Certain gut bacteria may contribute to misfolded proteins and inflammation in neurodegenerative diseases

From U of L School of Medicine News:

Study demonstrates role of gut bacteria in neurodegenerative diseases

Research at UofL funded by The Michael J. Fox Foundation shows proteins produced by gut bacteria may cause misfolding of brain proteins and cerebral inflammation
Study demonstrates role of gut bacteria in neurodegenerative diseases

Robert P. Friedland, M.D.

Alzheimer’s disease (AD), Parkinson’s disease (PD) and Amyotrophic Lateral Sclerosis (ALS) are all characterized by clumped, misfolded proteins and inflammation in the brain. In more than 90 percent of cases, physicians and scientists do not know what causes these processes to occur.

Robert P. Friedland, M.D., the Mason C. and Mary D. Rudd Endowed Chair and Professor of Neurology at the University of Louisville School of Medicine, and a team of researchers have discovered that these processes may be triggered by proteins made by our gut bacteria (the microbiota). Their research has revealed that exposure to bacterial proteins called amyloid that have structural similarity to brain proteins leads to an increase in clumping of the protein alpha-synuclein in the brain. Aggregates, or clumps, of misfolded alpha-synuclein and related amyloid proteins are seen in the brains of patients with the neurodegenerative diseases AD, PD and ALS.

Alpha-synuclein (AS) is a protein normally produced by neurons in the brain. In both PD and AD, alpha-synuclein is aggregated in a clumped form called amyloid, causing damage to neurons. Friedland has hypothesized that similarly clumped proteins produced by bacteria in the gut cause brain proteins to misfold via a mechanism called cross-seeding, leading to the deposition of aggregated brain proteins. He also proposed that amyloid proteins produced by the microbiota cause priming of immune cells in the gut, resulting in enhanced inflammation in the brain.

The research, which was supported by The Michael J. Fox Foundation, involved the administration of bacterial strains of E. coli that produce the bacterial amyloid protein curli to rats. Control animals were given identical bacteria that lacked the ability to make the bacterial amyloid protein. The rats fed the curli-producing organisms showed increased levels of AS in the intestines and the brain and increased cerebral AS aggregation, compared with rats who were exposed to E. coli that did not produce the bacterial amyloid protein. The curli-exposed rats also showed enhanced cerebral inflammation.

Similar findings were noted in a related experiment in which nematodes (Caenorhabditis elegans) that were fed curli-producing E. coli also showed increased levels of AS aggregates, compared with nematodes not exposed to the bacterial amyloid. A research group led by neuroscientist Shu G. Chen, Ph.D., of Case Western Reserve University, performed this collaborative study.

This new understanding of the potential role of gut bacteria in neurodegeneration could bring researchers closer to uncovering the factors responsible for initiating these diseases and ultimately developing preventive and therapeutic measures.

“These new studies in two different animals show that proteins made by bacteria harbored in the gut may be an initiating factor in the disease process of Alzheimer’s disease, Parkinson’s disease and ALS,” Friedland said. “This is important because most cases of these diseases are not caused by genes, and the gut is our most important environmental exposure. In addition, we have many potential therapeutic options to influence the bacterial populations in the nose, mouth and gut.”

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Is inflammation the driving factor in post-concussive syndrome?

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Image retrieved from CraigBrockie.com

From McMaster University News:

It doesn’t take a brain injury to have headache, dizziness and cognitive impairment

Published: May 6, 2015
Michel Rathbone

Michel Rathbone, professor, Department of Medicine

A team of researchers based at McMaster University has developed a new understanding of post-concussion syndrome, answering questions that have been plaguing researchers in the field.

Their study, published in the medical journal Brain, Behavior and Immunity, provides an explanation for why many people with even very trivial head injuries, or even injuries to other parts of their bodies, experience incapacitating post-concussion like syndromes.

These symptoms include headaches, dizziness, cognitive impairment and other neuropsychiatric symptoms such as irritability, anxiety and insomnia.

“It’s inflammation that they have in common,” said Michel Rathbone, a professor of medicine for McMaster’s Michael G. DeGroote School of Medicine and a lead author of the paper. “Rather than a concussion, we’d like to propose a unifying umbrella term of post-inflammatory brain syndromes or PIBS.”

He added that the research will encourage scientists to open up new lines of research into understanding the cause of post-concussion symptoms in the absence of obviously visible brain injury on conventional imaging and into the treatment of these symptoms by targeting inflammatory mediators. For example, people who have a very subtle genetic change in a certain inflammatory protein have poorer recovery after brain injury.

It also explains why many social factors appear to play a role in development of symptoms: “We know that the immune system can be modulated, or sensitized by the current and even the previous environment an individual was in. These social factors, such as preexisting stressors, depression or anxiety, may actually be, in a way, biological factors.”

Rathbone added that this will provide hope for individuals with cognitive dysfunction after major infections, surgeries and traumas, as it suggests that current and future treatments for concussion may hold a benefit for these individuals.

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Upregulation of hydrogen sulfide release by IL-1-beta results in impaired glucose utilization and synaptic damage in injured or diseased brain

From Georgia Regents University and Health System News:

sen-greport

Too much gas, too little food appear major factors in Injury, disease-related memory loss

JANUARY 7, 2015   TONI BAKER

Inflammation plays a role in learning and memory loss that can result from brain Injury or disease, and researchers now have evidence that neurons may be suffering from too much gas and too little food.

They’ve found that the immune cell interleukin 1β, or IL-1β, prompts production of the short-lived gas hydrogen sulfide, impacting the brain cells’ ability to use food and glucose, and ultimately resulting in the destruction of synapses, where the cells connect so information can be stored and memories made.

“So just think about this. If this protein is being chewed up, then neuron-to-neuron communication is disrupted,” says Dr. Nilkantha Sen, neuroscientist at the Medical College of Georgia at Georgia Regents University. “If it continues to happen in your brain or in my brain, our memory will be shut down.”

Sen, corresponding author of the study in the journal Molecular Cell, is referencing damage to the protein PSD95, which is essential to the framework of the synapses that connect brain cells and which gets modified by the gas hydrogen sulfide.

Loss of PSD95 already is implicated in dementia as well as depression, anxiety disorders, and addiction. IL-1β signaling in the brain plays a critical role in learning and memory however, the rapid accumulation that follows injury appears to have the opposite effect.

Two years ago, Sen was among the first to find that, at least in mice, stress, like an injury, upregulates expression of the IL-1β receptor on neurons, and that’s where the trouble begins. Essentially immediately, the activated receptor upregulates another transmitter, hydrogen sulfide, a gas better known for its ability to dilate blood vessels. But, as with IL-1β, at high levels, hydrogen sulfide seems more bent on cell destruction. “It is maintained at a threshold level in every tissue of our body,” Sen says. “But when it increases, it produces adverse reactions.”

In this case, hydrogen sulfide modifies GAPDH, an enzyme essential to the brain cell’s ability to use its major food source, glucose. The modified GAPDH then binds with Siah, a protein important to the body’s ability to degrade improperly folded proteins. In this situation, Siah binds to and degrades PSD95, a molecule essential to the scaffolding of the synapses. Sen and his colleagues write that Siah’s attack on PSD95 may be considered a general mechanism for inflammation-associated synaptic and memory damage.

“It kills a very important protein for synaptic plasticity,” Sen says. “This is a completely novel mechanism,” that he hopes will one day translate to a novel therapy for several neurodegenerative disorders as well as brain injury by targeting modified GAPDH.

The researchers also found that PSD95 was better protected in mice missing CBS, the enzyme that synthesizes hydrogen sulfide, as well as in neurons missing CBS or the receptor for IL-1β. Mice missing CBS also experienced significantly less synaptic destruction and resulting memory impairment.

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Cytokine release in hippocampus disrupts discrimination learning

From UCI News:

Press Release

  • September 10, 2014

In their study, UCI neurobiologists Jennifer Czerniawski and John Guzowski show for the first time a link among immune system activation, altered neural circuit function and impaired discrimination memory.

Brain inflammation dramatically disrupts memory retrieval networks, UCI study finds

Research sheds light on cognitive losses seen with chemotherapy, autoimmune diseases

Irvine, Calif., Sept. 10, 2014 — Brain inflammation can rapidly disrupt our ability to retrieve complex memories of similar but distinct experiences, according to UC Irvine neuroscientists Jennifer Czerniawski and John Guzowski.

Their study – which appears today in The Journal of Neuroscience – specifically identifies how immune system signaling molecules, called cytokines, impair communication among neurons in the hippocampus, an area of the brain critical for discrimination memory. The findings offer insight into why cognitive deficits occurs in people undergoing chemotherapy and those with autoimmune or neurodegenerative diseases.

Moreover, since cytokines are elevated in the brain in each of these conditions, the work suggests potential therapeutic targets to alleviate memory problems in these patients.

“Our research provides the first link among immune system activation, altered neural circuit function and impaired discrimination memory,” said Guzowski, the James L. McGaugh Chair in the Neurobiology of Learning & Memory. “The implications may be beneficial for those who have chronic diseases, such as multiple sclerosis, in which memory loss occurs and even for cancer patients.”

What he found interesting is that increased cytokine levels in the hippocampus only affected complex discrimination memory, the type that lets us differentiate among generally similar experiences – what we did at work or ate at dinner, for example. A simpler form of memory processed by the hippocampus – which would be akin to remembering where you work – was not altered by brain inflammation.

In the study, Czerniawski, a UCI postdoctoral scholar, exposed rats to two similar but discernable environments over several days. They received a mild foot shock daily in one, making them apprehensive about entering that specific site. Once the rodents showed that they had learned the difference between the two environments, some were given a low dose of a bacterial agent to induce a neuroinflammatory response, leading to cytokine release in the brain. Those animals were then no longer able to distinguish between the two environments.

Afterward, the researchers explored the activity patterns of neurons – the primary cell type for information processing – in the rats’ hippocampi using a gene-based cellular imaging method developed in the Guzowski lab. In the rodents that received the bacterial agent (and exhibited memory deterioration), the networks of neurons activated in the two environments were very similar, unlike those in the animals not given the agent (whose memories remained strong). This finding suggests that cytokines impaired recall by disrupting the function of these specific neuron circuits in the hippocampus.

“The cytokines caused the neural network to react as if no learning had taken place,” said Guzowski, associate professor of neurobiology & behavior. “The neural circuit activity was back to the pattern seen before learning.”

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