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Diagnostic biomarkers in saliva show promise in recognizing early Alzheimer’s disease

Your spit may hold a clue to future brain health. Investigators at the Beaumont Research Institute, part of Beaumont Health in Michigan, are hopeful that their study involving small molecules in saliva will help identify those at risk of developing Alzheimer’s disease – a neurologic condition predicted to reach epidemic proportions worldwide by 2050.

Their study, “Diagnostic Biomarkers of Alzheimer’s Disease as Identified in Saliva using 1H NMR-Based Metabolomics” was published in the Journal of Alzheimer’s Disease 58(2) on May 16.

Investigators found salivary molecules hold promise as reliable diagnostic biomarkers. The study exemplifies the quest by scientists to combat Alzheimer’s disease, a degenerative brain disorder with no cure and few reliable diagnostic tests. In the United States, Alzheimer’s is a health epidemic affecting more than 5 million Americans. Investigators seek to develop valid and reliable biomarkers, diagnosing the disease in its earliest stages before brain damage occurs and dementia begins.

Researcher Stewart Graham, Ph.D., said, “We used metabolomics, a newer technique to study molecules involved in metabolism. Our goal was to find unique patterns of molecules in the saliva of our study participants that could be used to diagnose Alzheimer’s disease in the earliest stages, when treatment is considered most effective. Presently, therapies for Alzheimer’s are initiated only after a patient is diagnosed and treatments offer modest benefits.”

Metabolomics is used in medicine and biology for the study of living organisms. It measures large numbers of naturally occurring small molecules, called metabolites, present in the blood, saliva and tissues. The pattern or fingerprint of metabolites in the biological sample can be used to learn about the health of the organism.

“Our team’s study demonstrates the potential for using metabolomics and saliva for the early diagnosis of Alzheimer’s disease,” explained Dr. Graham. “Given the ease and convenience of collecting saliva, the development of accurate and sensitive biomarkers would be ideal for screening those at greatest risk of developing Alzheimer’s. In fact, unlike blood or cerebrospinal fluid, saliva is one of the most noninvasive means of getting cellular samples and it’s also inexpensive.”

The study participants included 29 adults in three groups: mild cognitive impairment, Alzheimer’s disease and a control group. After specimens were collected, the researchers positively identified and accurately quantified 57 metabolites. Some of the observed variances in the biomarkers were significant. From their data, they were able to make predictions as to those at most risk of developing Alzheimer’s. Said Dr. Graham, “Worldwide, the development of valid and reliable biomarkers for Alzheimer’s disease is considered the No. 1 priority for most national dementia strategies. It’s a necessary first step to design prevention and early-intervention research studies.”

As Americans age, the number of people affected by Alzheimer’s is rising dramatically. According to the Alzheimer’s Association, by 2050, it’s estimated the number of Americans living with Alzheimer’s disease will triple to about 15-16 million.

Alzheimer’s disease is a type of dementia affecting a person’s ability to think, communicate and function. It greatly impacts their relationships, their independence and lifestyle. The condition’s toll not only affects millions of Americans, but in 2017, it could cost the nation $259 billion.

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Mayo Clinic Researchers Uncover New Agents That Eliminate Cells Associated with Age-Related Diseases

Mayo Clinic researchers have uncovered three new agents to add to the emerging repertoire of drugs that aim to delay the onset of aging by targeting senescent cells – cells that contribute to frailty and other age-related conditions. A recent study of human cell cultures shows that the drugs, fisetin and two BCL-XL inhibitors – A1331852 and A1155463 – cleared senescent cells in vitro. Findings appear online in Aging.

“Senescent cells accumulate with age and at sites of multiple chronic conditions, such as in fat tissue in diabetes, the lungs in chronic pulmonary diseases, the aorta in vascular disease, or the joints in osteoarthritis,” says James Kirkland, M.D., Ph.D., director of the Robert and Arlene Kogod Center on Aging. “At Mayo Clinic, we discovered the first senolytic drugs – agents that selectively eliminate senescent cells while leaving normal cells unaffected. These senolytic agents alleviated a range of age- and disease-related problems in mice. We used the hypothesis-driven approach that we used to discover the first senolytic drugs, two published in early 2015 and another later in 2015, to discover these three new senolytic drugs.”

Mayo Clinic researchers, working in collaboration with the University Medical Center Groningen and The Scripps Research Institute, induced senescence in human cell cultures by radiating human primary preadipocytes, Human Umbilical Vein Endothelial Cell cultures and IMR90 cell cultures. Then, using an ATPLite and a crystal violet assay, researchers measured cell viability and demonstrated that fisetin and BCL-XL inhibitors A1331852 and A1155463 cleared senescent cells in vitro.

In addition to fisetin and BCL-XL inhibitors, previously reported senolytics include dasatinib, quercetin, navitoclax (ABT263), and piperlongumine. Dr. Kirkland and collaborators are hopeful that fisetin, which is present in low concentrations in many fruits and vegetables, and the BCL-XL inhibitors may be better candidates for eventual translation into clinical interventions than some other senolytics due to their low toxicity levels.

“We predict many more senolytic drugs will appear at an accelerating pace over the next few years and that these drugs will be improved to more effectively target senescent cells,” says Dr. Kirkland. “These three drugs, if effective in clinical trials, could be transformative. While additional studies are needed to determine the safety and efficacy, we hope that they will be able to extend health span and delay the onset of multiple age-related diseases and disabilities.”

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Researchers Identify How Inflammation Spreads Through the Brain After Injury

Findings Could Transform How Understanding of Brain Injury and Disease

Researchers have identified a new mechanism by which inflammation can spread throughout the brain after injury. This mechanism may explain the widespread and long-lasting inflammation that occurs after traumatic brain injury, and may play a role in other neurodegenerative diseases.

The findings were published today in a study in the Journal of Neuroinflammation.

This new understanding has the potential to transform how brain inflammation is understood, and, ultimately, how it is treated. The researchers showed that microparticles derived from brain inflammatory cells are markedly increased in both the brain and the blood following experimental traumatic brain injury (TBI). These microparticles carry pro-inflammatory factors that can activate normal immune cells, making them potentially toxic to brain neurons. Injecting such microparticles into the brains of uninjured animals creates progressive inflammation at both the injection site and eventually in more distant sites.

Research has found that neuroinflammation often goes on for years after TBI, causing chronic brain damage. The researchers say that the microparticles may play a key role in this process.
Chronic inflammation has been increasingly implicated in the progressive cell loss and neurological changes that occur after TBI. These inflammatory microparticles may be a key mechanism for chronic, progressive brain inflammation and may represent a new target for treating brain injury.

The researchers on the paper include four University of Maryland School of Medicine researchers: Alan Faden, Stephen R. Thom, Bogdan A. Stoica, and David Loane.

“These results potentially provide a new conceptual framework for understanding brain inflammation and its relationship to brain cell loss and neurological deficits after head injury, and may be relevant for other neurodegenerative disorders such as Alzheimer disease in which neuroinflammation may also play a role,” said Dr. Faden. “The idea that brain inflammation can trigger more inflammation at a distance through the release of microparticles may offer novel treatment targets for a number of important brain diseases.”

The researchers studied mice, and found that in animals who had a traumatic brain injury, levels of microparticles in the blood were much higher. Because each kind of cell in the body has a distinct fingerprint, the researchers could track exactly where the microparticles came from. The microparticles they looked at in this study are released from cells known as microglia, immune cells that are common in the brain. After an injury, these cells often go into overdrive in an attempt to fix the injury. But this outsized response can change protective inflammatory responses to chronic destructive ones.

The findings have important potential clinical implications. The researchers say that microparticles in the blood have the potential to be used as a biomarker – a way to determine how serious a brain injury may be. This could help guide treatment of the injuries, whose severity is often difficult to gauge.

They also found that exposing the inflammatory microparticles to a compound called PEG-TB could neutralize them. This opens up the possibility of using that compound or others to treat TBI, and perhaps even other neurodegenerative diseases.

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New Understandings of Cell Death Show Promise for Preventing Alzheimer’s

New research on peptides important to understanding Alzheimer’s disease and their effects on cell toxicity could lead to treatments for preventing or delaying neurodegenerative diseases

Alzheimer’s disease is a progressive neurodegenerative disorder that leads to dementia via advanced neuronal dysfunction and death. A person with Alzheimer’s disease suffers loss of control over thought, memory and language abilities. Additionally, the disease takes an emotional, social and economic toll on family members of individuals living with the disease. Alzheimer’s disease is also a burden for health care system in the U.S., with as many as 5 million Americans living with the disease in 2013, according to the U.S. Centers for Disease Control and Prevention, and that number is expected to continue rising.

Currently, the predominant theory behind Alzheimer’s disease is the “amyloid hypothesis,” which states that abnormally increased levels of amyloid beta (Aβ) peptides outside of brain cells produce a variety of low molecular weight Aβ aggregates that are toxic to the nervous system. These Aβ aggregates interact directly with target cells and lead to cell death.

During the Biophysical Society’s 61st Annual Meeting, being held Feb. 11-15, 2017, in New Orleans, Louisiana, Antonio De Maio, a professor of surgery and neuroscience at the University of California, San Diego (UCSD), will present his work hunting for the specific mechanisms behind Aβ-induced toxicity to cells, or cytoxicity.

Cells exposed to stressful conditions respond by expressing heat shock proteins (hsps), whose job is to preserve cell viability. Hsp70, in particular, is a molecular chaperone that plays a major role in protein folding and the solubilization of misfolded, aggregated polypeptide proteins inside cells.

The researchers were interested in Hsp70 because, according to De Maio, it has also been found outside of cells, potentially coexisting with Aβ peptides.
His team observed that HsP70 did, in fact, reduce oligomerization of Aβ peptides.

Significantly, the researchers further inferred that the reduced oligomerization of Aβ, where individual monomer molecules join to form a longer oligomer, might result in lower cellular toxicity, perhaps by blocking the assembly of Aβ ion channels. And in fact this is what they found, demonstrating a substantial reduction — approximately 70 percent — of Aβ peptide’s toxicity upon co-exposure to Hsp70.

“Based upon these observations, we predicted that inducing the extracellular release of Hsp70 might have a beneficial effect on Alzheimer’s disease,” said De Maio. “But it should be taken into consideration that we don’t know any potential long-term side effects of extracellular Hsp70 for human health.”

While extremely promising at this stage, “more investigations of the interface between Hsp70 and Aβ peptides are necessary for any further developments,” De Maio said.

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Georgetown Clinical Trial of Nilotinib in Alzheimer’s Disease Begins

 A clinical trial to examine the effect of nilotinib on clinical outcomes and biomarkers in people with mild to moderate Alzheimer’s disease has opened at Georgetown University Medical Center (GUMC).

The clinical trial is a phase II, randomized, double blinded, placebo-controlled study to evaluate the impact of low doses of the cancer drug(Tasigna®). GUMC is conducting the study with its clinical partner, MedStar Georgetown University Hospital.

The rationale for using nilotinib is based on laboratory and clinical research conducted by the Georgetown Translational Neurotherapeutics Program (TNP). Nilotinib appears to aid in the clearance of accumulated beta-amyloid (Abeta) plaques and Tau tangles in the brain. Both are hallmarks of Alzheimer’s disease. Nilotinib appears to penetrate the blood-brain barrier and turn on the “garbage disposal” machinery inside neurons (a process known as autophagy) to clear the Tau, Abeta and other toxic proteins.

“In a 2015 proof of concept study at Georgetown, patients with Parkinson’s disease or dementia with Lewy bodies were treated with nilotinib. As my colleagues reported, those who completed the study had a reversal in disease progression, observed both clinically and in key biomarkers—the same biomarkers seen in Alzheimer’s,” explains Scott Turner, MD, PhD, medical co-director of the TNP, who will serve as principal investigator for the study. “But even before the Parkinson’s study, research in the laboratory strongly supported studying this drug in people with Alzheimer’s. The promising results of the Parkinson’s study give an even stronger rationale.”

“When used in higher doses for chronic myelogenous leukemia (CML), nilotinib forces cancer cells into autophagy or cell death. The dose used in CML treatment is significantly higher than what we will use in our Alzheimer’s study,” says Charbel Moussa, MB, PhD, scientific and clinical research director for the Translational Neurotherapeutics Program. “When used in smaller doses once a day, as in this study, it appears nilotinib turns on autophagy for about four to eight hours—long enough to clean out the cells without causing cell death. Toxic proteins that build up again then appear to be cleared when the drug is given again the next day.”

Moussa initially conducted the preclinical research that led to the discovery of nilotinib for the potential treatment of neurodegenerative diseases.

Moussa is an inventor on a US patent owned by Georgetown University and on other pending US and foreign patent applications for use of nilotinib and other tyrosine kinase inhibitors for the treatment of neurodegenerative diseases.

The Alzheimer’s Drug Discovery Foundation is supporting this clinical trial through a $2.1 million grant to Turner. The study has also received private philanthropic support.

Turner conducts additional clinical research supported by funding to Georgetown University from Lilly, Biogen, Merck, Acadia, and Toyama as well as the National Institutes of Health and Department of Defense.

To learn more about this clinical trial, please click here. To learn about other Alzheimer’s clinical studies, please visit the Georgetown Memory Disorders Program website.

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Researchers Find a Potential Target for Anti-Alzheimer’s Treatments

Scientists at the Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg have identified a gene that may provide a new starting point for developing treatments for Alzheimer’s disease (AD). The USP9 gene has an indirect influence on the so-called tau protein, which is believed to play a significant role in the onset of Alzheimer’s disease. This discovery by the LCSB researchers, led by Dr. Enrico Glaab, may open a new door to developing active ingredients to treat Alzheimer’s disease. The scientists recently published their findings in the journal Molecular Neurobiology (DOI: 10.1007/s12035-016-0299-z).

Alzheimer’s disease is characterised by the progressive destruction of brain cells and their contacts (neurons and synapses). The brains of Alzheimer patients exhibit protein deposits known as amyloid plaques. The symptoms of the disease are memory disorders, disorientation, speech impediments, impaired thinking and judgement, and even personality changes. The likelihood of developing AD increases dramatically with age. The number of people affected is therefore rising along with our increasing life expectancy: An estimated 35 million people in the world have Alzheimer’s disease today. By 2030, this number could rise to about 65 million, and by 2050 to over 100 million. It has never been fully explained how the disease develops. It is likely, however, that molecular malformations in brain cells play a crucial role, involving among other molecules the so-called tau proteins. In Alzheimer’s patients, tau proteins aggregate into tangles of threadlike structures, called neurofibrils, which deposit between the brain cells and disrupt their function.

“The risk of developing Alzheimer’s disease at an advanced age is much higher in women than in men – even after adjusting for the longer average life expectancy of women,” says Dr. Enrico Glaab, head of the research group Biomedical Data Science at LCSB. Glaab took this as a hint to start looking for molecular differences between the sexes that could contribute to the differences in frequency and characteristics of the disease. To do so, he and his team analysed thousands of data series on samples from the brains of around 650 deceased people of both sexes, some of whom had been afflicted with the disease and others who had not.

The researchers encountered a gene that could be an important determinant for the gender-specific differences in Alzheimer’s disease pathology. The gene, called ubiquitin-specific peptidase 9 (USP9), influences the activity of another gene that encodes the microtubule associated protein tau (MAPT). MAPT, in turn, is already suspected of being heavily involved in the onset of Alzheimer’s disease.

To study the action of USP9, and the relationship between its role and the role of tau in Alzheimer’s disease, Enrico Glaab and colleagues from other LCSB workgroups examined the gene in cell cultures and zebrafish experiments. The scientists blocked the activity of USP9 and measured the effects of this “knockdown” on MAPT gene activity in the two model systems of cell cultures and zebrafish.

“We were able to show that USP9 knockdown significantly reduces the activity of the tau gene in both models,” Glaab reports. Accordingly, USP9 could serve as a target for future tau-modulating small molecule compounds – even if there is still a long way to go before anti-Alzheimer’s drugs based on this principle can be developed.

To gain a deeper understanding of the molecular signal chain connecting USP9 and MAPT, the researchers at LCSB developed a computer model that combines the measured data with known regulatory information from the literature. They discovered that proteins that had already been suggested as potential drug targets are also influenced by USP9. Through parallel alteration of multiple tau regulators, USP9 could therefore have a greater effect as a pharmaceutical target than previously proposed targets.

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Weston Brain Institute Funds Clinical Trials of New Alzheimer’s Treatment

Electrocranial stimulation offers hope for Alzheimer’s patients

Funding for clinical trials of a new treatment for Alzheimer’s disease has been announced by the Weston Brain Institute. Dr. Zahra Moussavi, Canada Research Chair in Biomedical Engineering in the Faculty of Engineering, is receiving $1,737,960 for her project on investigating the efficacy of high-frequency rTMS treatment for Alzheimer’s disease.

Alzheimer’s disease has no known cure and is called the pandemic of the century. Recent trials applying repetitive transcranial magnetic stimulation (rTMS) in Alzheimer’s patients have reported encouraging results in improving or stabilizing cognition. This proposal is the first large placebo-controlled double-blind study designed with sufficient statistical rigor to measure the efficacy of rTMS treatment in Alzheimer’s.

“The Weston Brain Institute is pleased to support this kind of critical high-risk, high-reward work,” said Alexandra Stewart, Executive Director at the Weston Brain Institute.

“If successful, Dr. Moussavi’s work with rTMS will be a significant step forward in developing effective treatments for Alzheimer’s disease,” Stewart said.

Moussavi will lead a team of local, national and international collaborators on this research that includes: Drs. Mandana Modirrousta (Psychiatry), Colleen Millikin (Clinical Health Psychology), Xikui Wang (Statistics), Behzad Mansouri (Neurology), and Craig Omelan (Psychiatry) in collaboration with colleagues from McGill (Montreal – Drs. Lesley Fellows and Lisa Koski) and Monash (Australia – Dr. Paul Fitzgerald) universities.

“All Manitobans will benefit from the research discoveries this funding will fuel,” says Dr. John (Jay) Doering, Associate Vice-President (Partnerships) at the University of Manitoba. “New treatments for Alzheimer’s disease are being sought worldwide. Dr. Moussavi’s research program will result in better quality of life for patients, families and caregivers.”

Transcranial Magnetic Stimulation (TMS) is a procedure in which a current passes through a coil placed on the scalp producing a magnetic field. The magnetic field passes through the skull to the brain, wherein a small current is induced. Application of repetitive(r) TMS at either low or high frequencies has been used for treatment of many neurological and neurodegenerative disorders but is still at the research stage in all except depression, for which rTMS is approved for treatment worldwide.

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Eli Lilly, Biogen, and Neurotrope Fight to Find Viable Treatment for Alzheimer’s Disease

Repeated attempts to treat or even slow the relentless progression of Alzheimer’s disease by targeting just one red flag in patient’s brains have continued to lead to disappointing outcomes.

Last Sunday “Sixty Minutes” episode aired on Columbian extended families that inherited a genetic defect that causes early onset Alzheimer’s, by the time they reach 45 years old.

Watching the episode brings to light another case in which a young lady with a different genetic mutation caused her to be afflicted with Alzheimer’s, at the age of 30 years old.

That young lady lost the ability to swallow, causing her to be hooked up to a feeding tube.  She also lost the ability to move her limbs and recognize people.  Dr. Alkon, currently President and Chief Scientific Officer of Neurotrope, (NTRP) was allowed under an FDA compassionate use program to treat the young lady.  She was treated with a drug called bryostatin, which is not a statin, it activates PKC epsilon.  Within a short time she was able to recognize people, extend her arm to reach out to her husband and begin to swallow. This allowed her to be removed from the feeding tube so that she could drink from a straw and eventually regain the ability to speak some words.

The activation of PKC epsilon activates the main amyloid degrading enzymes, ECE, neprilysin, and IDE while activating Alpha Secretase.  Alpha Secretase has been a target for treating Alzheimer’s.  The problem has been finding a safe one.  Eli Lilly’s(LLY) and Biogen’s (BIIB) drugs are monoclonal antibodies that inhibit amyloid beta.  But Lilly’s drug, solanezumab, just failed a major Phase III trial, showing it was no better at slowing down cognitive decline than placebo. Merck (MRK) has a BACE inhibitor that also inhibits amyloid beta.  Neurotrope’s bryostatin, in addition to degrading amyloid, also normalizes GSK3 beta.  That mechanism prevents the hyperphosphorylation of tau.  So you don’t have to be a tauist or a baptist, bryostatin hits both targets.

Incredibly, bryostatin also activates growth factors in the brain, such as BDNF, NGF and IGF-1.  This mechanism causes synaptogenesis.  That allows the brain to restore damaged synapses and grow new synapses. The hope is that the damage caused by Alzheimer’s disease may actually be reversed through this mechanism.

Dr. Alkon didn’t start out by trying to find a drug to fight Alzheimer’s.  He was leading a department at the NIH trying to find out how to increase memory and he came upon PKC epsilon.  PKC epsilon was the conductor in the center of the orchestra, arranging the different mechanisms to create the masterpiece of memory.

Take that, Eli Lilly and Biogen.  You guys have to give your drugs extremely early in the disease, to have any hope of your drugs working, because you need to treat patients before any damage to the synapses has occurred.  So far all those drugs have failed, and the excuse is always that they haven’t been given early enough in the disease process.  If bryostatin can reverse the disease in moderate to severe patients, the drug would be given in all stages.  Perhaps even for prevention in the early onset mutations or APOE4 cases.  Yes, Dr. Alkon even has performed preclinical studies showing that bryostatin can counteract the negative genetic mechanism of the APOE4 gene.

The data that the company will be releasing in five months, April 2017, from their 148 patient Phase II placebo controlled trial.  Multi modal efficacy of bryostatin targeting PKC epsilon, versus everyone else’s drugs, that are just trying to hit one target.  It isn’t even a fair fight. Neurotrope’s bryostatin, if approved, is a blockbuster for one of the largest unmet medical needs in the world today.

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Dysfunction In Neuronal Transport Mechanism Linked To Alzheimer’s Disease

Researchers at University of California San Diego School of Medicine have confirmed that mutation-caused dysfunction in a process cells use to transport molecules within the cell plays a previously suspected but underappreciated role in promoting the heritable form of Alzheimer’s disease (AD), but also one that might be remedied with existing therapeutic enzyme inhibitors.

The findings published in the October 11 online issue of Cell Reports.

“Our results further illuminate the complex processes involved in the degradation and decline of neurons, which is, of course, the essential characteristic and cause of AD,” said the study’s senior author Larry Goldstein, PhD, Distinguished Professor in the Departments of Neuroscience and Cellular and Molecular Medicine at UC San Diego School of Medicine and director of both the UC San Diego Stem Cell Program and Sanford Stem Cell Clinical Center at UC San Diego Health. “But beyond that, they point to a new target and therapy for a condition that currently has no proven treatment or cure.”

Alzheimer’s disease is a neurodegenerative disorder characterized by progressive memory loss and cognitive dysfunction. It affects more than 30 million people worldwide, including an estimated 5.4 million Americans. One in 10 persons over the age of 65 has AD; one in three over the age of 85. There are currently no treatments proven to cure or reduce the progression of AD.

Genetically, AD is divided into two groups: the much more common sporadic (sAD) form of the disease in which the underlying primary cause is not known and the rarer familial (fAD) form, produced by inherited genetic mutations. In both forms, the brains of AD patients feature accumulations of protein plaques and neurofibrillary tangles that lead to neuronal impairment and eventual cell death.

The prevailing “amyloid cascade hypothesis” posits that these plaques and tangles are comprised, respectively, of amyloid precursor protein (APP) fragments and tau proteins that fuel cellular stress, neurotoxicity, loss of function and cell death. There has been some evidence, however, of another disease-driver: defects in endocytic trafficking — the process by which cells package large, external molecules into vesicles or membrane-bound sacs for transport into the cell for a variety of reasons or uses.

But previous research focused on non-neuronal cells and did not examine the effects of normal expression levels of AD-related proteins, leaving it unclear to what degree decreased endocytosis and other molecular movement within cells played a causative role.

Goldstein and colleagues analyzed neurons created from induced pluripotent stem cells in which they generated PS1 and APP mutations characteristic of fAD using the emerging genome editing technologies CRISPR and TALEN. In this “disease-in-a-dish” approach, they found that the mutated neurons displayed altered distribution and trafficking of APP and internalized lipoproteins (proteins that combine with or transport fat and other lipids in blood plasma). Specifically, there were elevated levels of APP in the soma or cell body while levels were reduced in the neuronal axons.

In previous work, Goldstein’s team had demonstrated that PS1 and APP mutations impaired the activity of specific cellular enzymes. In the latest work, they found that treating mutated fAD neurons with a beta-secretase inhibitor rescued both endocytosis and transcytosis (molecule movement within a cell) functions.

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New Clinical Trial Will Test Cancer Drug As Alzheimer’S Treatment

The Alzheimer’s Drug Discovery Foundation (ADDF) announces a $2.1 million grant awarded to R. Scott Turner, MD, PhD, of Georgetown University Medical Center to conduct a phase II clinical trial of low-dose nilotinib (marketed as Tasigna® for use as a cancer therapy) in patients with Alzheimer’s disease.

Nilotinib is an FDA-approved drug for the treatment of adult chronic myeloid leukemia. In preclinical studies conducted by Georgetown researchers, nilotinib reduced cognitive impairment by targeting two of the underlying causes of Alzheimer’s—neuroinflammation and misfolded proteins. Nilotinib triggers a process (called autophagy) that removes the toxic proteins tau and beta-amyloid from the brain before they accumulate into plaques and tangles.

Dr. Turner, co-medical director of Georgetown University Medical Center’s Translational Neurotherapeutics Program (TNP) and director of the Georgetown Memory Disorders Program, says, “By stimulating the brain’s normal autophagic process, which clears out these misfolded proteins in cells, we hope to prevent or slow the progression of Alzheimer’s. In fact, nilotinib may be a first—a broad-spectrum anti-neurodegenerative drug that targets all misfolded protein aggregates that accumulate in the brain of Alzheimer’s patients. By targeting both amyloid and tau, this study may point the way to a new strategy in Alzheimer’s disease treatment.”

The preclinical research was conducted by Charbel Moussa, MD, PhD, scientific and clinical research director for Georgetown’s TNP, who explains, “Nilotinib seems to activate the cell’s garbage disposal machine, reduce plaques and tangles and reverse cognitive decline in animal models of Alzheimer’s disease. We hope that this trial will clarify the effects of nilotinib in Alzheimer’s patients.” Moussa will be a co-investigator on the Alzheimer’s trial.

The trial is expected to start this year and will include 42 patients, with half randomized to receive an escalating dose of nilotinib, while the other half receives a placebo. The primary objectives of the study will be to test the drug’s safety and tolerability and to measure whether nilotinib reduces inflammation and the presence of beta-amyloid and tau in spinal fluid. Dr. Turner and his colleagues in the Georgetown Memory Disorders Program will also perform cognitive and functional abilities tests.

Dr. Howard Fillit, Founding Executive Director and Chief Science Officer of the ADDF, says: “The ADDF is proud to support a clinical trial that holds such promise for Alzheimer’s patients. This funding is part of our wider initiative to use the knowledge gained from cancer research to advance effective treatments for Alzheimer’s.”

The ADDF’s initiative “Learning from Cancer to Advance Treatments for Neurodegenerative Diseases” launched in 2015 with a conference held in partnership with the New York Academy of Sciences. Its goal is both to develop new therapies and test existing cancer therapies for their potential in treating Alzheimer’s disease. In addition to the nilotinib trial at Georgetown, this initiative includes funding for drug development projects at Oryzon Genomics, Rodin Therapeutics, and Yuma Therapeutics.

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Georgetown Receives FDA Clearance To Conduct Clinical Trial With Nilotinib In Alzheimer’s Disease

Georgetown University Medical Center (GUMC) today announces the U.S. Food and Drug Administration has completed its review of an investigational new drug application (IND) for the use of nilotinib in a phase II clinical trial for patients with mild to moderate Alzheimer’s disease.

The FDA also informed GUMC investigators that the study can proceed. The clinical trial is expected to begin this year at Georgetown University Medical Center with its clinical partner, MedStar Georgetown University Hospital.

The clinical trial is a phase II, randomized, double blinded, placebo-controlled study to evaluate the impact of low doses of nilotinib (sold as Tasigna®) on biomarkers and clinical outcomes in people with mild to moderate Alzheimer’s disease.

The rationale for using nilotinib is based on research conducted at Georgetown and involves clearing the brain of accumulated beta-amyloid (Abeta) plaques and Tau tangles. Both biomarkers are hallmarks of Alzheimer’s disease. Nilotinib appears to penetrate the blood-brain barrier and turn on the “garbage disposal” machinery inside neurons (a process known as autophagy) to clear Tau and Abeta and other toxic proteins.

“In a 2015 small study at Georgetown, patients with Parkinson’s and dementia with Lewy bodies were given nilotinib. As my colleagues reported, all who completed the study had a reversal in disease progression, observed both clinically and in key biomarkers — the same biomarkers seen in Alzheimer’s ,” explains Scott Turner, MD, PhD, co-medical director of Georgetown University Medical Center’s Translational Neurotherapeutics Program and director of the Georgetown Memory Disorders Program, who will lead the Alzheimer’s study. “But even before the Parkinson’s study, research in the laboratory strongly supported studying this drug in people with Alzheimer’s. The promising results of the Parkinson’s study gives an even stronger rationale.”

Charbel Moussa, MD, PhD, conducted the preclinical research that led to the discovery of nilotinib for the treatment of neurodegenerative diseases.

“When used in higher doses for chronic myelogenous leukemia (CML), nilotinib forces cancer cells into autophagy or cell death. The dose used in CML treatment is significantly higher than what we will use in our Alzheimer’s study,” says Moussa, scientific and clinical research director for the Georgetown Translational Neurotherapeutics Program. “When used in smaller doses once a day, as in this study, nilotinib turns on autophagy for about four to eight hours — long enough to clean out the cells without causing cell death. Toxic proteins that build up again will be cleared when the drug is given again the next day.”

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Genetic ‘Switch’ Identified As Potential Target For Alzheimer’S Disease

A team at the MRC Clinical Sciences Centre (CSC), based at Imperial College London, has found an important part of the machinery that switches on a gene known to protect against Alzheimer’s Disease.

Working in collaboration with scientists at the Hong Kong University (HKU) and the Erasmus University in Rotterdam, CSC associate professor Richard Festenstein explored the steps by which this Neuroglobin gene is gradually switched on, or up-regulated.

Neuroglobin has previously been shown to protect against Alzheimer’s disease in mice in which it makes the protective Neuroglobin. It is thought that the gene might play a protective role early in the disease in patients, but appears to be down-regulated as the disease progresses. It may therefore prove useful in developing new ways to try to prevent or treat this common cause of dementia, for which there is currently no cure.

Professor Festenstein and Dr Tan-Un from HKU, with help from Professor Sjaak Phillipsen at the Erasmus University, examined how the Neuroglobin gene ‘folds up’ in the cell using a technique called chromosome conformation capture. In results published today in the journal Nucleic Acids Research, they showed that a particular region of DNA, outside the coding region of the Neuroglobin gene itself, loops round to make contact with the start of the gene.

They tested the ability of this newly-identified DNA region to switch on the Neuroglobin gene using two approaches. First, they linked the DNA region directly to another so-called ‘reporter’ gene, and demonstrated simply that it does indeed act as an up-regulator. Second, they used the new ‘Crispr’ technique of gene editing to completely remove this section of DNA from the cell, and showed that the Neuroglobin gene was no longer switched on.

Together, the results gave the team confidence that this newly-identified DNA region is indeed a powerful switching mechanism of the Neuroglobin gene.

As Neuroglobin is thought to be protective in Alzheimer’s, it may be possible in the future to use this ‘switch’ in developing new treatments, such as gene therapy. Such therapeutic approaches require a compact ‘chunk’ of DNA to be most efficient. Importantly, the team pinpointed the position of the new regulatory region, and found that it is some distance away from the Neuroglobin gene itself. It may now be possible to remove the less relevant sections of DNA in between the Neuroglobin gene and its regulator to create an efficient therapeutic gene therapy unit. It may be that this target may prove useful not only in Alzheimer’s but also in other neurodegenerative diseases.

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Vesicles That Trap Amyloid Appear to Also Contribute to Alzheimer’s Disease

Vesicles, fluid-filled sacs that brain cells make to trap amyloid, a hallmark of Alzheimer’s, appear to also contribute to the disease, scientists report.

Reducing the production of these vesicles, called exosomes, could help reduce the amount of amyloid and lipid that accumulates, slow disease progression and help protect cognition, scientists at the Medical College of Georgia at Augusta University report in The Journal of Neuroscience.

When confronted with amyloid, astrocytes, plentiful brain cells that support neurons, start making exosomes, to capture and neutralize it, said Dr. Erhard Bieberich, neuroscientist in the MCG Department of Neuroscience and Regenerative Medicine and the study’s corresponding author.

“If you swarm astrocytes with amyloid, you trigger an aggressive response,” he said. Happy astrocytes, on the other hand, don’t make exosomes.

Not unlike a landfill, the real problems begin when the biological sacs get piled too high. In such volume and close proximity to neurons, exosomes begin to interfere with communication and nutrition, neurons stop functioning well and eventually begin to die, a scenario that fits with disease progression, Bieberich said.

MCG scientists followed the process in an animal model with several genetic mutations found in types of Alzheimer’s that tend to run in families and make brain plaques early in life. One mouse group also was genetically programmed to make a nonfunctional form of the enzyme neutral sphingomyelinase-2. Amyloid also activates this enzyme, which converts another lipid, called sphingomyelin, into ceramide, a component of the brain cell membrane known to be significantly elevated in Alzheimer’s. In fact, with disease, the brain has two to three times more of the lipid known for its skin-softening ability.

The MCG scientists found exosomes made by astrocytes accelerated the formation of beta amyloid and blocked its clearance in their animal model of Alzheimer’s. Male mice, which were also sphingomyelinase-deficient, developed fewer plaques and exosomes, produced less ceramide and performed better in cognitive testing.

For reasons that are unclear, female mice did not reap similar benefits, said Bieberich, noting that Alzheimer’s tends to be more aggressive in women. His earlier work has shown that female mice have higher levels of antibodies in response to the elevated ceramide levels that further contribute to the disease.

His new work is the first evidence that mice whose brain cells don’t make as many exosomes are somewhat protected from the excessive plaque accumulation that is the hallmark of Alzheimer’s. It is also an indicator that drugs that inhibit exosome secretion may be an effective Alzheimer’s therapy, Bieberich said. Current strategies to prevent plaque formation, have been unsuccessful, the researchers write.

“We show clearly that sphingomyelinase is causative here in making ceramide, making exosomes and in making plaques,” Bieberich said. He and his teams already are testing different drugs given to patients for reasons other than Alzheimer’s that may also inhibit sphingomyelinase and ultimately ceramide and exosome production.

Inside the brain, ceramide is an important component of the cell membrane, but too much starts collecting in the exosomes, combining with the amyloid to form a disruptive and eventually deadly aggregate. In fact, MCG scientists could see the ceramide and amyloid clustered together in the brains of mice without sphingomyelinase suppression, further implicating a close association.

In a scenario that seems to go full circle, Bieberich has mounting evidence that in Alzheimer’s, there is a shorter, “bad” form of ceramide coating the antennae of astrocytes. Normally, antennae help astrocytes focus on taking care of neurons. But the shorter version that he believes contributes to disease has astrocytes giving up their caretaker role, spending their energy on themselves and starting to divide.

Bieberich and his team already are looking for other exosome triggers such as inflammation-producing immune cells called cytokines as well as physical trauma. Ceramide levels have been proposed as an early Alzheimer’s biomarker as has evidence of amyloid-positive exosomes in the blood.

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Antibiotics Weaken Alzheimer’s Disease Progression Through Changes in the Gut Microbiome

Long-term treatment with broad spectrum antibiotics decreased levels of amyloid plaques, a hallmark of Alzheimer’s disease, and activated inflammatory microglial cells in the brains of mice in a new study by neuroscientists from the University of Chicago.

The study, published July 21, 2016, in Scientific Reports, also showed significant changes in the gut microbiome after antibiotic treatment, suggesting the composition and diversity of bacteria in the gut play an important role in regulating immune system activity that impacts progression of Alzheimer’s disease.

“We’re exploring very new territory in how the gut influences brain health,” said Sangram Sisodia, PhD, Thomas Reynolds Sr. Family Professor of Neurosciences at the University of Chicago and senior author of the study. “This is an area that people who work with neurodegenerative diseases are going to be increasingly interested in, because it could have an influence down the road on treatments.”

Two of the key features of Alzheimer’s disease are the development of amyloidosis, accumulation of amyloid-ß (Aß) peptides in the brain, and inflammation of the microglia, brain cells that perform immune system functions in the central nervous system. Buildup of Aß into plaques plays a central role in the onset of Alzheimer’s, while the severity of neuro-inflammation is believed to influence the rate of cognitive decline from the disease.

For this study, Sisodia and his team administered high doses of broad-spectrum antibiotics to mice over five to six months. At the end of this period, genetic analysis of gut bacteria from the antibiotic-treated mice showed that while the total mass of microbes present was roughly the same as in controls, the diversity of the community changed dramatically. The antibiotic-treated mice also showed more than a two-fold decrease in Aß plaques compared to controls, and a significant elevation in the inflammatory state of microglia in the brain. Levels of important signaling chemicals circulating in the blood were also elevated in the treated mice.

While the mechanisms linking these changes is unclear, the study points to the potential in further research on the gut microbiome’s influence on the brain and nervous system.

“We don’t propose that a long-term course of antibiotics is going to be a treatment—that’s just absurd for a whole number of reasons,” said Myles Minter, PhD, a postdoctoral scholar in the Department of Neurobiology at UChicago and lead author of the study. “But what this study does is allow us to explore further, now that we’re clearly changing the gut microbial population and have new bugs that are more prevalent in mice with altered amyloid deposition after antibiotics.”

The study is the result of one the first collaborations from the Microbiome Center, a joint effort by the University of Chicago, the Marine Biological Laboratory and Argonne National Laboratory to support scientists at all three institutions who are developing new applications and tools to understand and harness the capabilities of microbial systems across different fields. Sisodia, Minter and their team worked with Eugene B. Chang, Martin Boyer Professor of Medicine at UChicago, and Vanessa Leone, PhD, a postdoctoral scholar in Chang’s lab, to analyze the gut microbes of the mice in this study.

Minter said the collaboration was enabling, and highlighted the cross-disciplinary thinking necessary to tackle a seemingly intractable disease like Alzheimer’s. “Once you put ideas together from different fields that have largely long been believed to be segregated from one another, the possibilities are really amazing,” he said.

Sisodia cautioned that while the current study opens new possibilities for understanding the role of the gut microbiome in Alzheimer’s disease, it’s just a beginning step.

“There’s probably not going to be a cure for Alzheimer’s disease for several generations, because we know there are changes occurring in the brain and central nervous system 15 to 20 years before clinical onset,” he said. “We have to find ways to intervene when a patient starts showing clinical signs, and if we learn how changes in gut bacteria affect onset or progression, or how the molecules they produce interact with the nervous system, we could use that to create a new kind of personalized medicine.”

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Estrogen Patch in Newly Postmenopausal Women May Reduce Alzheimer’s Risk

Can estrogen preserve brain function and decrease the risk of Alzheimer’s disease when given early in menopause? Newly postmenopausal women who received estrogen via a skin patch had reduced beta-amyloid deposits, the sticky plaques found in the brains of people with Alzheimer’s disease, a Mayo Clinic study published this month in the Journal of Alzheimer’s Disease found. Ultimately, these deposits harm neurons, leading to cognitive problems.

In the study, women with APOE e4 — one form of the most common gene associated with late-onset Alzheimer’s disease — had lower levels of amyloid deposits.

“This study showed, for the first time, that the brain amyloid deposition ─ a hallmark of Alzheimer’s disease ─ is reduced in newly postmenopausal women who received 17beta-Estradiol patch form of hormone therapy,” says lead author Kejal Kantarci, M.D., a Mayo Clinic radiologist. “Women with APOE e4, who have a greater genetic risk for Alzheimer’s disease, particularly benefited from this therapy.”

Menopause is defined as occurring 12 months after a woman’s last menstrual period and marks the end of menstrual cycles. In the U.S., the average age of menopause is 51. A rapid decline in estrogen with menopause may be associated with an increased risk of Alzheimer’s disease risk in women.

The Women’s Health Initiative study by the National Institutes of Health (NIH) reported that menopausal hormone therapy started in women 65 or older increased the risk of dementia. In contrast, the multicenter Kronos Early Estrogen Prevention Study tested the hypothesis that healthy and younger women would respond to menopausal hormone therapy more favorably.

The Mayo Clinic study used data from the Kronos study to determine the effects of menopausal hormone therapy shortly after menopause, during the critical window of rapid estrogen depletion — five to 36 months past menopause. Researchers investigated the brain amyloid deposition in 68 women ages 42 to 59 who participated in the Kronos trial during this critical window. The researchers used positron emission tomography, also known as a PET scan, to look for the brain amyloid deposits three years after the trial ended.

Of the 68 women, 21 received estrogen via a skin patch, 17 received estrogen orally and 30 received a placebo. Amyloid deposition was lower in women who received the patch, compared to the placebo, and the effect was most apparent in women with the APOE e4 genotype. The oral treatment was not associated with lower amyloid deposition.

The authors are seeking funding to perform amyloid PET imaging at eight more Kronos Early Estrogen Prevention study sites around the U.S.

“If our results are confirmed in the larger group of women, this finding has the potential to change the concepts for preventive interventions that drive the Alzheimer’s disease field today,” Dr. Kantarci says. “It also may have a significant impact on women making the decision to use hormone therapy in the early postmenopausal years.”

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Sac to the future: Cellular vessels predict likelihood of developing dementia

Researchers at University of California San Diego School of Medicine say tiny micro-vesicle structures used by neurons and other cells to transport materials internally or dispose of them externally carry tell-tale proteins that may help to predict the likelihood of mild cognitive impairment (MCI) developing into full-blown Alzheimer’s disease (AD).

The findings, published online this week in the journal Alzheimer’s & Dementia, represent a quicker and less invasive way to identify impending cognitive decline and begin treatment before progression to established, irreversible dementia.

“MCI is often a transitional stage between normal aging and dementia,” said senior author Robert A. Rissman, PhD, associate professor in the Department of Neurosciences at UC San Diego School of Medicine, director of the Biomarker Core for the Alzheimer’s Disease Cooperative Study (ADCS) and director of the Neuropathology Core and Brain Bank for the UC San Diego Shiley-Marcos Alzheimer’s Disease Research Center. “It’s associated with more minor cognitive impairment and carries an increased risk of developing Alzheimer’s dementia.”

MCI patients progress to AD at rates as high as 10 to 15 percent per year, prompting an increased emphasis upon diagnosing MCI early and developing treatments that can delay or prevent conversion to AD. The need is underscored, write the authors, by the fact that clinical trials of treatments for established AD have thus far failed.

While clinically distinguishable from normal aging and AD, MCI remains nonetheless a complex condition with many and varied causes. “That has prompted great interest in pinpointing underlying biomarkers that can predict the conversion from MCI to AD dementia,” said Rissman. “Finding such biomarkers would also identify persons most likely to be responsive to preventive treatments.”

Currently, the accepted methods for diagnosing preclinical AD patients is to detect protein biomarkers found in cerebrospinal fluid (CSF), in combination with advanced neuroimaging and neuropsychological testing. But CSF sampling involves an invasive, often painful, process. Neuroimaging is expensive. Neuropsychological testing is time-consuming and can often vary from visit to visit.

The new method described in the Alzheimer’s & Dementia study evaluated the potential of exosomes – extremely small vesicles or sacs found in most cell types, including neurons. Exosomes are thought to move materials inside cells and are used to dump cellular trash into the bloodstream for disposal. In the case of disease, Rissman’s group predicted that neuronal derived exosomes (NDEs) would carry damaged or excess proteins and metabolites out of brain cells, among them amyloid and tau biomarker proteins that are strongly associated with AD.

The researchers harvested NDEs from human blood plasma of 60 patients who participated in an 18-month ADCS clinical trial that enrolled MCI patients only. Some of these MCI patients converted to AD over the course of the study and some did not. Rissman’s lab also gathered samples from control patients and samples from known AD patients. They enriched the NDE content of those originating from neurons. The samples represented patients with normal cognitive function, diagnoses of stable MCI and stable AD and patients who had recently transitioned from MCI to AD.

After characterizing NDEs by size, shape and concentration, the researchers compared that data with the different patient cohorts. They found that NDEs carried targeted biomarker proteins, which have previously been found to predict development of AD up to 10 years before onset of clinical symptoms, and correctly distinguished 100 percent of patients with AD from normal cohorts.

Moreover, the researchers showed for the first time that plasma NDEs from AD and MCI patients may propagate tau tangles in the brains of normal mice similar to what is seen in human AD brains. The fact that these NDEs could induce pathological-like structures in “naïve” mice (animals not previously subjected to experiments) suggests that the contents of NDEs are bioactive, said Rissman. It also suggests that released NDEs can be taken up by cells, raising the possibility of NDEs potential for drug delivery.

The development of blood-based biomarkers for AD (and other neurodegenerative diseases) diagnostics could significantly improve the effectiveness and reliability of patient care and future research, said the authors, who encouraged further studies to refine and validate the approach.

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Understanding How Chemical Changes in the Brain Affect Alzheimer’s Disease

A new study from Western University is helping to explain why the long-term use of common anticholinergic drugs used to treat conditions like allergies and overactive bladder lead to an increased risk of developing dementia later in life. The findings show that long-term suppression of the neurotransmitter acetylcholine – a target for anticholinergic drugs – results in dementia-like changes in the brain.

“There have been several epidemiological studies showing that people who use these drugs for a long period of time increase their risk of developing dementia,” said Marco Prado, PhD, a Scientist at the Robarts Research Institute and Professor in the departments of Physiology and Pharmacology and Anatomy & Cell Biology at Western’s Schulich School of Medicine & Dentistry. “So the question we asked is ‘why?'”

For this study, published in the journal Cerebral Cortex, the researchers used genetically modified mouse models to block acetylcholine in order to mimic the action of the drugs in the brain. Neurons that use acetylcholine are known to be affected in Alzheimer’s disease; and the researchers were able to show a causal relationship between blocking acetylcholine and Alzheimer’s-like pathology in mice.

“We hope that by understanding what is happening in the brain due to the loss of acetylcholine, we might be able to find new ways to decrease Alzheimer’s pathology,” said Prado.

Prado and his partner Dr. Vania Prado, DDS, PhD, along with PhD candidates Ben Kolisnyk and Mohammed Al-Onaizi, have shown that blocking acetylcholine-mediated signals in neurons causes a change in approximately 10 per cent of the Messenger RNAs in a region of the brain responsible for declarative memory. Messenger RNA encodes for specific amino acids which are the building blocks for proteins and several of the changes they uncovered in the brains of mutant mice are similar to those observed in Alzheimer’s disease.

“We demonstrated that in order to keep neurons healthy you need acetylcholine,” said Prado. “So if acetylcholine actions are suppressed, brain cells respond by drastically changing their messenger RNAs and when they age, they show signs of pathology that have many of the hallmarks of Alzheimer’s disease.” Importantly, by targeting one of the messenger RNA pathways they uncovered, the researchers improved pathology in the mutant mice.

The study, conducted at Western’s Robarts Research Institute, used human tissue samples to validate the mouse data and mouse models to show not only the physical changes in the brain, but also behavioral and memory changes. The researchers were able to show that long-term suppression of acetylcholine caused brain cell to die and as a consequence decrease memory in the aging mice.

“When the mutant mice were old, memory tasks they mastered at young age were almost impossible for them, whereas normal mice still performed well,” said Kolisnyk.

The researchers hope their findings will have an impact on reducing the burden of dementia by providing new ways to reverse the loss of acetylcholine.

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Case Western Reserve University Receives NIH Funding to Participate in Launch of Genomics Center on Alzheimer’s Disease

Case Western Reserve University School of Medicine is one of six recipients of a five-year, $10.8 million award from the National Institute on Aging, part of the National Institutes of Health, to establish the Coordinating Center for Genetics and Genomics of Alzheimer’s disease.

The hope is that discovering genetic risk and prevention factors will enable and accelerate development of prevention and treatments.

The project is a joint venture of researchers from the Perelman School of Medicine at the University of Pennsylvania in Philadelphia and five other institutions, including Case Western Reserve. The other four sites are Boston University, Columbia University, the University of Miami, and the Indiana University. It is part of the NIH Alzheimer’s Disease Sequencing Project, a project involving the same six institutions that began in 2012.

The Coordinating Center for Genetics and Genomics of Alzheimer’s disease will include genomic sequence data from thousands of people with Alzheimer’s disease as well as older cognitively normal subjects. Genome sequencing entails mapping out the order of chemical letters in a cell’s DNA. The goal is to identify genes that contribute to or help guard against Alzheimer’s disease. This work is done using highly sophisticated technology and statistical analysis.

“Understanding Alzheimer’s disease requires massive amounts of data,” said Jonathan Haines, PhD, chair of the department of epidemiology and biostatistics, and director of the Institute for Computational Biology at Case Western Reserve University School of Medicine, where much of the data analysis will occur. “By enabling us to create a common database to which potentially hundreds of researchers will have access, this funding will allow critical sharing of information and interpretation, which is essential for making progress against this insidious disease.”

William S. Bush, PhD, assistant professor of epidemiology and biostatistics at the School of Medicine, is participating in the project as well.

Haines and Bush will use their analytical and biomedical informatics expertise in this project in two ways. First, they will analyze the possible effects of multiple genes in helping cause or prevent Alzheimer’s. Second, they will provide guidance in connecting and interpreting the Alzheimer’s data with data from over 30 different databases of biological knowledge. This includes looking at correlations between the Alzheimer’s data and genes for: 1) other traits and medical conditions and 2) more basic biological mechanisms, such as determining if possible Alzheimer’s-related genes are even expressed — active — in the brain. “Placing our new statistical findings within the current understanding of Alzheimer’s disease biology is essential to move towards new therapies and preventions,” said Bush.

The Alzheimer’s Association defines Alzheimer’s as “a type of dementia that causes problems with memory, thinking and behavior. Symptoms usually develop slowly and get worse over time, becoming severe enough to interfere with daily tasks.” It affects as many as five million people age 65 and older in the United States.

Current drugs are only minimally effective in reducing the severity and progression of the disease. There are no known ways to prevent Alzheimer’s disease.

The new center comprises a major part of the NIH’s National Plan to Address Alzheimer’s Disease to prevent and effectively treat Alzheimer’s disease by 2025.

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Penn Medicine Team and Collaborators Receive NIH Award to Launch Genomics Center on Alzheimer’s Disease

A five-year, projected $10.8 million award from the National Institute on Aging (NIA), part of the National Institutes of Health (NIH), will establish the Coordinating Center for Genetics and Genomics of Alzheimer’s Disease, a joint venture of researchers from the Perelman School of Medicine at the University of Pennsylvania and five other institutions. Penn will receive an estimated $4.5 million from the grant.

The Center is led by Gerard D. Schellenberg, PhD, a professor of Pathology and Laboratory Medicine and Li-San Wang, PhD, an associate professor of Pathology and Laboratory Medicine, in partnership with investigators from five other sites — Boston University, Case Western Reserve University, Columbia University, the University of Miami, and the University of Indiana.
“By coordinating the identification of Alzheimer’s-related genes, the Center’s team aims to find new therapeutic targets to reduce the economic and human burden caused by this disease,” Schellenberg said. “This is an exciting opportunity to apply new technologies to improve our understanding of the biological pathways underlying this devastating disease. The new center will stimulate collaborations between hundreds of U.S. and international Alzheimer’s genetics researchers by aggregating and analyzing very large data sets and sharing the results. This type of global interaction is needed if we are to make progress in solving this devastating illness.”

Alzheimer’s disease, a progressive neurodegenerative disorder, has become an epidemic that currently affects as many as five million people age 65 and older in the United States, with economic costs that are comparable to, if not greater than, caring for those of heart disease or cancer. Available drugs only marginally affect disease severity and progression. While there is no way to prevent this disease, the discovery of genetic risk factors for Alzheimer’s is bringing researchers closer to learning how the genes work together and may help identify the most effective interventions.
“The Genomics Center will be a state-of-the-art national clearinghouse for Alzheimer’s genomics information based at Penn,” Wang said. “We have an important mission to move the field of Alzheimer’s genetics forward by coordinating all NIA-funded activities for the Alzheimer’s Disease Sequencing Project.”

Center collaborators will collect and “harmonize” available AD genetics and associated physiological data into a common database to maximize statistical power to find therapeutic targets.

“Data-sharing and collaboration among cutting-edge research teams is key to advancing our understanding of complex genetic underpinnings of Alzheimer’s and related dementias,” said NIA director Richard Hodes, MD. “This new Center will play an important role in achieving our nation’s ultimate research goal, outlined under the National Plan to Address Alzheimer’s Disease to prevent and effectively treat Alzheimer’s disease by 2025.”

The Genomics Center will also bring in data from other non-NIA-funded studies, reprocess into a consistent format, and add to the common database housed at the NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS), the national genetics data repository for Alzheimer’s disease developed and maintained by Wang’s team since 2012 and the Data Coordinating Center for the ADSP. The Genomic Center will amass genomic sequence data from subjects with Alzheimer’s disease and elderly cognitively normal subjects and use these data to identify genes that cause or protect against AD and other diseases.
“As the amount of data acquired increases, this will be a valuable resource for the study of other genetic disorders at Penn and other institutions,” Wang said.

The NIH Alzheimer’s Disease Sequencing Program (ADSP), a collaboration that also began in 2012 between NIA and the National Human Genome Research Institute (NHGRI), also part of NIH, has been analyzing data from 6,000 volunteers with Alzheimer’s disease and 5,000 older cognitively normal, unaffected individuals. In addition, the teams will study genomic data from 111 large families with multiple Alzheimer’s disease members, of Caucasian and Caribbean Hispanic descent to identify rare genetic variants. For the next phase of the project, the new Center will analyze new sequence data from an additional 3,000 AD cases.

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Researchers show the transmission of the genetic disorder HD in normal animals

Mice transplanted with cells grown from a patient suffering from Huntington’s disease (HD) develop the clinical features and brain pathology of that patient, suggests a study published in the latest issue of Acta Neuropathologica by CHA University in Korea, in collaboration with researchers at Université Laval in Québec City, Canada.

“Our findings shed a completely new light onto our current understanding of how HD begins and develops. We believe that they will also lead to the development of a whole new range of therapies for neurodegenerative diseases of the central nervous system”, explains corresponding author of the study Jihwan Song, professor and director of Neural Regeneration and Therapy Group at the CHA Stem Cell Institute of CHA University.

The researchers have now provided further evidence for this new theory by showing that the abnormal protein coded for this genetic disorder can be transmitted to normal animals by the injection of diseased cells into their brain. “This is the first demonstration that cells carrying a genetic disease are capable of spreading into the normal mammalian brain and lead to the manifestation of behavioral abnormalities associated with the disease”, says Francesca Cicchetti, professor at the Université Laval Faculty of Medecine and researcher at Centre de recherche du CHU de Québec-Université Laval.

HD is an inherited chronic degenerative disorder of the brain characterized by major thinking and motor problems as well as psychiatric disturbances. There is no cure for HD and current treatments are of very limited efficacy. It is caused by a single gene abnormality which leads to the production of a mutant form of a protein called huntingtin (mHtt). The production of this protein in a nerve cell eventually kills it but it has long been thought that this protein cannot spread out of the cell and infect and kill neighbouring ones.

However, in recent post mortem analyses of HD patients who received transplants of non-HD tissue in an attempt to repair their brain, the researchers showed that the mHtt can be found in the graft itself. This suggests that the patient with HD transmitted the mHtt from their brain into the transplant.