Alzheimer’s-Related Tau Protein Can Disrupt Blood Flow in the Brain, Long Before Neurodegeneration Sets In


Abnormal forms of a brain-cell protein called tau, which have long been implicated in Alzheimer’s and other neurodegenerative disorders, may contribute to neurodegeneration earlier than was previously understood, by interfering with the normal dynamics of blood flow in the brain, suggests a study from scientists at Weill Cornell Medicine. The results pave the way for research efforts that seek to prevent early neurodegeneration by restoring normal blood flow.

Published August 10 in Nature Neuroscience, the study revealed that in mice carrying mutant versions of tau, the protein disrupts the normal ability of brain cells to induce more blood flow from cerebral vessels when the cells are more active.

This defect in normal cerebral blood-flow dynamics was evident even in young tau-mutant mice, long before they showed signs of neurodegeneration.

Although scientists have known for many decades that abnormal aggregates of tau protein form within affected brain regions in some neurodegenerative disorders, they have never fully understood how tau drives these disorders. The new finding raises the possibility that tau does so, at least in part, by preventing active neurons from getting the level of oxygen and nutrients they need.

“Neurodegenerative disease research has tended to focus on the direct effects of tau and other proteins on neurons, but our findings imply that we should be broadening our research to examine these proteins’ effects on other aspects of brain function,” said senior author Dr. Costantino Iadecola, the Anne Parrish Titzell Professor of Neurology and Neuroscience and director of the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine.

Roughly six million people in the United States have Alzheimer’s disease, and hundreds of thousands of others have less well known tau-related neurodegenerative disorders such as frontotemporal dementia and progressive supranuclear palsy. These disorders are all considered “tauopathies” because they feature the accumulation in affected brain regions of large aggregates of tau proteins, often called tau tangles. To date, however, no one has conclusively shown how tau drives neurodegeneration, and in clinical trials no anti-tau therapy has ever helped patients who have tauopathies.

In the new study, Dr. Iadecola and colleagues examined mice that had been genetically engineered to have mutant, tauopathy-linked forms of tau. Such mice, which develop tau tangles and neurodegeneration, are commonly used as animal models for studying Alzheimer’s and other tauopathies.

The researchers found that even at just two to three months old, a basic process in the tau-mutant mice that ensures proper blood flow to energy-hungry neurons in the cortex was markedly reduced—long before the development of tau tangles or neurodegeneration. The process, called neurovascular coupling, normally causes local blood vessels supplying neurons to dilate and increase their blood flow in response to increases in the neurons’ activities.

The scientists found evidence in the mice that among neurons using the neurotransmitter glutamate for signaling, tau proteins bind to a large protein complex linked to the glutamate receptor. This binding of tau interrupts the normal connection between glutamate signaling activity and the production of nitric oxide, a molecule that causes vessels to dilate.

Shutting off the production of tau restored normal neurovascular coupling. The researchers observed this restorative effect even in older mice whose neurons were riddled with tau tangles. Thus, the disruption of neurovascular coupling appeared to be caused by a form of tau other than tangles.

“The tangles seem more like ‘tombstones’ marking the disease process than active drivers of neurodegeneration,” said first author Dr. Laibaik Park, an associate professor of research in neuroscience at Weill Cornell Medicine.

The results suggest that in Alzheimer’s and other tauopathies, mutations in tau or other events that displace tau from its usual locations in neurons may allow some non-tangle form of the protein to disrupt normal neurovascular coupling.

Though it remains to be proven, it’s conceivable that this subtle disruption of normal cerebral blood-flow dynamics may contribute to the degeneration of neurons that is observed in tauopathies.

Dr. Iadecola and Dr. Park, with Dr. Karin Hochrainer, assistant professor of neuroscience in the Feil Family Brain and Mind Research Institute, and other colleagues, now plan experiments to see if restoring neurovascular coupling can prevent neurodegeneration. They are also studying the molecular details of how tau interrupts nitric oxide production.

“I think we are moving into a new era in which we’ll understand much better what neurodegeneration-associated proteins such as tau are doing in these disorders,” Dr. Iadecola said.

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Dr. Makoto Ishii Wins Beeson Career Development Award


Dr. Makoto Ishii, an assistant professor of neurology and neuroscience in the Feil Family Brain and Mind Research Institute, has been awarded the prestigious Paul B. Beeson Career Development Award in Aging Research from the National Institute on Aging and the American Federation for Aging Research.

The Beeson award program supports physician-scientists who are committed to advancing the study of geriatric illness and health. The program seeks to groom these researchers to become leaders in the field by providing financial awards and granting access to a distinguished network of Beeson mentors and alumni. The program selects a limited number of junior faculty from medical schools nationwide to receive a $600,000 to $800,000 grant for three to five years of mentored aging-related research.

Dr. Ishii received one of eight Beeson awards given nationwide in 2015, joining more than 200 Beeson scholars including many who are chairs and division chiefs at major academic centers around the country. An important component of the award is mentorship and academic development, which will be provided by a mentorship team led by Dr. Costantino Iadecola, director of the Feil Family Brain and Mind Research Institute.

"I feel honored and am very thankful for all of the support that I receive at Weill Cornell Medicine, and from my mentors first and foremost," Dr. Ishii said. "I'm elated — it's a very big honor to receive at this point of my career. It helps a lot in terms of establishing myself as a future career clinician-scientist."

Dr. Ishii investigates the effect that Alzheimer's disease has on the region of the brain known as the hypothalamus, and how that in turn affects the body's metabolism, hormonal balances, weight and other vital physiological functions. While Alzheimer's is commonly seen as primarily associated with age-related memory loss, there are many other symptoms that present themselves, one of the most visible of which is rapid weight loss that occurs sometimes even before the onset of memory loss.

"When I was a neurology resident, my grandmother was diagnosed with Alzheimer's," Dr. Ishii said. "I was only able to visit her about once a year — it really hits home when it happens in your family. And I personally saw her lose significant amount of weight."

With the five-year grant, Dr. Ishii will continue to investigate the mechanisms underlying weight loss in Alzheimer's disease by combining detailed molecular studies in mice with studies using clinically-relevant human samples from volunteers. Dr. Ishii hopes that these studies reveal weight loss as an important clinical aspect of Alzheimer's disease, which may lead to the development of new therapies and diagnostic tools.

"Winning this award was really a great feeling," Dr. Ishii said. "This is not just a personal achievement, but rather an award that also recognizes the superb mentorship and rich supportive academic environment here at Weill Cornell Medicine, which enables clinician-scientists, such as myself, the opportunity to follow their research intuition and tackle important open medical questions."

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Power Failure


Dr. Giovanni Manfredi traces the link between mitochondrial disruption and diseases like ALS

Behind the mechanics of every step we take, cellular powerhouses called mitochondria are hard at work, enabling us to walk and talk with relative ease. These fascinating metabolic hubs convert food into energy. Brain cells depend on this energy to interact with each other and to make muscles contract; muscle cells, in turn, use this power source to move and maintain posture.

Since 1999, researchers at Weill Cornell Medicine have been exploring why this apparently seamless process sometimes goes awry, causing motor neurons — the muscle controlling nerve cells — to begin withering away, resulting in conditions such as amyotrophic lateral sclerosis (ALS). A team led by Dr. Giovanni Manfredi, professor of neuroscience in the Feil Family Brain and Mind Research Institute, has pioneered research illuminating how impaired mitochondria play a pivotal role in the development of ALS, the rapidly progressive and fatal neurodegenerative affliction commonly known as Lou Gehrig's disease. "Mitochondria are terribly important for the understanding of neurological disorders, being the final common pathway in which many of these diseases — Alzheimer's, Parkinson's, ALS and others — converge," says the institute's director Dr. Costantino Iadecola, the Anne Parrish Titzell Professor of Neurology. "Even stroke and trauma converge in mitochondria as a major mechanism of disease."

By better understanding the molecular mechanisms underlying mitochondrial changes, Dr. Manfredi and his colleagues hope to spur the development of targeted therapeutics for neurodegenerative conditions. For instance, researchers already know that abnormal protein deposits accumulate in the motor neurons of many people with ALS. Normal protein molecules are folded nearly flawlessly in a three-dimensional configuration. If disruption occurs, proteins can form aggregates — clumps in the cells. Using mouse models, Dr. Manfredi's lab demonstrated that aggregates of misfolded proteins manifest within the mitochondria of the mutant enzyme SOD1, resulting in one of the most common causes of inherited ALS. His laboratory also pioneered work highlighting how faulty calcium regulation in mitochondria and secretion of toxic molecules by supportive cells in the brain, known as astrocytes, result in the death of motor neurons.

Because many neurological conditions involve mitochondrial dysfunction, symptoms can overlap and appear similar, even if the diseases are distinctly different. For instance, some genetic forms of ALS may occur in families with a prevalence of dementia. Contrary to the frequent misperception that the mind remains fully intact in people with ALS, cognitive dysfunction often ensues after paralysis and interferes with memory and behavior. It's also common for dementia to develop in people with Parkinson's disease. "The same person can have both diseases," says Dr. Manfredi, who directs the graduate program in neuroscience, "or different individuals in the same family may have one or the other."

By interfering with the disease pathways that damage mitochondria, Dr. Manfredi aims to stabilize these cellular powerhouses against stress and halt further damage. His team has begun searching for approaches to unravel the mystery surrounding the causes of sporadic ALS, which arises without any known genetic link or family history, and accounts for about 80 percent of all cases. "Sporadic ALS is probably a combination of diseases," he says, with paralysis being the main unifying symptom. His research focuses on genetically altering proteins in human cells and mice — work that could pave the way for promising drugs.

— Susan Kreimer

This story first appeared in Weill Cornell Medicine, Vol. 14, No. 2.

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Awards and Honors Across Weill Cornell Medical College - Week of Sept. 11 - Sept. 18


Dr. Costantino Iadecola Wins Excellence Award in Hypertension Research

Dr. Costantino Iadecola, director of the Feil Family Brain and Mind Research Institute and the Anne Parrish Titzell Professor of Neurology, has won the 2015 Excellence Award for Hypertension Research from the American Heart Association's Council on Hypertension.

Dr. Costantino Iadecola

The accolade, sponsored by Novartis, is the council's most prestigious award and carries a $10,000 honorarium. It recognizes researchers' contributions to the field of hypertension that have led to improved treatment and a greater understanding of high blood pressure.

A neurobiologist and neurologist, Dr. Iadecola was honored for his research into the connection between hypertension and stroke and Alzheimer's disease. He discovered that blood vessels in the brain are uniquely and highly susceptible to the effects of hypertension. The resulting damage to the vessels may lead not only to stroke and vascular dementia, but also to an increased risk of developing Alzheimer's disease. Dr. Iadecola received the award at a reception on Sept. 18 during the American Heart Association's 2015 Hypertension Scientific Sessions in Washington, D.C. Dr. Iadecola also gave a lecture during the four-day conference.

"I am honored and humbled to have been selected for this award, which I am delighted to accept on behalf of my associates in the Feil Family Brain and Mind Research Institute who made the research possible," Dr. Iadecola said.

"This recognition has been typically bestowed on scientists working on the heart and blood vessels," he added. "Giving this award for research on the link between high blood pressure and Alzheimer's disease highlights the fact that the hypertension community worldwide acknowledges that the brain is a critical target of hypertension. This realization strengthens my resolve to continue this work, with the ultimate goal of developing new therapies to shield the brain from the devastating impact of hypertension."

Additional Awards and Honors

Dr. Wallace Carter, an associate professor of emergency medicine in clinical medicine and an adjunct associate professor of clinical medicine, received the Council of Emergency Medicine Residency Directors CORD Impact Award at its annual academic assembly on April 15 in Phoenix. The council is a scientific and educational organization focused on improving the quality of emergency medical care, enhancing the quality of emergency medicine instruction and encouraging communication between the faculty of various emergency medicine training programs. The Impact Award is given annually to faculty members who have made significant contributions toward those goals.

Dr. Marisa Censani, an assistant professor of pediatrics, was appointed to the Pediatric Endocrine Society's Obesity Committee for a three-year term, effective May 1. The society's mission is to advance the care of children and adolescents with endocrine disorders. The committee focuses on the problem of childhood and adolescent obesity caused, at least in part, by endocrine disorders.

Dr. Nikolaos Skubas, a professor of clinical anesthesiology and of anesthesiology in clinical cardiothoracic surgery, was elected into the Society of Cardiovascular Anesthesiologists Nominating Committee in May for a two-year term. The society is an international organization of anesthesiologists that promotes excellence in clinical care, education and research in the subspecialty.

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The Transporter


Could ‘retromer' be the key to Alzheimer's treatment?

A key to cellular function — and to life itself — is the movement of proteins and lipids within a cell. As these substances follow their paths, a part of the cell called the endosome acts as the traffic hub, sorting them to be recycled, diverted, secreted or degraded. When the endosome sends them to be recycled back to the cell surface, a complex of proteins plays a role like that of a school crossing guard: it encircles them and helps them on their way. That complex is known as retromer — and its performance may be key to treating Alzheimer's and Parkinson's diseases.

Dr. Gregory Petsko

Dr. Gregory Petsko. Photo Credit: Carlos Rene Perez

Last spring, in a paper published in Nature Chemical Biology, biochemist Dr. Gregory Petsko revealed a potential new therapeutic approach for these devastating neurodegenerative diseases — one that boosts the function of retromer. In an editorial highlighting the work, noted that the results, while preliminary, have impressed veteran researchers in the Alzheimer's field. As one neurologist told the journal: "The new pro-retromer drug is brilliant."

Dr. Petsko, director of the Helen & Robert Appel Alzheimer's Disease Research Institute and the Arthur J. Mahon Professor of Neuroscience in Weill Cornell's Feil Family Brain and Mind Research Institute, began his work on retromer function a decade ago, not long after retromer was discovered in yeast cells in 1998 and in mammalian cells in 2003. "We were looking for an approach to Alzheimer's research that was different from what other people were doing, an approach that got to something fundamental in the cell," says Dr. Petsko. He found it by collaborating with Dr. Scott Small, a neurologist at Columbia University College of Physicians & Surgeons who in 2004 found that retromer levels were low in the area of the brain where Alzheimer's originates; other collaborators have found that genes active in Alzheimer's disease regulate retromer levels.

Retromer transports amyloid precursor protein. It's a protein thought to be essential for the health of brain cells — but which, when it breaks into fragments, becomes amyloid-beta peptide (or "a-beta"), the substance that clumps into the hallmark plaques of Alzheimer's disease. The researchers hypothesized that when retromer levels are too low or when retromer malfunctions, it allows APP to linger too long in the endosome — an area that's enlarged in the brains of Alzheimer's patients — and there APP encounters the enzyme that begins to break it down. The a-beta plaques are the final fragment of APP's disintegration, and there is some evidence that the intermediate fragments may actually (or also) be what's toxic to the neuron. So Dr. Petsko and his collaborators aimed to find a way to keep APP flowing quickly through the cell by increasing retromer levels. "This was a difficult problem for us experimentally," Dr. Petsko says. "Most therapeutic studies require that you inhibit something, but it's quite another matter to get more of it."

He and his team turned to a strategy they'd pursued, along with the biotechnology company Amicus Therapeutics, for the treatment of Gaucher and Fabry diseases, two genetic, lipid- storage disorders that affect children. By binding a small molecule to an enzyme, they'd increased its stability, thus inducing its levels to rise; drugs based on this work are now in clinical trials. "If you made an origami bird and you wanted to keep it from falling apart, you'd tape one of the seams," Dr. Petsko explains. "The idea would be to use a drug as a kind of molecular tape and hold the protein together more tightly." Dr. Petsko's lab found a site between two of the proteins in the retromer complex into which a drug could fit, interacting with both at the same time. The compound, which acts as what scientists call a "chaperone," stabilized the retromer structure, boosted its overall numbers, and reduced levels of amyloid-beta and other APP misprocessing products in neurons. While it isn't viable as a drug — it is not very stable and would require too-frequent dosing in humans, for one thing — it was proof of concept. "It has shown, I think fairly conclusively, that retromer deficiency is a key issue, and that there is therapeutic promise in fixing that deficiency," Dr. Petsko says. "That tells us a lot more about the nature of the disease — that it isn't just a protein-misfolding disease, but it also involves issues of trafficking in the cell."

The idea that fixing an imbalance in a cell could remove the issue of toxicity is exciting, Dr. Petsko says. Rather than attacking plaques — an approach he likens to traditional thinking about cancer treatment, in which clinicians hit the disease with the equivalent of a nuclear weapon — this approach opens up the possibility for thinking about this disease in a more subtle way. "Philosophically," Dr. Petsko says, "my colleagues and I feel this has real merit."

Dr. Petsko and his collaborators are now researching other conditions that may be affected by retromer levels, including lysosomal storage diseases — such as Sandhoff disease, a rare disorder in which neurons are destroyed — and osteoporosis. Retromer has already been shown to play a role in Parkinson's, and the team is currently seeking to identify the mechanism by which it does so. That effort holds considerable promise for drug discovery, as it's easier to design clinical trials for Parkinson's than Alzheimer's, given that the former is simpler to diagnose and has a well-defined progression. And until scientists determine how to prevent neurodegenerative diseases completely, Dr. Petsko says, the goal is to either stop them in their tracks or turn them into manageable chronic conditions. "Alzheimer's typically progresses over a 10- to 15-year period," he notes. "If it progressed over a 30-year period, it wouldn't be so much of an issue. To really win, we might not have to do much more than change things a little bit."

— Andrea Crawford

This story first appeared in Weill Cornell Medicine,Vol. 14, No. 1.

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Leon Levy Fellowship in Neuroscience Renewed For $1.92 Million


Alzheimer's is a disease that likely touches everyone's lives, and neuroscientist Dr. Jacqueline Burré's is no exception. Having witnessed her grandmother's decline, Dr. Burré became devoted to understanding neurodegenerative diseases at the cellular level. That drive — and a fellowship from the Leon Levy Foundation — led her to study a protein linked to Alzheimer's and Parkinson's diseases, called alpha-synuclein, which she hopes will lead to the development of new biomarkers and therapeutic targets.

"Neurodegenerative diseases are devastating, not only to patients but also their families,"said Dr. Burré, an assistant professor of neuroscience in the Feil Family Brain and Mind Research Institute at Weill Cornell Medical College, who is a 2015 Leon Levy Fellow in neuroscience. "I want to do something to alleviate this burden on patients, their families and society. The Leon Levy Fellowship has allowed me to investigate the early events in the brain that trigger these diseases, and I'm really thankful for it and the foundation for providing me and other young investigators with the help and guidance to advance our work."

Since its launch at Weill Cornell in 2012 with a $1.5 million grant, the Leon Levy Fellowship has empowered seven young neuroscientists to pursue their innovative research. The fellowship provides them with funds to develop and advance their research projects and publish their findings in journals — all of which lay the foundation for additional financial support down the road. They also get the opportunity to network with other neuroscientists during an annual symposium sponsored by the Leon Levy Foundation.

Now, with a new $1.92 million grant, the Leon Levy Foundation is renewing the fellowship at Weill Cornell through 2019 and doubling the length of the program, expanding the term from one year to two. This will ensure that more burgeoning physicians and scientists have the chance to follow in Dr. Burré's footsteps.

"This fellowship gives junior faculty a year or two to establish their laboratory and develop some preliminary results so that they can go to the National Institutes of Health or other funding institutions and get a full-fledged grant, which is what really gets the science going,"said Dr. Costantino Iadecola, director of the Feil Family Brain and Mind Research Institute and the Anne Parrish Titzell Professor of Neurology and Neuroscience at Weill Cornell, who leads the fellowship program at the medical college.

Dr. Makoto Ishii, an assistant professor of neurology in the Department of Neurology and of neuroscience in the Feil Family Brain and Mind Research Institute, is an alumnus of the Leon Levy Fellowship. After watching his grandmother lose both cognitive function and weight because of Alzheimer's disease, he started coming up with research ideas that would tie the two together.

While "trying to get people to fund ideas is really difficult, particularly for those early in their careers and making a transition from medical trainee to independent research investigator,"Dr. Ishii said, once he received the Leon Levy Fellowship he was able to test his ideas in the lab and obtain tangible results. He discovered that protein pieces called amyloid-beta, "the bad culprit of Alzheimer's disease,"not only affect memory cells but also areas in the brain that control body weight. These results directly led to several presentations at international meetings, publication of his findings in scientific journals and importantly allowed him to garner additional external funding to continue his research. The fellowship also helped him directly with his career — he was promoted this year to assistant professor at Weill Cornell, leading to his own independent lab space where he can further develop his research program. "It is a wonderful fellowship, and I think it was integral and essential for my career,"he said.

Philanthropist Shelby White created the Leon Levy Foundation in 2004 in honor of her late husband, who had a passion for learning about how the brain impacts human behavior. "Though he was a financier, he was really a neuroscientist at heart,"Dr. Iadecola said.

In addition to Dr. Ishii, alumni who have benefited from the fellowship in years past include Dr. Amy Kuceyeski, an assistant professor of mathematics in the Department of Radiology; Dr. Victoria Blaho, an instructor in pathology and laboratory medicine; and Dr. Lakshman Puli, a former instructor in neuroscience in the Feil Family Brain and Mind Research Institute. Dr. Kuceyeski and Dr. Blaho also have appointments in the Feil Family Brain and Mind Research Institute.

Along with Dr. Burré, this year's Leon Levy fellows include Dr. Brendon Watson, an instructor in psychiatry and of neuroscience in the Feil Family Brain and Mind Research Institute, and Dr. Alon Seifan, an assistant professor of neurology.

"Our three fellows this year are really a perfect embodiment of what the Leon Levy Foundation and Leon Levy himself would have liked to see,"Dr. Iadecola said.

Dr. Watson, who uses silicon probes to study sleep at the cellular level in rats, has found that groups of cells become weaker and less coordinated as sleep persists, possibly allowing for better learning and performance when the animal reawakens.

"This fellowship served as a link in the chain to help me get additional funding, which is great,"Dr. Watson said. "I'm at a stage in my career where having extra funding means I can continue to be a scientist.”

Dr. Seifan studies Alzheimer's disease, specifically in people who had childhood learning disabilities. He believes there may be a correlation between childhood learning disabilities and the 10 percent of adult patients who are diagnosed with atypical forms of Alzheimer's, in which memory loss is not the initial symptom. He hopes that a better understanding of how childhood neurodevelopment relates to late- life neurodegeneration could lead to earlier diagnoses of atypical cases and could also provide clues as to why the disease begins in the first place.

"This fellowship enabled me to have my first faculty appointment at Weill Cornell and is helping me launch into the next step of my career,"Dr. Seifan said. "I wouldn't be where I am right now without it.”

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Mapping Alzheimer's Disease


Memory loss in older adults often raises the scary specter of Alzheimer's disease — even if the dragging memory is just routine aging. And if Alzheimer's is diagnosed, patients have no idea what to expect, and when.

pattern of atrophy in a patient with Alzheimer’s Disease

This image shows how the baseline pattern of atrophy (top panel) in a patient with Alzheimer’s Disease can be extrapolated to 5 years (middle) and 10 years out (bottom). Image credit: Eve LoCastro and Ashish Raj, IDEAL Laboratory, Weill Cornell Medical College

But this big gap in clinical practice surrounding dementia may soon be closed. A research team at Weill Cornell Medical College and the University of California, San Francisco has developed a mathematical model that determines where in the brain Alzheimer's has spread, predicts where it will appear next and how fast the brain's atrophy patterns will change — giving patients a roadmap of their future.

It can also tell when mild cognitive impairment (MCI) — often believed to be a precursor to Alzheimer's — is just simple memory loss, without further progressing to the Alzheimer phase.

The model, published Jan. 15 in the journal Cell Reports, is based on the new understanding that the two toxic proteins that are the hallmarks of Alzheimer's — tau and amyloid beta — spread in a neuron-to-neuron, prion-like fashion from the hippocampus, where the disease develops, to networks of neurons throughout the brain in a very predictable way.

"Neurologists today cannot tell a person with any certainty what a person with MCI or Alzheimer's is going to experience in the future," said lead author Dr. Ashish Raj, an associate professor of computer science in radiology at Weill Cornell. "This is a very debilitating problem if you are the person who is undergoing early signs of dementia and you want to know what will happen to you and when.

"With our model, we know exactly where Alzheimer's will go, how fast it will go and which parts of the brain it will affect," added Dr. Raj, who is also an associate professor of neuroscience at the Feil Family Brain and Mind Research Institute at Weill Cornell. "Because of this, we might be able to say with some confidence the time frame in which a person will convert to dementia or whether they will convert to dementia at all. This is very unique — and long needed."

The team studied the brains of 418 living participants with diagnoses of Alzheimer's or MCI, using a MRI brain atrophy scan and PET glucose metabolism scan, a test that looks at activity in the brain. Together, the scans provide a spatial map of brain atrophy in individual patients.

Dr. Raj expects that roadmaps of many neurodegenerative diseases, such as Parkinson's, will soon be possible. He says the maps will be based on the new understanding that all types of dementia is caused by toxic proteins that spread from one neuron to the next one, in distinct patterns.

"We have long known that neurodegeneration is linked to one group of toxic proteins or another, but the discovery that these proteins spread, in a prion-like pattern, is relatively new," Dr. Raj said. "That tells us that the trajectory of the neurodegenerative disease is purely a deterministic process — one that we can now use to inform our clinicians and patients."

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Blood Vessel Damage Plays Key Role in Alzheimer's-related Dementia


For many years, scientists have known that degeneration of neurons — nerve cells that transmit signals to and from the brain — caused Alzheimer's dementia, an incurable disease afflicting more than 35 million people worldwide and approaching epidemic proportions. Now, a new study from Weill Cornell Medical College reveals that changes occurring in blood vessels also play a major role — by limiting the supply of oxygen and glucose to the brain and contributing to the neuronal damage causing the disease.

Amyloid-beta — a protein fragment that accumulates in the brains of Alzheimer's patients — alters the normal function of neurons and sets the stage for dementia to develop. At the same time, it also acts directly on endothelial cells, the cells lining blood vessels that control the delivery of oxygen and glucose to the brain, thereby damaging their DNA, or genetic makeup, according to the study published Oct. 29 in Nature Communications.

Certain repair processes are put in place to override the damage, including activation of the DNA repair enzyme poly(ADP)-ribose polymerase, which ends up producing large amounts of the chemical ADP-ribose. ADP-ribose, in turn, activates a cellular surface channel — known as transient receptor potential melastatin-2 (TRPM2) — unleashing a flood of calcium ions into the endothelial cells. This sudden and massive calcium overload cripples the endothelial cells and disrupts the supply of blood to the brain, resulting in insufficient delivery of vital oxygen and glucose to the working brain cells.

"The brain blood vessels become unable to supply the oxygen and nutrients needed to fuel the most energy-demanding brain functions, such as learning and memory," says the senior author of the study, Dr. Costantino Iadecola, director of the Feil Family Brain and Mind Research Institute and the Anne Parrish Titzell Professor of Neurology.

The research, conducted in mice, identified a mechanism by which this amyloid-beta peptide impedes the regulation of blood flow to the brain. It also highlighted TRPM2 channels as a potential therapeutic target to counteract cerebrovascular dysfunction in Alzheimer's dementia and related conditions. Drugs are being developed that act on this channel to rescue the dysfunction of endothelial cells, enhance blood-flow delivery to the energy-deprived brain and delay disease progression.

Controlling hypertension, diabetes and obesity — so-called vascular risk factors — also may retard the progression and reduce the risk of Alzheimer's dementia, Dr. Iadecola says. Studies in which patients have been carefully monitored for decades have revealed that people who have these vascular risk factors in their 50s and 60s have an increased risk of developing Alzheimer's later in life.

About half of patients with an Alzheimer's diagnosis also have brain damage resulting from insufficient blood flow, indicating that the blood vessel alterations that contribute to stroke also could accelerate Alzheimer's decline, Dr. Iadecola says. Autopsy studies have confirmed that stroke and Alzheimer's pathologies often coexist in the same brain.

"No one knows why exactly," Dr. Iadecola says. "But most likely, as you get older, especially if vascular risk factors are present, you also tend to have more damage to your blood vessels, which favors accumulation of amyloid beta in the brain. In turn, amyloid beta causes even more damage to blood vessels and further reduces their ability to nourish the brain. It's a vicious cycle that eventually harms brain centers involved in learning and memory and leads to dementia; drugs inhibiting TRPM2 may break this cycle and help reduce the amyloid burden in the brain."

The paper was first authored jointly by Drs. Laibaik Park, assistant professor, and Gang Wang, associate research professor, both in the Feil Family Brain and Mind Research Institute.

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Researchers Discover Link Between Alzheimer's Disease Diagnosis and Accelerated Weight Loss


Alzheimer's disease and weight loss may seem like an unrelated clinical pair, but researchers at Weill Cornell Medical College have uncovered a connection between the two, revealing a potential early biomarker of the disease that may lead to improved diagnostic tools and targeted therapies for patients.

The research team at Weill Cornell's Feil Family Brain and Mind Research Institute discovered that the accumulation of a peptide called amyloid-beta inside the brain disrupts the body's mechanism to regulate its weight, leading to accelerated weight loss years before diagnosis. The findings, reported in the Journal of Neuroscience and presented at the Leon Levy Symposium last spring, reveal the complex cascade of events, from the initial buildup of amyloid-beta peptides that form Alzheimer's disease's hallmark plaques to the final decrease in weight. This knowledge could eventually be used to diagnose the disease and intervene earlier in patients' illnesses, and to potentially restore healthy body weight in those whose disease has progressed.

"Most researchers including myself have shifted focus to what's happening in the early stages of Alzheimer's disease," said lead author Dr. Makoto Ishii, the Leon Levy Fellow and an instructor of neuroscience in the institute. "There have been a lot of big clinical trials in the news that have failed, so the thought is that perhaps once patients develop dementia it may be irreversible. Therefore, can we intervene earlier?"

Like other physicians, Dr. Ishii had noticed that Alzheimer's patients — as well as his beloved grandmother — began losing weight up to six years before their diagnoses, with weight loss accelerating in the final year of their lives. The weight loss often occurs in the pre-symptomatic phase of the disease, before patients display symptoms of cognitive impairment. Dr. Ishii observed this process firsthand, noticing his grandmother lose weight before being diagnosed with Alzheimer's disease four years later. He was a neurology resident at the time, and there was little he could do.

"When you see this in your family you say, ‘We have to do something,'" he said. "My grandmother was a big impetus for me personally."

Using animal models to understand the connection between weight loss and Alzheimer's disease, and working with senior author Dr. Constantino Iadecola, the institute's director, Dr. Ishii compared the body weights of normal mice to mice with a mutant protein that expresses amyloid-beta peptides. He discovered that as amyloid-beta peptides increasingly accumulate in the brain, so does the weight disparity between the two groups. Accordingly, the investigators found that the mutant mice had low levels of the hormone leptin proportional to their fat stores. The low leptin should signal that the animal's fat stores are depleted and to therefore eat more or use less energy to maintain a healthy body weight. Since the mice did not do either of these activities, the researchers knew there was a problem with the signaling process.

To investigate the missing signal, Dr. Ishii and Dr. Gang Wang, an associate research professor in neuroscience at the institute, used electrophysiology, a method that reveals the behavior of brain cells by measuring their electrical activity. They found that a key sub-type of brain cells that produce the appetite-stimulating signal Neuropeptide Y (NPY) in the hypothalamus, one of the major physiological control centers of the brain, were not responding to leptin and other important metabolic signals, thereby preventing the brain from receiving the message to correctly regulate body weight. They discovered that this kink in the signaling system could short-circuit the body's mechanism for regulating its weight, resulting in a spiral of weight loss.

The scientists are optimistic that future research may yield similar results in humans. If it does, using significant drops in leptin concentration — in conjunction with other tools — could more accurately diagnose the disease since Alzheimer's can be hard to identify and to differentiate from other forms of cognitive decline, especially early in the disease process when the symptoms may be subtle. Identifying high-risk patients could also help place them in clinical trials for emerging medications.

And if doctors are eventually able to replenish the dysfunctional NPY signaling to restore healthy body weight, they may be able to help already-diagnosed Alzheimer's patients. Low body weight leads to increased illness and death in Alzheimer's patients and the elderly population overall, so maintaining a healthy body weight would mitigate this risk, Dr. Ishii said. Since his team found that the disease process leading to Alzheimer's disrupts the response of neurons to leptin in the hypothalamus, neurons in other areas — like the hippocampus, which controls memory, and the cortex, which controls executive function — could be similarly affected. Replenishing disrupted signaling in these regions could potentially promote brain health and boost cognitive function.

Dr. Ishii developed his investigation as part of his Leon Levy Fellowship, a neuroscience training program funded by the Leon Levy Foundation and led by Dr. Iadecola. The related symposium, hosted by Weill Cornell on April 30, provided fellows with the opportunity to learn about the work being done by their peers.

"The symposium brought forth not only the senior mentors of the Leon Levy Fellows, but also people who are at my stage, so we can get to know each other and bounce ideas off each other," said Dr. Ishii, whose mentor is Dr. Iadecola. "That was invaluable. This is a great tool because it helps advance neuroscience and neurology research at Weill Cornell by being part of the larger New York City community."

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"Chaperone" Compounds Offer New Approach to Alzheimer's Treatment


Compounds identified that stabilize retromer protein complex, which protects neurons from amyloid-beta

NEW YORK, NY (April 20, 2014) — A team of researchers from Columbia University Medical Center (CUMC), Weill Cornell Medical College, and Brandeis University has devised a wholly new approach to the treatment of Alzheimer's disease involving the so-called retromer protein complex. Retromer plays a vital role in neurons, steering amyloid precursor protein (APP) away from a region of the cell where APP is cleaved, creating the potentially toxic byproduct amyloid-beta, which is thought to contribute to the development of Alzheimer's.

pharmacologic chaperones compounds; retromer protein complex

Researchers have identified a new class of compounds—pharmacologic chaperones—that can stabilize the retromer protein complex (the blue and orange structure shows part of the complex). Retromer plays a vital role in keeping amyloid precursor from being cleaved and producing the toxic byproduct amyloid beta, which contributes to the development of Alzheimer's. The study found that when the chaperone named R55 (the multicolored molecule) was added to neurons in cell culture, it bound to and stabilized retromer, increasing retromer levels and lowering amyloid-beta levels. Image credit: Nature Chemical Biology and lab of Scott A. Small, MD/Columbia University Medical Center

Using computer-based virtual screening, the researchers identified a new class of compounds, called pharmacologic chaperones, that can significantly increase retromer levels and decrease amyloid-beta levels in cultured hippocampal neurons, without apparent cell toxicity. The study was published today in the online edition of the journal Nature Chemical Biology.

"Our findings identify a novel class of pharmacologic agents that are designed to treat neurologic disease by targeting a defect in cell biology, rather than a defect in molecular biology,"said Scott Small, MD, the Boris and Rose Katz Professor of Neurology, Director of the Alzheimer's Disease Research Center in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at CUMC, and a senior author of the paper. "This approach may prove to be safer and more effective than conventional treatments for neurologic disease, which typically target single proteins."

In 2005, Dr. Small and his colleagues showed that retromer is deficient in the brains of patients with Alzheimer's disease. In cultured neurons, they showed that reducing retromer levels raised amyloid-beta levels, while increasing retromer levels had the opposite effect. Three years later, he showed that reducing retromer had the same effect in animal models, and that these changes led to Alzheimer's-like symptoms. Retromer abnormalities have also been observed in Parkinson's disease.

In discussions at a scientific meeting, Dr. Small and co-senior authors Gregory A. Petsko, DPhil, Arthur J. Mahon Professor of Neurology and Neuroscience in the Feil Family Brain and Mind Research Institute and Director of the Helen and Robert Appel Alzheimer's Disease Research Institute at Weill Cornell Medical College, and Dagmar Ringe, PhD, Harold and Bernice Davis Professor in the Departments of Biochemistry and Chemistry and in the Rosenstiel Basic Medical Sciences Research Center at Brandeis University, began wondering if there was a way to stabilize retromer (that is, prevent it from degrading) and bolster its function. "The idea that it would be beneficial to protect a protein's structure is one that nature figured out a long time ago,"said Dr. Petsko. "We're just learning how to do that pharmacologically.”

Other researchers had already determined retromer's three-dimensional structure. "Our challenge was to find small molecules—or pharmacologic chaperones—that could bind to retromer's weak point and stabilize the whole protein complex,"said Dr. Ringe.

This was accomplished through computerized virtual, or in silico, screening of known chemical compounds, simulating how the compounds might dock with the retromer protein complex. (In conventional screening, compounds are physically tested to see whether they interact with the intended target, a costlier and lengthier process.) The screening identified 100 potential retromer-stabilizing candidates, 24 of which showed particular promise. Of those, one compound, called R55, was found to significantly increase the stability of retromer when the complex was subjected to heat stress.

The researchers then looked at how R55 affected neurons of the hippocampus, a key brain structure involved in learning and memory. "One concern was that this compound would be toxic,"said Dr. Diego Berman, assistant professor of clinical pathology and cell biology at CUMC and a lead author. "But R55 was found to be relatively non-toxic in mouse neurons in cell culture."

More important, a subsequent experiment showed that the compound significantly increased retromer levels and decreased amyloid-beta levels in cultured neurons taken from healthy mice and from a mouse model of Alzheimer's. The researchers are currently testing the clinical effects of R55 in the actual mouse model.

"The odds that this particular compound will pan out are low, but the paper provides a proof of principle for the efficacy of retromer pharmacologic chaperones,"said Dr. Petsko. "While we're testing R55, we will be developing chemical analogs in the hope of finding compounds that are more effective.”

The paper is titled, "Pharmacological chaperones stabilize retromer to limit APP processing."The other contributors are Vincent J. Mecozzi (Brandeis University), Sabrina Simoes (CUMC), Chris Vetanovetz (CUMC), Mehraj R. Awal (Brandeis University), Vivek M. Patel (CUMC), and Remy T. Schneider (CUMC).

The authors declare no financial or other conflicts of interests.

The study was supported by the grants from the National Institutes of Health (AG025161), the Alzheimer's Association, Developmental Therapeutics Program of the National Cancer Institute, Medkoo Biosciences, the Fidelity Biosciences Research Initiative, the McKnight Endowment for Neuroscience, the Ellison Medical Foundation, and the Gottlieb Family Foundation.

The Taub Institute for Research on Alzheimer's Disease and the Aging Brain

The Taub Institute for Research on Alzheimer's Disease and the Aging Brain at Columbia University Medical Center is a multidisciplinary group that has forged links between researchers and clinicians to uncover the causes of Alzheimer's, Parkinson's, and other age-related brain diseases and to discover ways to prevent and cure these diseases. It has partnered with the Gertrude H. Sergievsky Center at Columbia University Medical Center, which was established by an endowment in 1977 to focus on diseases of the nervous system, and with the Departments of Pathology & Cell Biology and of Neurology to allow the seamless integration of genetic analysis, molecular and cellular studies, and clinical investigation to explore all phases of diseases of the nervous system. For more information, visit The Taub Institute at

Columbia University Medical Center

Columbia University Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. For more information, visit or

The Helen and Robert Appel Alzheimer's Disease Research Institute

The Helen and Robert Appel Alzheimer's Disease Research Institute at Weill Cornell Medical College uses a multidisciplinary approach to study the causes of dementia and develop ways to prevent and treat them. Close cooperation between clinicians and basic researchers allows the Appel Institute to take discoveries from bench to bedside and back again, learning from patients as well as from cellular and animal models of disease. Its motto, "No Stone Unturned,"reflects its mission: to do everything possible to rid humanity of the scourge of neurodegenerative disorders. The Appel Institute is part of the Feil Family Brain and Mind Research Institute at Weill Cornell. For more information, visit

Weill Cornell Medical College

Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside, aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, Cornell University is the first in the U.S. to offer a M.D. degree overseas. Weill Cornell is the birthplace of many medical advances — including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, and most recently, the world's first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork- Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with Houston Methodist. For more information, visit

Brandeis University

Characterized by academic excellence since its founding in 1948, Brandeis University is one of the youngest private research universities in the United States, as well as the only nonsectarian Jewish-sponsored college or university in the country. Brandeis, named for the late Justice Louis Dembitz Brandeis of the U.S. Supreme Court, combines the faculty and resources of a world-class research institution with the intimacy and personal attention of a small liberal arts college. Brandeis is recognized for its distinguished community of scholars and students who are united in the passionate pursuit of knowledge with a steadfast commitment to social justice.

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