Update on SIV remission studies

Recently presented insights on how an antibody used to treat intestinal diseases can suppress Read more

Granulins treasure not trash - potential FTD treatment strategy

Granulins are of interest to neuroscientists because mutations in the granulin gene cause frontotemporal dementia (FTD). However, the functions of granulins were previously Read more

Blood vessels and cardiac muscle cells off the shelf

How to steer induced pluripotent stem cells into becoming endothelial cells, which line blood Read more

inflammation

Opioid abuse medicine can control genetic skin disease

Evidence is emerging that naltrexone, a medicine used to treat opioid and alcohol abuse, can also control a genetic skin disease that causes painful, itchy rashes and blisters.

Two separate brief reports last week in JAMA Dermatology, from Emory and Cleveland Clinic investigators, describe the treatment of six patients with Hailey-Hailey disease.

Dermatologist Ron Feldman, MD, PhD is the senior author on the Emory report, which says:

“Low-dose naltrexone has been widely touted on social media platforms, including multiple YouTube videos, as an anecdotal treatment for patients with HHD, with surprisingly no published evidence until this year.”

Feldman tells Lab Land: “We decided to try it based on the patients; we had no clue about low-dose naltrexone until we met one of the patients with Hailey-Hailey disease, who came in asking for this therapy based on social media.”

At Emory, each of the three patients had tried at least four prior treatments, such as antibiotics and corticosteroids, but all were unsuccessful in controlling the disease. Read more

Posted on by Quinn Eastman in Immunology Leave a comment

Drug discovery: selective anti-inflammatory approach to AD

Anyone familiar with Alzheimer’s disease research can say what a challenge drug development has been. In Emory’s Department of Pharmacology, Thota Ganesh is focusing on an anti-inflammatory approach. Ganesh’s work has been supported by the Alzheimer’s Drug Discovery Foundation and more recently by a five-year, $3.6 million grant from the National Institute on Aging.

Medicinal chemist Thota Ganesh, PhD, is focusing on an anti-inflammatory approach to Alzheimer’s disease, targeting the prostaglandin receptor EP2.

An assistant professor at Emory since 2011, he is continuing research he undertook with Ray Dingledine on EP2 antagonists. In animals, they showed that this class of compounds could reduce injury to the brain after a prolonged seizure. Since then, they have shown that EP2 antagonists have similar effects in protecting against organophosphate pesticides/nerve agents.

EP2 is one of the four receptors for prostaglandin E2, a hormone involved in processes such as fever, childbirth, digestion and blood pressure regulation. Before Ganesh and colleagues from the Emory Chemical Biology Discovery Center started looking for them, chemicals that could block EP2 selectively were not available.

Their idea is: blocking EP2 is a better strategy than the more general approach of going after prostaglandins, the targets for non-steroid anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen and celecoxib (Celebrex). Read more

Posted on by Quinn Eastman in Neuro Leave a comment

Emory neuro-researchers in Alzforum

Just a shoutout regarding Emory folks in Alzforum, the research news site focusing on Alzheimer’s and other neurodegenerative disorders.

Alzforum recently highlighted proteomics wizard Nick Seyfried’s presentation at a June meeting in Germany (Alzheimer’s Proteomics Treasure Trove). This includes work from the Emory ADRC and Baltimore Longitudinal Study of Aging that was published in Cell Systems in December: the first large-scale systems biology analysis of post-mortem brain proteins in Alzheimer’s. The idea is to have a fresh “unbiased” look at proteins involved in Alzheimer’s.

Also, neuroscientists Malu Tansey and Tom Kukar have been teaming up to provide detailed comments on papers being reported in Alzforum. Here’s one on inflammation related to gene alterations in frontotemporal dementia, and another on auto-immune responses in Parkinson’s.

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Anti-TNF vs Alzheimer’s mouse model

An experimental anti-inflammatory drug has positive effects on neuron function and amyloid plaques in a mouse model of Alzheimer’s disease, Emory neuroscientists report. The findings are published in the journal Neurobiology of Disease.

Inflammation’s presence in Alzheimer’s is well established, but it is usually thought of as an accelerator, rather than an initiating cause. While everybody argues about the amyloid hypothesis, there’s a case to be made for intervening against the inflammation. Exactly how is an open question.

The drug tested, called XPro1595, targets the inflammatory signaling molecule tumor necrosis factor (TNF). Commercialized drugs such as etanercept and infliximab, used to treat autoimmune diseases, also block TNF. However, XPro1595 only interferes with the soluble form of TNF and is supposed to have less of an effect on overall immune function.

Senior author Malu Tansey (pictured) and her colleagues say that interfering with TNF could have direct effects on neurons, as well as indirect effects on the immune cells infiltrating the brain. They write that “the most promising finding in our study” is the ability of XPro1595 to restore long-term potentiation or LTP, which is impaired in the Alzheimer’s model mice. Read more

Posted on by Quinn Eastman in Immunology, Neuro Leave a comment

Breath test for Parkinson’s?

Using one to see into the other. Left: canister for breath sample. Right: basal ganglia, a region of the brain usually affected by Parkinson’s.

Scientists think that it may be possible to detect signs of Parkinson’s disease through a breath test.

The Michael J. Fox Foundation for Parkinson’s Research is supporting a clinical study at Emory that will probe this idea. Neuro-immunologist Malu Tansey is working with Hygieia, a Georgia-based company that has developed technology for analyzing volatile organic compounds present in exhaled air.

From the MJFF’s blog:

By collecting and analyzing breath samples in 100 people (50 non-smoking early-stage PD patients and 50 age and sex-matched controls), the researchers hope to define a unique inflammatory PD-specific breath fingerprint that could be used to predict and monitor disease in combination with blood analyses of conventional or newly discovered biomarkers.

“We hypothesize that breath volatile organic compounds (BVOCs) fingerprinting can enable sensitive and specific measures of ongoing inflammation and other processes implicated in the development and/or progression of PD, and thus could represent an early detection tool,” Tansey says.

If results indicate moving forward, Tansey says it will be important to compare the breath sample method against blood tests for inflammatory markers. Other reports on the breath test approach for Parkinson’s have been encouraging. Read more

Posted on by Quinn Eastman in Neuro 1 Comment

Insane in the membrane – inflamed in the brain

Inflammation in the brain is a feature of several neurological diseases, ranging from Parkinson’s and Alzheimer’s to epilepsy. Nick Varvel, a postdoc with Ray Dingledine’s lab at Emory, was recently presenting his research and showed some photos illustrating the phenomenon of brain inflammation in status epilepticus (prolonged life-threatening seizures).

The presentation was at a Center for Neurodegenerative Disease seminar; his research was also published in PNAS and at the 2016 Society for Neuroscience meeting.green-red-brain

Varvel was working with mice in which two different types of cells are marked by fluorescent proteins. Both of the cell types come originally from the blood and can be considered immune cells. However, one kind – marked with green — is in the brain all the time, and the red kind enters the brain only when there is an inflammatory breach of the blood brain barrier.

Both markers, CX3CR1 (green) and CCR2 (red), are chemokine receptors. Green fluorescent protein is selectively produced in microglia, which settle in the brain before birth and are thought to have important housekeeping/maintenance functions.

Monocytes, a distinct type of cell that is not usually in the brain in large numbers, are lit up red. Monocytes rush into the brain in status epilepticus, and in traumatic brain injury, hemorrhagic stroke and West Nile virus encephalitis, to name some other conditions where brain inflammation is also seen.

In the PNAS paper, Varvel and his colleagues include a cautionary note about using these mice for studying situations of more prolonged brain inflammation, such as neurodegenerative diseases: the monocytes may turn down production of the red protein over time, so it’s hard to tell if they’re still in the brain after several days.

Targeting CCR2 – good or bad? Depends on the disease model

The researchers make the case that “inhibiting brain invasion of CCR2+ monocytes could represent a viable method for alleviating several deleterious consequences of status epilepticus.” Read more

Posted on by Quinn Eastman in Immunology, Neuro Leave a comment

How metabolic syndrome interacts with stress – mouse model

Emory researchers recently published a paper in Brain, Behavior and Immunity on the interaction between psychological stress and diet-induced metabolic syndrome in a mouse model.

“The metabolic vulnerability and inflammation associated with conditions present in metabolic syndrome may share common risk factors with mood disorders. In particular, an increased inflammatory state is recognized to be one of the main mechanisms promoting depression,” writes lead author Betty Rodrigues, a postdoc in Malu Tansey’s lab in the Department of Physiology.

This model may be useful for identification of possible biomarkers and therapeutic targets to treat metabolic syndrome and mood disorders. As a follow-up, Tansey reports that her team is investigating the protective effects of an anti-inflammatory agent on both the brain and the liver using the same model.

Metabolic syndrome and stress have a complex interplay throughout the body, the researchers found. For example, psychological stress by itself does not affect insulin or cholesterol levels, but it does augment them when combined with a high-fat, high-fructose diet. In contrast, stress promotes adaptive anti-inflammatory markers in the hippocampus (part of the brain), but those changes are wiped out by a high-fat, high-fructose diet.

The findings show synergistic effects by diet and stress on gut permeability promoted by inflammation, and the biliverdin pathway. Biliverdin, a product of heme breakdown, is responsible for a greenish color sometimes seen in bruises.

“Stress and high-fat high-fructose diet promoted disturbances in biliverdin, a metabolite associated with insulin resistance,” Rodrigues writes. “To the best of our knowledge, our results reveal for the first time evidence for the synergistic effect of diet and chronic psychological stress affecting the biliverdin pathway.”

Read more

Posted on by Quinn Eastman in Heart, Immunology, Neuro Leave a comment

More on Alzheimer’s-blood pressure link

Emory’s Alzheimer’s Disease Research Center recently announced a grant that will support studies on the connections between blood pressure regulation and Alzheimer’s disease. It focuses on the roles of the renin-angiotensin system, the targets of common blood pressure medications, and endothelial cells, which line blood vessels.

Research on that theme is already underway at Emory. Malu Tansey is leading a large project funded by the National Institute on Aging ($3.4 million) with a similar title: “Inflammation and Renin-Angiotensin System Dysfunction as Risk Factors for Alzheimer’s Disease.” Co-investigators are Felicia Goldstein and Lary Walker at Emory and Christopher Norris at the University of Kentucky.

Both studies build on evidence that molecules that control blood pressure and inflammation also drive progression of Alzheimer’s disease, including work by Emory’s Whitney Wharton and Ihab Hajjar. They had found in an observational study that people who take medications targeting the renin-angiotensin system have a lower risk of progressing from mild cognitive impairment to Alzheimer’s.

Wharton is gearing up to test that idea more directly in an interventional study with the generic angiotensin receptor blocker telmisartan. This study is part of a Part the Cloud initiative supported by the Alzheimer’s Association.

Tansey’s project has started bearing fruit in an animal model of Alzheimer’s, according to this Keystone meeting report from Alzforum. Last summer, her graduate student Kathryn Macpherson described initial findings on the effects of an anti-inflammatory (anti-TNF) agent, which also has positive effects in a Parkinson’s model, and her plans to investigate the effects of high-sugar, high-fat diet.

Posted on by Quinn Eastman in Immunology, Neuro Leave a comment

Starvation signals control intestinal inflammation in mice

Intestinal inflammation in mice can be dampened by giving them a diet restricted in amino acids, the building blocks of proteins, researchers have found. The results were published online by Nature on Wednesday, March 16.

The findings highlight an ancient connection between nutrient availability and control of inflammation. They also suggest that a low protein diet — or drugs that mimic its effects on immune cells — could be tools for the treatment of inflammatory bowel diseases, such as Crohn’s disease or ulcerative colitis.

The research team, led by Emory Vaccine Center immunologist Bali Pulendran, discovered that mice lacking the amino acid sensor GCN2 are more sensitive to the chemical irritant DSS (dextran sodium sulfate), often used to model colitis in animals. This line of research grew out of the discovery by Pulendran and colleagues that GCN2 is pivotal for induction of immunity to the yellow fever vaccine.

“It is well known that the immune system can detect and respond to pathogens, but these results highlight its capacity to sense and adapt to environmental changes, such as nutritional starvation, which cause cellular stress,” he says.

Read more

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Sidestepping the placebo effect when studying depression

Research on depression must deal with a major obstacle: the placebo effect. This is the observation that patients improve in response to the sugar pills given as controls in clinical studies.

Clinical trial designers can incorporate various clever strategies to minimize the placebo effect, which is actually comprised of several statistical and psychological factors. Investigators can try to enhance, dissect or even “harness” them. [A recent piece in the New York Times from Jo Marchant focuses on the placebo effect in studies of pain relief.]

Emory psychiatrist Andrew Miller and his team have been developing a different approach over the last few years: studying symptoms of depression in people who are being treated for something else. This allows them to sidestep, at least partially, the cultural construct of depression, from William Styron to Peter Kramer to direct-to-consumer television ads.

Interferon alpha, a treatment used against hepatitis C virus infection and some forms of cancer, is a protein produced by the immune system that spurs inflammation. It also can induce symptoms of depression, such as fatigue and malaise. There are some slight differences with psychiatric depression, which Miller’s team describes here (less guilt!), but they conclude that there is a “high degree of overlap.”

Miller and his colleagues, including Jennifer Felger and Ebrahim Haroon, have documented how interferon-alpha-induced inflammation affects the brains of hepatitis C and cancer patients in several papers. That research, in turn, informs their more recent fruitful investigations of inflammation in the context of major depression. More on that soon.

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