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
Posted on May 16, 2017
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
Emoryâ€™s Alzheimerâ€™s Disease Research Center recently announced a grant that will support studies on the connections between blood pressure regulation and Alzheimerâ€™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: â€œInflammation and Renin-Angiotensin System Dysfunction as Risk Factors for Alzheimerâ€™s Disease.â€ 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 Alzheimerâ€™s disease, including work by Emoryâ€™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 Alzheimerâ€™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 â€œPart the Cloudâ€ initiative supported by the Alzheimerâ€™s Association.
Tanseyâ€™s project has started bearing fruit in an animal model of Alzheimerâ€™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 Parkinsonâ€™s model, and her plans to investigate the effects of high-sugar, high-fat diet.
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.
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
On Friday, NINDS director Walter Koroshetz made an interesting remark in a lecture to Emoryâ€™s Department of Neurology. He said that in the 2016 National Institues of Health budget, neuroscience is now the largest â€œbucket of money,â€ especially with the recent boost in funding for Alzheimerâ€™s research. Thatâ€™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. [Hereâ€™s some official category tracking that the NIH does â€“ his breakdown checks out.]
Koroshetz highlighted a project from Dieter Jaeger and Garret Stanley that is part of the White Houseâ€™s BRAIN Initiative focused on mapping brain circuits and connectivity. He also noted NINDSâ€™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 â€œoutstanding investigatorsâ€ for up to eight years continuously.
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
If youâ€™ve come anywhere near Alzheimerâ€™s research, youâ€™ve come across the â€œamyloid hypothesisâ€ or â€œamyloid cascade hypothesis.â€
This is the proposal that deposition of amyloid-beta, a major protein ingredient of the plaques that accumulate in the brains of Alzheimerâ€™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.
Lary Walker and Matthias Jucker in TÃ¼bingen, 2014
In a recent Nature News article, Boer Deng highlights an emerging idea in the Alzheimerâ€™s field that may partly explain why: not all forms of aggregated amyloid-beta areÂ the same. Moreover, some â€œstrainsâ€ of amyloid-beta may resemble spooky prions in their ability to spread within the brain, even if they can’tÂ infect other people (important!).
Prions are the “infectious proteins” behind diseases such as bovine spongiform encephalopathy. TheyÂ fold into a particular structure, aggregate and then propagate by attracting moreÂ 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 TÃ¼bingen, Germany and spent four months there on a sabbatical last year. Their paper, describing how aggregated amyloid-beta is â€œseededâ€ and spreads through the brain in mice, was recently published in Brain Pathology.
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.
Pathologist Keqiang Ye and his colleagues have been studying the functions of an enzyme called AEP, or asparagine endopeptidase, in the brain. AEP is activated by acidic conditions, such as those induced by stroke or seizure.
AEP is a protease. That means it acts as a pair of scissors, snipping pieces off other proteins. In 2008, his laboratory published a paper in Molecular Cell describing how AEPâ€™s acid-activated snipping can unleash other enzymes that break down brain cellsâ€™ DNA.
Following a hunch that AEP might be involved in neurodegenerative diseases, Yeâ€™s team has discovered that AEP also acts on tau, which forms neurofibrillary tangles in Alzheimerâ€™s disease.
â€œWe were looking for additional substrates for AEP,â€ Ye says. â€œWe knew it was activated by acidosis. And we had readÂ in the literature that the aging brain tends to be more acidic, especially in Alzheimerâ€™s.â€
The findings, published in Nature Medicine in October, point to AEP as a potential target for drugs that could slow the advance of Alzheimerâ€™s, and may also lead to improved diagnostic tools. Read more
The locus coeruleus is a part of the brain that has been getting a lot of attention recently from Emory neuroscienceÂ researchers.
The locus coeruleus is the biggest source of the neurotransmitter norepinephrine in the brain. Located deep in the brainstem, it has connections all over the brain, and is thought to be involved in arousal and attention, stress, memory, the sleep-wake cycle and balance.
Researchers interested in neurodegenerative disease want to look at the locus coeruleus because it may be one of the first structures to degenerate in diseases such as Alzheimerâ€™s and Parkinsonâ€™s. In particular, the influential studies of German neuro-anatomist Heiko Braak highlight the locus coeruleus as a key â€œcanary in the coal mineâ€ indicator of neurodegeneration.
Thatâ€™s why neurologist Dan Huddleston, working with biomedical imaging specialists Xiangchuan Chen and Xiaoping Hu and colleagues at Emory, hasÂ been developing a method for estimating the volume of the locus coeruleus by magnetic resonance imaging (MRI). Their procedure uses MRI tuned in such a way to detect the pigment neuromelanin (see panel), whichÂ accumulate in both theÂ locus coeruleus and in the substantia nigra. Read more