In recent debate over the FDA’s approval of the Alzheimer’s drug aducanumab, we’ve heard a lot about the “amyloid hypothesis.” In that context, it’s refreshing to learn about a model of Alzheimer’s neurodegeneration that doesn’t start with the pathogenic proteins amyloid or Tau.
Instead, a new paper in Alzheimer’s & Dementia from Emory neuroscientist Shan Ping Yu and colleagues focuses on an unusual member of the family of NMDA receptors, signaling molecules that are critical for learning and memory. Their findings contain leads for additional research on Alzheimer’s, including drugs that are already FDA-approved that could be used preventively, and genes to look at for risk factors.
“It’s not just another rodent model of Alzheimer’s,” Yu says. “We are emphasizing a different set of mechanisms leading to neurodegeneration.”
Loss of balance and falls are big concerns for people living with Parkinson’s disease and their caregivers. Researchers at Emory and Georgia Tech recently published a paper in PLOS ONE providing insights into how sensory and motor information are misrouted when people with Parkinson’s are attempting to adjust their balance.
When the researchers examined 44 people with Parkinson’s, their history of recent falls correlated with the presence and severity of abnormal muscle reactions. This could help clinicians predict whether someone is at high risk of falling and possibly monitor responses to therapeutic interventions.
People with Parkinson’s tend to lose their balance in situations when they are actively trying to control their center of mass, like when they are getting up from a chair or turning around. Disorganized sensorimotor signals cause muscles in the limbs to contract, such that both a muscle promoting a motion and its antagonist muscle are recruited. It’s like stepping on the gas and the brake at the same time, says J. Lucas McKay, who is first author of the paper.
Physical therapists are sometimes taught that balance reactions in Parkinson’s patients are slower than they should be.
“We show this is not true,” McKay says. “The reactions are on-time but disorganized.”
The paper extends groundbreaking work on how muscles maintain balance, conducted by co-author Lena Ting in animals and healthy young humans, to people with Parkinson’s. Co-authors of the PLOS One paper include Ting and Parkinson’s specialists Madeleine Hackney and Stewart Factor, director of Emory’s movement disorders program. McKay is assistant professor of neurology and biomedical informatics.
McKay says that sensorimotor problems may be a result of degeneration of regions of the brain, outside of and after the dopaminergic cells in the basal ganglia.
“We have to speculate, but the sensory misrouting would be occurring in brain regions like the thalamus — not usually the ones we think about in Parkinson’s, such as the basal ganglia,” he says. “This suggests that future therapies involving these areas could reduce falls.”
The set-up that researchers used to measure balance reactions resembles an earthquake simulator, and was designed and customized by Ting. The photo shows one of the Parkinson’s study participants, being watched by a physical therapy student.
“Flicker” treatment is a striking non-pharmaceutical approach aimed at slowing or reversing Alzheimer’s disease. It represents a reversal of EEG: not only recording brain waves, but reaching into the brain and cajoling cells to dance. One neuroscientist commentator called the process “almost too fantastic to believe.”
With flashing lights and buzzing sounds, researchers think they can get immune cells in the brain to gobble up more amyloid plaques, the characteristic clumps of protein seen in Alzheimer’s. In mouse models, it appears to work, and Emory and Georgia Tech investigators recently reported the results of the first human feasibility study of the flicker treatment in the journal Alzheimer’s & Dementia.
“So far, this is very preliminary, and we’re nowhere close to drawing conclusions about the clinical benefit of this treatment,” said neurologist James Lah, who supervised the Flicker study at Emory Brain Health Center. “But we now have some very good arguments for a larger, longer study with more people.”
The good news: most participants in the study could tolerate the lights and sounds, and almost all stuck with the eight-week regimen of experimental treatment. (Some even joined an optional extension.) In addition, researchers observed that brain cells were dancing to the tunes they piped in, at least in the short term, and saw signs of a reduction in markers of inflammation. Whether the approach can have a long-term effect on neurodegeneration in humans is still to be determined.
Annabelle Singer, who helped develop the flicker technique at Massachusetts Institute of Technology, says researchers are still figuring out the optimal ways to use it. Recent studies have been assessing how long and how often people should experience the lights and sounds, and more are underway.
“We need to collect all the information we have about how to measure someone’s progress,” says Singer, who is now an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory.
In the feasibility study, ten people diagnosed with mild cognitive impairment used goggles and headphones that provided light/sound stimulation at home for an hour every day. This video from Georgia Public Broadcasting’s Your Fantastic Mind series demonstrates what that was like.
“To me — It’s not painfully loud. And the lights are not as bright as you would think they are… I don’t find them to be annoying,” says retired psychotherapist Jackie Spierman in the video.
Tap tap tap ka-CHUNK! That was the sound of fruit flies being given concussions in an Emory laboratory recently.
Emory MD/PhD student Joe Behnke, working with neuroscientist James Zheng, has developed a model for studying repetitive head trauma in the fruit fly Drosophila melanogaster – analogous to CTE (chronic traumatic encephalopathy) in humans. The results were published in Scientific Reports.
CTE is a term for neurodegeneration linked to repeated concussions or blows to the head, which has been observed in athletes and military veterans. Head trauma has also been linked to other neurodegenerative diseases such as Alzheimer’s, Parkinson’s and ALS (amyotrophic lateral sclerosis).
What’s critical about using fruit flies is that it speeds up time. It can take years or decades for CTE or other neurodegenerative conditions to appear in humans, but Behnke and Zheng can experiment with a mutant fly strain or other interventions in a few weeks. They describe their model as a platform for future studies, in which they can unleash all of the genetic tools fruit flies have to offer.
To begin with, Behnke worked out a system for giving flies controlled blows to the head. He says that it exploits the climbing instinct flies have when startled, called negative geotaxis. When he taps a vial with flies in it three times, they reorient themselves and begin climbing up. Then a stronger blow, delivered in a crash test-like apparatus, gives flies the desired head injury. Previous models in flies hadn’t really focused on the head, but gave them injuries all over their bodies.
Already, Behnke and Zheng have been able to demonstrate that female fruit flies are more vulnerable to repeated head injuries than males. Repeated head injury results in locomotor deficits and shortened lifespan and accelerates age-related degeneration.
The Emory laboratories of Keqiang Ye and David Weinshenker recently published a paper on ApoE, the most common genetic risk factor for late-onset Alzheimer’s. The findings, published in Acta Neuropathologica, suggest how the risk-conferring form of ApoE (ApoE4) may exacerbate pathology in the locus coeruleus.
The LC, part of the brainstem, is thought to be the first region of the brain where pathological signs predicting future cellular degeneration show up. The LC (“blue spot”) gets its name from its blue color; it regulates attention, arousal, stress responses and cognition. The LC is also the major site for production of the neurotransmitter norepinephrine.
ApoE, which packages and transports cholesterol, was known to modulate the buildup of the toxic protein fragment beta-amyloid, but this proposed mechanism goes through Tau. Tau is the other pesky protein in Alzheimer’s, forming neurofibrillary tangles that are the earliest signs of degeneration in the brain. Tau pathology correlates better with dementia and cognitive impairments than beta-amyloid, which several proposed Alzheimer’s therapeutics act on.
The new paper shows that ApoE4 inhibits the enzyme VMAT2, which packages norepinephrine into vesicles. As a result, free/unpackaged norepinephrine lingers in the cytoplasm, and forms a harmful oxidative byproduct that triggers enzymatic degradation of Tau. Thus, norepinephrine may have a “too hot to handle” role in Alzheimer’s – with respect to the LC — somewhat analogous to dopamine in Parkinson’s, which has also been observed to form harmful byproducts. Dopamine and norepinephrine are similar chemically and both are substrates of VMAT2, so this relationship is not a stretch.
The Emory results make the case for inhibiting the enzyme AEP (asparagine endopeptidase), also known as delta-secretase, as an approach for heading off Alzheimer’s. AEP is the Tau-munching troublemaker, and is activated by the norepinephrine byproduct DOPEGAL
An alternative approach may be to inhibit monoamine oxidase (MAO-A above) enzymes — several old-school antidepressants are available that accomplish this.
At Emory, Ye’s lab has been tracing connections for AEP/delta-secretase in the last few years, and Weinshenker’s group is expert on all things norepinephrine, so the collaboration makes sense.
Delta-secretase’s name positions it in relation to beta- and gamma-secretase, enzymes for processing APP (amyloid precursor protein) into beta-amyloid, but AEP/delta-secretase has the distinction of having its fingers in both the beta-amyloid and Tau pies.
We have to caution that most of the recent research on delta-secretase has been in mouse models. Ye’s collaborators in China have been testing an inhibitor of delta-secretase in animals but it has not reached human studies yet, he reports. That said, this work has been oriented toward figuring out the web of interactions between known players such as ApoE and Tau, whose importance has been well-established in studies of humans with Alzheimer’s.
In the emergency department, the temperature of the brain is critical information after someone has a stroke or cardiac arrest, and even more important during treatment. Yet it is difficult for doctors to accurately or directly measure brain temperature.
Magnetic resonance imaging technology being developed at Emory University School of Medicine could provide more accurate measurements. A team of researchers has received a three-year, $400,000 grant from the National Institute of Biomedical Imaging and Bioengineering (NIBIB) to monitor brain temperature while patients are undergoing therapeutic hypothermia after cardiac arrest. Therapeutic hypothermia, or controlled cooling, is a treatment used to protect the brain after loss of blood flow. While cooling is used in many hospitals, it is not widely implemented nor has it been optimized in terms of dosage or timing.
The project is led by Candace Fleischer, PhD, an assistant professor of radiology and imaging sciences at Emory. The grant is part of NIBIB’s Trailblazer program, which is designed for early stage investigators to pursue research in new directions.
“Our goals are to develop a new method for non-invasive brain temperature monitoring, and to demonstrate the ability to measure brain-body temperature differences in cardiac arrest patients during therapeutic cooling,” says Fleischer, who is also a member of the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory.
“Currently, therapeutic hypothermia is monitored using core body temperature due to a lack of non-invasive tools,” she adds. “Yet, we know brain temperature tends to be higher than body temperature, and brain and body temperatures are decoupled after injury. Accurate measurements of brain temperature are needed to optimize clinical implementation.”
Researchers interested in Alzheimer’s and other neurodegenerative diseases are focusing their attention on microglia, cells that are part of the immune system in the brain.
Author Donna Jackson Nakazawa titled her recent book on microglia “The Angel and the Assassin,” based on the cells’ dual nature; they can be benign or malevolent, either supporting neuronal health or driving harmful inflammation. Microglia resemble macrophages in their dual nature, but microglia are renewed within the brain, unlike macrophages, which are white blood cells that infiltrate into the brain from outside.
At Emory, neurologist Srikant Rangaraju’s lab recently published a paper in PNAS on a promising drug target on microglia: Kv1.3 potassium channels. Overall, the results strengthen the case for targeting Kv1.3 potassium channels as a therapeutic approach for Alzheimer’s.
Kv1.3 potassium channels have also been investigated as potential therapeutic targets in autoimmune disorders, since they are expressed on T cells as well as microglia. The peptide dalazatide, based on a toxin from the venom of the Caribbean sea anemone Stichodactyla helianthus, is being developed by the Ohio-based startup TEKv Therapeutics. The original venom peptide needed to be modified to make it more selective toward the right potassium channels – more about that here.
It appears that Kv1.3 levels on microglia increase in response to exposure to amyloid-beta, the toxic protein fragment that accumulates in the brain in Alzheimer’s, and Kv1.3 may be an indicator that microglia are turning to the malevolent side.
In the Emory paper, researchers showed that Kv1.3 potassium channels are present on a subset of microglia isolated from Alzheimer’s patients’ brains. They also used bone marrow transplant experiments to show that the immune cells in mouse brain that express Kv1.3 channels are microglia (internal brain origin), not macrophages (transplantable w/ bone marrow).
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.
Lead author Thomas Wingo and his team — wife Aliza Wingo is first author – identified the targets by taking a new approach: tracing connections between proteins that are altered in abundance in patients’ brains and risk genes identified through genome-wide association studies.
The list of 11 genes/proteins named as “consistent with being causal” may be contributing to AD pathogenesis through various mechanisms: vesicular trafficking, inflammation, lipid metabolism and hypertension. We asked Wingo which ones he wanted to highlight, and he provided this comment:
“The most interesting genes, to me, are the ones involved in the SNARE complex (in the paper, STX4 and STX6) and the others involved in vesicular trafficking. There is already a deep body of literature that describe a role for some of these components in AD, and I’m hopeful providing specific targets might be useful to those studies.”
A simplistic way to look at the mechanism of Alzheimer’s disease is: proteins build up in the brain, in the form of amyloid plaques and neurofibrillary tangles. The functions of neurons and other brain cells are thought to be impaired by bits of beta-amyloid floating around.
Inside neurons, the SNARE complex is the core of the machinery that pushes vesicles to fuse with the cell membrane. Neurons communicate with each other by having vesicles inside the cell – bags full of neurotransmitters – release their contents. They’re like tiny packets of pepper or other spices that make the neuron next door sneeze. In Alzheimer’s, amyloid oligomers have been reported to block SNARE complex assembly, which may explain aspects of impaired cognition.
Investigators at Emory Brain Health Center have developed a platform for evaluating visual memory, while someone views photos for a few minutes on an iPad.
Emory researchers, led by Goizuieta Alzheimer’s Disease Research Center director Allan Levey and biomedical informatics chair Gari Clifford, are working with the company Linus Health to develop the VisMET (Visuospatial Memory Eye-Tracking Test) technology further. Results from the most recent version were published in the journal IEEE Transaction on Biomedical Engineering, and the Emory/Linus team continues to refine the technology.
The goal is to screen people for memory issues, identifying those with mild cognitive impairment (MCI) or Alzheimer’s disease. The task — difficult to call it a test — was designed to be more efficient, easier to administer, and more enjoyable than tests currently used.
“We think this could be a sensitive and specific method for detecting visual memory impairment, and it’s convenient enough for use on a wider scale,” Levey says.
The VisMET technology is based on this observation. When someone with MCI or Alzheimer’s views a photo twice, and the photo has been changed the second time (example: an object in the scene has been removed), their eyes spend less time checking the new or missing element in the photo, compared with healthy people. This is because the regions of the brain that drive visual memory formation, such as the entorhinal cortex and hippocampus, are some of the earliest to deteriorate in MCI or Alzheimer’s.
“The current way memory tests are implemented can be stressful,” says software engineer Alvince Pongos, who is co-first author of the IEEE TBME paper, now at MIT’s McGovern Institute for Brain Research. “The difficulty of standard memory tests can lead to test-givers repeating task instructions many times, and to test-takers being confused and frustrated. If we design simpler tasks and make our tools available in the comfort of one’s home, then we remove barriers allowing more people to engage with their health information.”
The neuropeptide oxytocin, known for promoting social interactions, has attracted interest as a possible treatment for autism spectrum disorder. A challenge is getting the molecule past the blood-brain barrier. Many clinical studies have used delivery via nasal spray, but even then, oxytocin doesn’t last long in the body and shows inconsistent effects.
Emory neuroscientist Andrew Escayg has been collaborating with Mercer/LSU pharmacologist Kevin Murnane on a nanoparticle delivery approach that could get around these obstacles. One of Escayg’s primary interests is epilepsy — specifically Dravet syndrome, a severe genetic form of epilepsy — and oxytocin has previously displayed anti-seizure properties in animal models.
Escayg and Murnane’s recent paper in Neurobiology of Disease shows that when oxytocin is packaged into nanoparticles, it can increase resistance to induced seizures and promote social behavior in a mouse model of Dravet syndrome.
This suggests properly delivered oxytocin could have benefits on both seizures and behavior. In addition to seizures, children and adults with Dravet syndrome often have autism – see this Spectrum News article on the connections.
Escayg reports he is planning a collaboration with oxytocin expert Larry Young at Yerkes, who Tweeted “This is a promising new area of oxytocin research” when the paper was published. Senior postdoc Jennifer Wong has already been working on extending the findings to other mouse models of epilepsy and adding data on spontaneous seizure frequency.