ROCK’n the Tau Pathway?
A kinase inhibitor that is an approved medication for people and improves memory in rats also promotes degradation of toxic tau in lab models, according to a paper in the January 27 Journal of Neuroscience. Inhibiting the Rho-associated protein kinases ROCK1 and ROCK2 with the drug fasudil got rid of tau in cultured human neurons and the eyes of fruit flies, report senior author Jeremy Herskowitz and colleagues from the University of Alabama in Birmingham. Fasudil is a vasodilator approved in Japan and China to prevent tightening of arteries and ischemia following surgery in the subarachnoid space surrounding the brain. It has undergone preclinical investigation in several neurodegenerative conditions thanks to its effects on autophagy and inflammation. The drug, or related compounds, might be more broadly applicable to prevent a variety of tauopathies, Herskowitz suggested. Alas, efforts to study fasudil in those diseases have been limited thus far.
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Does medical marijuana oil work? UAB shares insight into Carly's Law study
UAB study says Alzheimer’s plaques can also affect the brain’s blood vessels
In findings published Nov. 23 in the journal Brain, the team shows that when amyloid beta accumulates around blood vessels — where it is known as vascular amyloid — it appears to prevent the brain from properly regulating blood flow, which is essential to normal brain function.
“We have increasingly become aware that the disruption of blood flow in the brain can increase the risk of Alzheimer’s disease,” said Erik Roberson, M.D., Ph.D., associate professor in the UAB Department of Neurology. “While we have known that vascular amyloid built up around blood vessels, we did not fully understand its effects, and new technology now allows us to visualize how it affects the function of those vessels.”
Increased brain activity — remembering the lyrics to a song, for example — requires an increase in energy to the neurons responsible for memory. Neurons draw energy from glucose, which is transported by the blood stream. Cells called astrocytes regulate the diameter of blood vessels to increase or decrease blood flow and the corresponding glucose transportation. Astrocytes also tell the blood vessel to return to normal when the need has passed.
Astrocytes accomplish this signaling by means of projections called astrocytic endfeet, which wrap around the smooth muscle cells of the blood vessel wall. When a neuron calls for more glucose, the message is passed via the astrocytic endfeet, and the blood vessel expands and boosts blood volume.
The fate of astrocytic endfeet in a brain tumor study published last year at UAB led the research team to look more closely at vascular amyloid. UAB researchers led by Harald Sontheimer, Ph.D., then a professor in the Department of Neurobiology, published a paper in Nature Communications in June 2014 which showed that, in brain tumors, malignant astrocytes called glioma cells could travel along blood vessels and push astrocytic endfeet away, severing their connection to the vessel and interfering with their ability to regulate blood flow.
“We know vascular amyloid accumulates around the outside of blood vessels, and after seeing those research findings from the Sontheimer group, we wondered if these plaques could be doing the same thing,” Roberson said. “Working with Dr. Sontheimer and his laboratory, we used advanced imaging techniques — including high-resolution, 3-D image reconstructions from multiphoton laser scanning microscopes, and sophisticated labeling and experimental techniques — and were able to determine that, yes, vascular amyloid did push the astrocytic endfeet away and interfered with normal regulation of blood vessels.”
3-D microscope image of blood vessels (in red) with surrounding vascular amyloid plaques (in green). Courtesy Ian Kimbrough.“In a live animal model of Alzheimer’s disease, we then activated the vascular smooth muscle cells with a pulsed laser, allowing us to mimic neuron-induced astrocyte-vascular signaling,” said Ian Kimbrough, a graduate research assistant in Neurobiology and a collaborator on the original brain tumor study. “In locations where no vascular amyloid was present, we saw a very dramatic and robust vessel response; however, on blood vessels that were surrounded by plaque, we saw a much diminished response.”
Kimbrough says that UAB is one of the few research centers in the Southeast with multiphoton laser-scanning microscopes, instruments capable of capturing images deep into a living brain. These images can then be used to create three-dimensional, volumetric representations of brain morphology.
“Using this 3-D model, which we can rotate and manipulate,” he said, “we can see the exact spatial relationship between the vasculature, the astrocytic endfeet and the vascular amyloid. This allows us to analyze how these elements interplay in a normal, healthy brain compared to an Alzheimer’s disease brain.”
Roberson and Kimbrough say that, as the plaque buildup worsens, the vascular amyloid forms rings around the blood vessels, with bridges eventually linking one ring to the next. These rings form a rigid exoskeleton on the vessels, restricting their ability to change in diameter when increased blood flow is demanded by neurons.
“The vessel has to be able to expand and contract, to dilate and constrict, if it’s going to regulate blood flow,” Roberson said. “If they have become rigid like a pipe, instead of having a flexible wall that can go back and forth, then they cannot do their job of regulating blood flow to the brain properly.”
“This was among the first studies to really attempt to understand the relationship between vascular amyloid and blood flow in the brain,” he said. “For the first time, using the amazing technology at our disposal, we can see what is happening in the vessel walls in real time, to better understand how the presence of vascular amyloid effects the function of that vessel.”
Funding for the study came from the National Institutes of Health.
By: Bob Shepard
UAB Media Relations
UAB Big Data Research and Analytics Lab to help in developing NSF Big Data regional system
The lab is a joint initiative of the School of Engineering’s Department of Electrical and Computer Engineering, the Department of Neurology in the School of Medicine, and UAB IT Research Computing.The Big Data Research and Analytics Lab in the UAB School of Engineering, along with UAB Information Technology Research Computing and the School of Medicine’s Department of Neurology, will be part of a national effort to develop a Big Data Regional Innovation Hub serving 16 Southern states and the District of Columbia.
The South Big Data Regional Innovation Hub, or South BD Hub — to be managed jointly by Georgia Tech and the University of North Carolina — is part of the National Science Foundation’s four Big Data Regional Innovation Hubs announced today. The new initiative aims to build innovative public-private partnerships that address regional challenges through big data analysis.
“The award of the South Big Data Regional Innovation Hub to Georgia Tech and UNC-Chapel Hill provides the right context for collaboration among 116 stakeholders in academia, industry and the nonprofit sectors, which will enable us to — for the first time — address large-scale challenges facing many Southern states,” said Srinivas Aluru, co-principal investigator and professor in the School of Computational Science and Engineering at Georgia Tech.
Each of the NSF BD Hubs will engage businesses and research organizations in their region to develop common big data goals that would be impossible for individual members to achieve alone. The hubs will develop community-driven governance structures as well as “spoke projects” based on regional priorities and partnerships.
“Big data analysis is changing the way we see the world and is one of the more profound developments in science that we’ve seen in our lifetime,” said Iwan Alexander, Ph.D., dean of the UAB School of Engineering. “At UAB, we are uniquely positioned because of the wide range of expertise here in areas from engineering to medicine to business. Our Big Data Research and Analytics Lab has the potential to touch every part of campus, and as such, it can provide valuable input to this national network.”
In particular, UAB’s contributions to the South BD Hub are expected to be concentrated around the issues of health care, industrial big data and smart cities. UAB’s effort is being led by Thomas Anthony, director of the Big Data Research and Analytics Lab.
The lab is a joint initiative of the School of Engineering’s Department of Electrical and Computer Engineering, the Department of Neurology in the School of Medicine, and UAB IT Research Computing. The lab has been set up to bring together engineers, physicians, computer scientists and statisticians to develop novel ways to manage, analyze and visualize very large data sets.
UAB’s contributions to the South BD hub are expected to be concentrated around the issues of health care, industrial big data and smart cities.In addition to serving as a facility to process data generated at UAB and gathered through research of publicly available datasets, the lab is also working on emerging technologies and approaches to big data analytics that would be applicable to a large number of fields, which demonstrates the potential for big data to make a big impact on 21st century life.
“The important problems of our time — from solving disparities in health care to understanding the risks of coastal storms and floods — involve making sense of massive amounts of data,” said Ashok Krishnamurthy, deputy director at RENCI and co-PI with Aluru on the South BD Hub project. “The chance to lead this project with Georgia Tech means we will be at the forefront of using data for the public good.”
The South BD Hub will serve Alabama, Arkansas, Delaware, the District of Columbia, Florida, Georgia, Kentucky, Louisiana, Maryland, Mississippi, North Carolina, Oklahoma, South Carolina, Tennessee, Texas, Virginia and West Virginia. It will be developed in three phases — an initial bootstrap phase that will establish the basic governance structure, a transitional phase that will move toward an operational structure and a final operational phase.
Initial spokes of the South BD Hub will aim to apply big data analysis to scientific and social issues in five areas:
- Health Care, including disparities in health, access to health care, health outcomes, precision medicine and health analytics.
- Coastal Hazards, including understanding and mitigating the consequences of natural and manmade disasters.
- Industrial Big Data, including cyberphysical systems, the Internet of Things, data-driven management of physical infrastructure, and power generation, transmission and distribution from a variety of sources.
- Materials and Manufacturing, including data-driven contributions to the materials genome initiative and bridging the gap between materials science and manufacturing practice.
- Habitat Planning, including urban infrastructure, smart cities efforts, transportation, rural-urban infrastructure, and wildlife habitat and conservation.
by Katherine Shonesy