Genetically Engineered Mice Suggest New Model for How Alzheimer’s Disease Causes Dementia

July 5th, 2016

Using a novel, newly developed mouse model that mimics the development of Alzheimer’s disease in humans, Johns Hopkins researchers say they have been able to determine that a one-two punch of major biological “insults” must occur in the brain to cause the dementia that is the hallmark of the disease. A description of their experiments is published online in the journal Nature Communications.

For decades, Alzheimer’s disease, the most common cause of dementia, has been known to be associated with the accumulation of so-called neurofibrillary tangles, consisting of abnormal clumps of a protein called tau inside brain nerve cells, and by neuritic plaques, or deposits of a protein called beta-amyloid outside these cells along with dying nerve cells, in brain tissue.

In Alzheimer’s disease, tau bunches up inside the nerve cells and beta-amyloid clumps up outside these cells, mucking up the nerve cells controlling memory, notes Philip C. Wong, Ph.D., professor of pathology at the Johns Hopkins University School of Medicine.

What hasn’t been clear is the relationship and timing between those two clumping processes, since one is inside cells and one is outside cells, says lead and corresponding study author Tong Li, Ph.D., an assistant professor of pathology at Johns Hopkins. Prior studies of early-onset Alzheimer’s disease have suggested that the abnormal accumulation of beta-amyloid in the brain somehow triggers the aggregation of tau leading directly to dementia and brain cell degeneration. But the new research from Li, Wong and colleagues suggests that the accumulation of beta-amyloid in and of itself is insufficient to trigger the conversion of tau from a normal to abnormal state. Instead, their studies show, it may set off a chain of chemical signaling events that lead to the “conversion” of tau to a clumping state and subsequent development of symptoms.

“For the first time, we think we understand that the accumulation of amyloid plaque alone can damage the brain, but that’s actually not sufficient to drive the loss of nerve cells or behavioral and cognitive changes,” Wong says. “What appears to be needed is a second insult — the conversion of tau — as well.”

In humans, the lag between development of the beta-amyloid plaques and the tau tangles inside brain nerve cells can be 10 to 15 years or more, Li says, but because the lifetime of a mouse is only two to three years, current animal models that successfully mimic the appearance of beta-amyloid plaques did not offer enough time to observe the changes in tau.

To address that problem, the Johns Hopkins researchers genetically engineered a mouse model that used a tau fragment to promote the clumping of normal tau protein. They then cross-bred these mice with mice engineered to accumulate beta-amyloid. The result was a mouse model that developed dementia in a manner more similar to what happens in humans, Li says.

The researchers found during brain dissections of the animals that the presence of beta-amyloid plaque alone was not sufficient to cause the biochemical conversion of tau, the repeat domain of tau — the part of tau protein that is responsible for the conversion of normal tau to an abnormal state — alone was insufficient for the conversion of tau, beta-amyloid plaques must be present in the brain for the conversion of tau and the tau fragments could “seed” the plaque-dependent pathological conversion of tau.

One implication of the new research, Wong says, is to possibly explain why some drugs designed to attack the disease after the conversion of tau haven’t worked. “The timing may be off,” he says. “If you were to intervene in the time period before the conversion of tau, you might have a good chance of ameliorating the deficits, brain cell loss and ensuing consequence of the disease.”

The work also suggests that combination therapy designed to prevent both the beta-amyloid plaque formation as well as pathological conversion of tau may provide optimal benefit for Alzheimer’s disease, the researchers say. Their mouse model could be used to test new therapies.

An estimated 5.4 million Americans are living with Alzheimer’s disease, according to 2016 statistics from the Alzheimer’s Association. There is no cure, but there are some medications that may help stabilize cognition for a limited time or help with related depression, anxiety or hallucinations.

Co-authors were Kerstin E. Braunstein, Juhong Zhang, Ashley Lau, Leslie Sibener and Christopher Deeble of Johns Hopkins.

The work was supported by the Ellison Medical Foundation, the Brain Science Institute at Johns Hopkins, the Johns Hopkins University Neuropathology Pelda Fund and the Johns Hopkins Alzheimer’s Disease Research Center.

Dr. Barbara Crain Receives Award From AANP

June 22nd, 2016

Michael N. Hart, MD presented Dr. Crain with an award for her many Crain award 2016 AANP smmeritorious contributions on behalf of members of the American Association of Neuropathologists at their 92nd annual meeting. Drs. Crain and Troncoso are show after she received the award.

New WHO Classification of CNS Tumors

May 21st, 2016

An update of the WHO brain tumor classification has been released by IARC press. Drs. Burger, Eberhart and Rodriguez are all authors of multiple chapters. Key changes include molecular definitions of multiple tumor types such as Glioblastoma – IDH mutant and Diffuse midline glioma – H3K27M mutant.

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Dr. Fausto Rodriguez Appointed Director of Clinical Neuropathology Service

May 13th, 2016

Congratulations to Dr. Fausto Rodriguez, who has succeeded Dr. Peter Burger as Director of the Neuropathology Clinical Service.

Dr. Shuying Sun joins Neuropathology Division

May 6th, 2016

Memo from Dr. Ralph Hruban:

Please join me in welcoming Shuying Sun, Ph.D. from the Ludwig Institute for Cancer Research at the University of California at San Diego. Shuying will join our faculty in the Division of Neuropathology on July 1st, 2016. Shuying received her B.S. degree from Shandong University in China, and her Ph.D. from Stony Brook University, where she worked in the laboratory of Dr. Adrian Krainer at the Cold Spring Harbor Laboratory, and trained in basic molecular mechanisms of post-transcriptional RNA processing. Shuying has been a Postdoctoral Fellow in Don Cleveland’s laboratory since 2010.

A K99/R00 grant recipient, and author of papers in PNAS, Nature Genetics, Nature Communications, Shuying’s research here at Hopkins will focus on disease mechanisms of neurodegenerative disorders and advanced novel RNA-targeting therapy using her knowledge of RNA Biology and technology. In particular, Shuying will focus on a C9orf72 hexanucleotide repeat expansion seen in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).

Welcome Shuying!

Ralph Hruban, M.D.
Baxley Professor and Director of Pathology

Friday Interesting Case Conference

April 22nd, 2016

A range of interesting cases including CNS tumors, ocular pathology, neurodegenerative disease, forensic CNS pathology and developmental abnormalities are reviewed each week at 10 AM in Ross 555. All with an interest in neurological and ophthalmic disease are welcome to attend.

 

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Dr. Nikolaos Ziogas Wins First Place; Post-Doctoral Fellow Poster Awards at National Capital Area TBI Research Symposium 2016

April 18th, 2016

Nikolaos Ziogas M.D., LIBRA – post doctoral fellow at the Koliatsos Laboratory, was the winner of the “Post-Doctoral Fellow Poster Awards” at the annual National Capital Area Traumatic Brain Injury Symposium held at National Institutes of Health, Bethesda, DC for his work on the “Characterization of corticospinal tract pathology in mice exposed to impact acceleration injury”. For this work a novel neuroscience technique that makes the brain transparent, CLARITY, has been used to 3D reconstruct the corticospinal tract after traumatic brain injury, the specialized axonal tract responsible for fine movements.

Hidden damage revealed in veterans’ brains

September 3rd, 2015

The discovery of a ”honeycomb pattern” in the brains of combat veterans’ who survived IED blasts may provide clues to the neurological impact of warfare, according to researchers at Johns Hopkins University. Jillian Kitchener of Reuters reports.

Professor Vassili Koliatsos and his team at Johns Hopkins School of Medicine, believe they may have found the signature of “shell shock” in the brains of war veterans. Shell shock has afflicted soldiers since WWI…but it is a phenomenon that is still poorly understood. (SOUNDBITE) (English) PROFESSOR OF PATHOLOGY AND NEUROLOGY AT JOHNS HOPKINS SCHOOL OF MEDICINE, VASSILI KOLIATSOS, SAYING: “Is it neurological, psychological or both?” Professor Koliatsos believes scientists may soon be able to answer that question. His team has found what they call a unique honeycomb pattern of broken and swollen nerve fibers in brains of Iraq and Afghanistan combat veterans exposed to IED blasts but who later died of other causes. They compared these brains to 24 other people who died of causes such as car accidents, drug overdoses and heart attacks. The honeycomb pattern, Koalitis says, was caused by the FORCE of the blast. (SOUNDBITE) (English) PROFESSOR OF PATHOLOGY AND NEUROLOGY AT JOHNS HOPKINS SCHOOL OF MEDICINE, VASSILI KOLIATSOS, SAYING: “In this particular case, the force is coming against your chest so the blood gets squeezed. And as the blood gets squeezed, there’s a lot of bad apple blood into the brain. And because there’s a pulse of over-pressure wave that happens (like this), the brain also swells (like this). And when the brain swells, it pushes against some of the fixed elements inside the skull.” The damage, he says, is concentrated in the frontal lobe of the brain. (SOUNDBITE) (English) PROFESSOR OF PATHOLOGY AND NEUROLOGY AT JOHNS HOPKINS SCHOOL OF MEDICINE, VASSILI KOLIATSOS, SAYING: “And that’s very important because this is the site, the center, of the executive functions of the brain. Functions that allow you to put your life together, organize, plan ahead, understand abstract. And you can imagine this can make your life difficult.” U.S. veteran Aragorn Thor Wold says he has seen how a brain injury can take over a soldier’s entire life. Wold was a Navy Corpsman who served with the marines in combat medicine for nine years. He says it’s hard for medics to diagnose a moderate traumatic brain injury – or TBI – at the scene because troops are busy fighting. (SOUNDBITE) (English) U.S. VETERAN ARAGORN THOR WOLD, SAYING: “How can we differentiate TBI from PTSD. Is it an organic brain injury. Is it an anxiety disorder, illness side, you know. There’s a lot of those questions floating around. So I won’t say the holy grail but a huge deal would be a biomarker.” And while a biomarker has yet to be found, Koliatsos says his study shows there may be a neurological element to psychological suffering. (SOUNDBITE) (English) PROFESSOR OF PATHOLOGY AND NEUROLOGY AT JOHNS HOPKINS SCHOOL OF MEDICINE, VASSILI KOLIATSOS, SAYING: “If there is an executive disfunction, and disfunction of the front of the brain, you may think of different medications.” He says he would also like to see improved body gear that would give greater protection to the chest… and minimize the impact of explosive blasts upon the brain.

Here is the video link: http://www.reuters.com/video/2015/08/13/hidden-damage-revealed-in-veterans-brain?videoId=365278244&videoChannel=118065&channelName=Moments+of+Innovation

 

 

Major advance in our understanding of amyotrophic lateral sclerosis (ALS)

August 12th, 2015

Autopsies of nearly every patient with the lethal neurodegenerative disorder amyotrophic lateral sclerosis (ALS), and many with frontotemporal dementia (FTD), show pathologists telltale clumps of a protein called TDP-43. Now, working with mouse and human cells, Johns Hopkins researchers report they have discovered the normal role of TDP-43 in cells and why its abnormal accumulation may cause disease.

In an article published Aug. 7 in Science, the researchers say TDP-43 is normally responsible for keeping unwanted stretches of the genetic material RNA, called cryptic exons, from being used by nerve cells to make proteins. When TDP-43 bunches up inside those cells, it malfunctions, lifting the brakes on cryptic exons and causing a cascade of events that kills brain or spinal cord cells. “TDP-43’s role in both healthy and diseased cells has long been a mystery, and we hope that solving it will open new pathways toward preventing and treating ALS and FTD,” says Philip Wong, Ph.D., a professor of pathology at the Johns Hopkins University School of Medicine and senior author of the study.

Almost a decade ago, Wong says, scientists first described the clumps of TDP-43 that commonly appear in the degenerated brain or nerve cells of those with FTD or ALS. But whether the clumps were a cause or an effect of the diseases, and exactly what they did, was unknown.

“Some people thought that the aggregates themselves were toxic,” says Jonathan Ling, a graduate student in Wong’s lab and first author of the new paper. “Another theory is that the aggregates were just preventing TDP-43 from doing what it should be doing, and that was the problem.”

To figure out which theory might be right, Ling deleted the gene for TDP-43 from both lab-grown mouse and human cells and detected abnormal processing of strands of RNA, genetic material responsible for coding and decoding DNA blueprint instructions for making proteins. Specifically, they found that cryptic exons — segments of RNA usually blocked by cells from becoming part of the final RNA used to make a protein — were in fact working as blueprints. With the cryptic exons included rather than blocked, proteins involved in key processes in the studied cells were abnormal.

When the researchers studied brain autopsies from patients with ALS and FTD, they confirmed that not only were there buildups of TDP-43, but also cryptic exons in the degenerated brain cells.

In the brains of healthy people, however, they saw no cryptic exons. This finding, the investigators say, suggests that when TDP-43 is clumped together, it no longer works, causing cells to function abnormally as though there’s no TDP-43 at all.

TDP-43 only recognizes one particular class of cryptic exon, but other proteins can block many types of exons, so Ling and Wong next tested what would happen when they added one of these blocking proteins to directly target cryptic exons in cells missing TDP-43. Indeed, adding this protein allowed cells to block cryptic exons and remain disease-free.

“What’s thought provoking is that we may soon be able to fix this in patients who have lots of accumulated TDP-43,” says Ling.

Ling cautions that questions remain about the role of TDP-43 in ALS and FTD. “We’ve explained what happens after TDP-43 is lost, but we still don’t know why it aggregates in the first place,” he says. Wong’s group is planning studies that may answer these questions, as well as additional tests on how to treat TDP-43 pathology in humans.

The ALS Association estimates that as many as 30,000 Americans are living with ALS at any given time, and more than 5,000 people are newly diagnosed each year. There is no cure for the disease, and most people live two to five years after diagnosis. Similarly, FTD — thought to affect around 50,000 people in the U.S. — has no treatment and shortens life span.

Other authors on this study are Juan C. Troncoso and Olga Pletnikova from the Johns Hopkins University School of Medicine.

This work was supported in part by the Robert Packard Center for ALS Research, the Muscular Dystrophy Association, the Amyotrophic Lateral Sclerosis Association, Target ALS, the Johns Hopkins University Neuropathology Pelda Fund, the Johns Hopkins Alzheimer’s Disease Research Center (NIH grant number P50AG05146) and the Samuel I. Newhouse Foundation.

Watch Jonathan Ling & Dr. Philip Wong take the ALS Ice Bucket Challenge! (as seen on CBS and Fox News)

Koliatsos Reports on TBI in Veterans’ Brains

January 20th, 2015

Dr. Vassilis Koliatsos and colleagues in neuropathology recently published a study on traumatic brain injury (TBI) findings in veterans with histories of blast exposure in Iraq. Their research suggests that a unique microscopic damage signature may be associated with IEDs. Articles from JHU and the Washington Post discussing this research are found below.

 JHU – Combat Veterans’ Brains Reveal Hidden Damage from IED Blasts

FAST FACTS:

  • Autopsies of combat veterans who survived IEDs and later died of other causes reveal a unique pattern of injuries in parts of the brain involved in decision making, memory, reasoning and other executive functions.
  • The honeycomb pattern of IED survivors’ brain injury is different than the effects of motor vehicle crashes, opiate overdoses or punch-drunk syndrome.
  • The Johns Hopkins-led research team may have found the signature of “shell shock,” or blast neurotrauma, a mysterious ailment that has afflicted soldiers since World War I.

The brains of some Iraq and Afghanistan combat veterans who survived blasts from improvised explosive devices (IEDs) and died later of other causes show a distinctive honeycomb pattern of broken and swollen nerve fibers throughout critical brain regions, including those that control executive function. The pattern is different from brain damage caused by car crashes, drug overdoses or collision sports, and may be the never-before-reported signature of blast injuries suffered by soldiers as far back as World War I.

Vassilis Koliatsos, M.D., professor of pathology, neurology, and psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine, recently published a study in Acta Neuropathologica Communications that found survivable blasts may cause hidden brain injuries that play a role in the psychological and social problems some veterans face after coming home.

“This is the first time the tools of modern pathology have been used to look at a 100-year-old problem: the lingering effect of blasts on the brain,” says Koliatsos, senior author of the study that used molecular probes to reveal details in the brains of veterans who died months or years after an IED blast. “We identified a pattern of tiny wounds, or lesions, that we think may be the signature of blast injury. The location and extent of these lesions may help explain why some veterans who survive IED attacks have problems putting their lives back together.”
Soldiers have struggled with bomb-induced brain damage since 1914, when German and Allied forces tried to blast one another out of entrenched positions with monthslong bombardments. Many World War I fighters survived the barrage outwardly unscarred, but with an array of cognitive and psychological difficulties known as shell shock. After World War I, mass bombardments of troops were rare, and shell shock became uncommon. Now renamed blast neurotrauma or blast injury to brain, it has re-emerged due to insurgent forces’ widespread use of IEDs in Iraq and Afghanistan.
To understand this puzzling ailment, a team of eight researchers examined the brains of five male United States military veterans who survived IED attacks but later died. The remains were donated to the Armed Forces Institute of Pathology. Three died of methadone overdoses that could have been accidental, Koliatsos says, since the drug is commonly prescribed to treat soldiers’ chronic pain. One died of a gunshot wound to the head, and one died of multiple organ failure. The researchers compared the veterans’ brains to those of 24 people who died of a range of causes, including motor vehicle crashes, opiate overdoses and heart attacks.

The researchers used a molecular marker to track a protein called APP that normally travels from one nerve cell to another via a long nerve fiber, or axon. When axons are broken by an injury, APP and other proteins accumulate at the breaks, causing swelling. In the brains of people killed in car accidents, the swellings are large and bulb-shaped. In cases of methadone overdose, these axonal swellings are small.

In the brains of four of the five veterans who survived wartime blast injuries, the axonal bulbs were medium-sized and usually arrayed in a honeycomb pattern near blood vessels. “We did not see that pattern in other types of brain injury,” says Koliatsos.

The veterans’ brains did not show signs of the neurodegenerative disease known as punch-drunk syndrome, which is caused by multiple concussions. But near the damaged axons, a second molecular probe revealed specialized cells, called microglia, that are involved in brain inflammation.
“In brains that had been exposed to blasts, we see microglial cells right next to these unusual axonal abnormalities,” Koliatsos says. Brain inflammation develops slowly, so microglia don’t normally appear in drug overdose cases. Their presence suggests the veterans who overdosed had pre-existing brain injuries.

The researchers found these distinctive lesions in a number of places in veterans’ brains, including in the frontal lobes, which control decision making, memory, reasoning and other executive functions. The lesions may be fragments of nerve fibers that broke at the time of the blast and slowly deteriorated, or they may have been weakened by the blast and broken by some later insult like a concussion or drug overdose.

“When you look at a brain, you are looking at the life history of an individual, who may have a history of blasts, fighting, substance abuse or all of those,” Koliatsos says. “If researchers could study survivors’ brains at different times after a blast — a week, a month, six months, one year,  three years —that would be a significant step forward in figuring out what actually happens over time after a blast.”

A century after the first reported cases of shell shock, the struggle to overcome this invisible injury continues. Doctors treating IED survivors “often see depression, anxiety, post-traumatic stress, and substance abuse or adjustment disorders. Life is very difficult for some of these veterans,” says Koliatsos. “It’s important to understand that at least a portion of these difficulties may have a neurological foundation.”

This research was funded by the Johns Hopkins Alzheimer’s Disease Research Center (Grant RFA AG-09-001) and gifts from the Kate Sidran Family Foundation and the Sam and Sheila Geller family.

Other authors on the paper are Jiwon Ryu, Leyan Xu, Olga Pletnikova, Francesco Leri, Charles Eberhart and Juan C. Troncoso of the Johns Hopkins University School of Medicine and Iren Horkayne-Szakaly of the Veterans Administration Medical Center in Washington, D.C.

 

 

Washington Post

By Amy Ellis Nutt January 19 at 2:26 PM 

Scientists have discovered what a traumatic brain injury, or TBI, suffered by a quarter-million combat veterans of Iraq and Afghanistan looks like, and it’s unlike anything they’ve seen before: a honeycomb pattern of broken connections, primarily in the frontal lobes, our emotional control center and the seat of our personality.

“In some ways it’s a 100-year-old problem,” said Vassilis Koliatsos, a Johns Hopkins pathologist and neuropsychiatrist. He was referring to the shell-shock victims of World War I, tens of thousands of soldiers who returned home physically sound but mentally wounded, haunted by their experiences and unable to fully resume their lives.

“When we started shelling each other on the Western Front of World War I, it created a lot of sick people . . . . [In a way,] we’ve gone back to the Western Front and created veterans who come back and do poorly, and we’re back to the Battle of the Somme,” he said. “They have mood changes, commit suicide, substance abuse, just like in World War I, and they really do poorly and can’t function. It’s a huge problem.”

Many of the lingering symptoms of shell shock, or what today is known as neurotrauma, are the same as they were a century ago. Only the nature of the blast has changed, from artillery to improvised explosive devices.

Koliatsos and colleagues, who published their findings in the journal Acta Neuropathologica Communications in November, examined the brains of five recent U.S. combat veterans, all of whom suffered a traumatic brain injury from an IED but died of unrelated causes back home. Their controls included the brains of people with a history of auto accidents and of those with no history of auto accidents or TBI. Koliatsos says he was prompted to do this study because he is both a pathologist and a neuropsychiatrist, and he sees many TBI cases, both in veterans and in young people with sports concussions.

“Their attention is off, mood is off, personality is off. They’re impulsive, aggressive, do poorly in school. . . . I wanted to help my patients by trying to understand what is going on in their brains.”

What he found surprised him. The “neural signature” for blast victims was distinctly different from those who suffer TBIs in car accidents.

“We saw a type of disease in the brain not seen before,” he said. “We didn’t even know if we’d see any sign of disease.”

The scientists searched for amyloid precursor protein, which is transmitted between neurons along a fiber known as an axon. TBIs cause those axons to break, and the protein coalesces at those breaks, causing swelling. In car accidents, those swellings are large and bulbous, but in the veterans’ brains they were smaller and formed a honeycomb pattern near blood vessels.

The researchers also noticed that these unusual swellings were particularly evident in the frontal lobes, the seat of executive functions.
Once World War I ended, blast injuries were not the leading cause of combat injury until the American-led invasion of Iraq in 2003. The Vietnam War, however, did produce the first diagnosed cases of post-traumatic stress disorder, which Koliatsos believes has helped to stigmatize IED survivors who return home but have enormous difficulties adjusting.

“We thought it was hysteria in World War I and then came PTSD in Vietnam,” he said, so we continued to think of these [hidden] injuries only as psychological.”

So did the poet Wilfred Owen, one of Great Britain’s most famous shell-shock victims, who spent a year in a psychiatric hospital before returning to the front, where he was killed in action a week before the armistice of 1918.

Of himself and his fellow shell-shock patients, Owen wrote: “These are men whose minds the Dead have ravished.”