Simpler, more portable ECGs: Emory experts hosting computing challenge

Emory biomedical informatics specialists are hosting an international computing contest to support simpler, more potable electrocardiogram Read more

First (and massive) whole-genome study of IBD in African Americans

In African Americans, the genetic risk landscape for inflammatory bowel disease (IBD) is very different from that of people with European ancestry, according to results of the first whole-genome study of IBD in African Americans. The authors say that future clinical research on IBD needs to take ancestry into account. Findings of the multi-center study, which analyzed the whole genomes of more than 1,700 affected individuals with Crohn’s disease and ulcerative colitis and more than Read more

Emory researchers SNARE new Alzheimer’s targets

Diving deep into Alzheimer’s data sets, a recent Emory Brain Health Center paper in Nature Genetics spots several new potential therapeutic targets, only one of which had been previous linked to Alzheimer’s. The Emory analysis was highlighted by the Alzheimer’s site Alzforum, gathering several positive comments from other researchers. Thomas Wingo, MD Lead author Thomas Wingo and his team -- wife Aliza Wingo is first author – identified the targets by taking a new approach: tracing Read more

Alzheimer’s Disease

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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Drug discovery: Alzheimer’s and Parkinson’s spurred by same enzyme

Alzheimer’s disease and Parkinson’s disease are not the same. They affect different regions of the brain and have distinct genetic and environmental risk factors.

But at the biochemical level, these two neurodegenerative diseases start to look similar. That’s how Emory scientists led by Keqiang Ye, PhD, landed on a potential drug target for Parkinson’s.

Keqiang Ye, PhD

In both Alzheimer’s (AD) and Parkinson’s (PD), a sticky and sometimes toxic protein forms clumps in brain cells. In AD, the troublemaker inside cells is called tau, making up neurofibrillary tangles. In PD, the sticky protein is alpha-synuclein, forming Lewy bodies. Here is a thorough review of alpha-synuclein’s role in Parkinson’s disease.

Ye and his colleagues had previously identified an enzyme (asparagine endopeptidase or AEP) that trims tau in a way that makes it both more sticky and more toxic. In addition, they have found that AEP similarly processes beta-amyloid, another bad actor in Alzheimer’s, and drugs that inhibit AEP have beneficial effects in Alzheimer’s animal models.

In a new Nature Structural and Molecular Biology paper, Emory researchers show that AEP acts in the same way toward alpha-synuclein as it does toward tau.

“In Parkinson’s, alpha-synuclein behaves much like Tau in Alzheimer’s,” Ye says. “We reasoned that if AEP cuts Tau, it’s very likely that it will cut alpha-synuclein too.”

A particular chunk of alpha-synuclein produced by AEP’s scissors can be found in samples of brain tissue from patients with PD, but not in control samples, Ye’s team found.

In control brain samples AEP was confined to lysosomes, parts of the cell with a garbage disposal function. But in PD samples, AEP was leaking out of the lysosomes to the rest of the cell.

The researchers also observed that the chunk of alpha-synuclein generated by AEP is more likely to aggregate into clumps than the full length protein, and is more toxic when introduced into cells or mouse brains. In addition, alpha-synuclein mutated so that AEP can’t cut it is less toxic. Read more

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Amyloid vs tau? With this AD target, no need to choose

Keqiang Ye’s lab at Emory recently published a paper in Nature Communications that offers a two for one deal in Alzheimer’s drug discovery.

Periodically we hear suggestions that the amyloid hypothesis, the basis of much research on Alzheimer’s disease, is in trouble. Beta-amyloid is a toxic protein fragment that accumulates in extracellular brain plaques in Alzheimer’s, and genetics for early-onset Alzheimer’s point to a driver role for amyloid too.

In mice, inhibiting AEP hits two targets (amyloid and tau) with one shot

Unfortunately, anti-amyloid agents (either antibodies that sop up beta-amyloid or drugs that steer the body toward making less of it) have not shown clear positive effects in clinical trials.

That may be because the clinical trials started too late or the drugs weren’t dosed/delivered right, but there is a third possibility: modifying amyloid by itself is not enough.

Ye’s lab has been investigating an enzyme called AEP (asparagine endopeptidase), which he provocatively calls “delta secretase.” AEP is involved in processing both amyloid and tau, amyloid’s intracellular tangle-forming counterpart. Read more

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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

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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.

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Proteomics making fantastic routine

Much of basic biomedical research concerns proteins. The enzymes that keep cells running, the regulators and receptors that control what our cells do, the antibodies that defend us against invaders — all of these are proteins.

That means every day, scientists are asking questions like:

What’s happening to my favorite protein? Is there more or less of it in this sample? What other proteins work with it or stick to it?

That’s where a proteomics core facility comes in. Given a mixture of hundreds or even thousands of proteins, proteomics specialists can separate, identify and quantify them.Proteomics1smaller

Researchers in the areas of Alzheimer’s disease, cancer metabolism, schizophrenia and vaccines all make use of Emory’s proteomics core facility. It was key to the Alzheimer’s Disease Research Center’s 2013 discovery of a new form of Alzheimer’s disease protein pathology.

Director Nick Seyfried reports that the core has acquired close to $3 million in sophisticated mass spectrometry equipment in the last few years. The Emory Integrated Proteomics Core, one of the Emory Integrated Core Facilities, is supported in part by the Winship Cancer Institute, the Atlanta Clinical and Translational Science Institute, and a recently renewed grant for ENNCF (Emory Neurosciences NINDS Core Facilities).

Protein mass spectrometry is like Wonkavision

There’s a scene in both the 1971 and 2005 film adaptations of Roald Dahl’s Charlie and the Chocolate Factory, in which a chocolate bar is separated into millions of tiny pieces and sent flying across a clean room. Protein mass spectrometry resembles the first part of this process. Read more

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NINDS director: neuroscience now largest ‘bucket of money’

On Friday, NINDS director Walter Koroshetz made an interesting remark in a lecture to Emory’s Department of Neurology. He said that in the 2016 National Institues of Health budget, neuroscience is now the largest “bucket of money,” especially with the recent boost in funding for Alzheimer’s research. That’s larger than the bucket for cancer. To be sure, biomedical research in general got a boost from Congress, with the NIH receiving its largest increase in a decade, and cancer is still a big deal!

Koroshetz explained that neuroscience research is spread out among NINDS (National Institute for Neurological Disorders and Stroke), NIMH (National Institute of Mental Health), NIDA (National Institute for Drug Abuse) and several others, while cancer research is concentrated at the National Cancer Institute. [Here’s some official category tracking that the NIH does – his breakdown checks out.]

Koroshetz highlighted a project from Dieter Jaeger and Garret Stanley that is part of the White House’s BRAIN Initiative focused on mapping brain circuits and connectivity. He also noted NINDS’s efforts in promoting translational research, since pharmaceutical companies were frustrated by repeated failures in the 1990s with difficult areas such as stroke, and the R35 mechanism for funding “outstanding investigators” for up to eight years continuously.

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The secrets of a new Alzheimer’s secretase

The title of Keqiang Ye’s recent Nature Communications paper contains a provocative name for an enzyme: delta-secretase.

Just from its name, one can tell that a secretase is involved in secreting something. In this case, that something is beta-amyloid, the toxic protein fragment that tends to accumulate in the brains of people with Alzheimer’s disease.

Aficionados of Alzheimer’s research may be familiar with other secretases. Gamma-secretase was the target of some once-promising drugs that failed in clinical trials, partly because they also inhibit Notch signaling, important for development and differentiation in several tissues. Now beta-secretase inhibitors are entering Alzheimer’s clinical trials, with similar concerns about side effects.

Many Alzheimer’s researchers have studied gamma- and beta-secretases, but a review of the literature reveals that so far, only Ye and his colleagues have used the term delta-secretase.

This enzyme previously was called AEP, for asparagine endopeptidase. AEP appears to increase activity in the brain with aging and cleaves APP (amyloid precursor protein) in a way that makes it easier for the real bad guy, beta-secretase, to produce bad beta-amyloid.*At Alzforum, Jessica Shugart describes the enzyme this way:

Like a doting mother, AEP cuts APP into bite-sized portions for toddler BACE1 [beta-secretase] to chew on, facilitating an increase in beta-amyloid production. Read more

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Do Alzheimer’s proteins share properties with prions?

If you’ve come anywhere near Alzheimer’s research, you’ve come across the “amyloid hypothesis” or “amyloid cascade hypothesis.”

This is the proposal that deposition of amyloid-beta, a major protein ingredient of the plaques that accumulate in the brains of Alzheimer’s patients, is a central event in the pathology of the disease. Lots of supporting evidence exists, but several therapies that target beta-amyloid, such as antibodies, have failed in large clinical trials.

Jucker_Walker_May_2014

Lary Walker and Matthias Jucker in Tübingen, 2014

In a recent Nature News article, Boer Deng highlights an emerging idea in the Alzheimer’s field that may partly explain why: not all forms of aggregated amyloid-beta are the same. Moreover, some “strains” of amyloid-beta may resemble spooky prions in their ability to spread within the brain, even if they can’t infect other people (important!).

Prions are the “infectious proteins” behind diseases such as bovine spongiform encephalopathy. They fold into a particular structure, aggregate and then propagate by attracting more proteins into that structure.

Lary Walker at Yerkes National Primate Research Center has been a key proponent of this provocative idea as it applies to Alzheimer’s. To conduct key experiments supporting the prion-like properties of amyloid-beta, Walker has been collaborating with Matthias Jucker in Tübingen, Germany and spent four months there on a sabbatical last year. Their paper, describing how aggregated amyloid-beta is “seeded” and spreads through the brain in mice, was recently published in Brain Pathology.
Read more

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A structure for SorLA/LR11

The importance of the SorLA or LR11 receptor in braking Alzheimer’s was originally defined here at Emory by Jim Lah and Allan Levey’s labs. Japanese researchers recently determined the structure of SorLA and published the results in Nature Structural and Molecular Biology. Their findings point toward a direct role for SorLA in binding toxic circulating beta-amyloid and transporting it to the lysosome for degradation. Hat tip to Alzforum.

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