T cells localized near TH17 cells in the substantia nigra of LBD patients. These findings suggest the involvement of TH17 cells and immunoreactivity in LBD neurodegeneration. 

What's the impact?

In summary, this study demonstrated a link between the immune system, specifically CXCR4-CXCL12 signaling that recruits T cells to the brain, and neurodegeneration in LBD. The authors highlight a pathological mechanism in human patients that was previously only established in animal models of neurodegeneration. This signaling mechanism may be a potential therapeutic target for the treatment of LBD.

Access the original scientific publication here.