New Study Proves That Antibody Treatments Can Remove Amyloid Deposits from the Brain

Amyloid deposits in the brain is known to be a causative agent in the development of Alzheimer’s disease. Developing effective antibody treatments has been one of the goals of researchers. According to the results of a clinical trial by Biogen scientists recently published in “Nature”, it appears that we are drawing closer to our goal.

Biogen researchers conducted a one-year trial of the monoclonal antibody drug aducanumab in early stage Alzheimer’s patients. A total of 165 subjects were included, 40 of whom received a placebo. Only patients defined as mildly affected or prodromal were included in the study. Aducanumab was successful in removing amyloid deposits, and even though the results are somewhat tempered by the fact that patients were in early stages of the disease, it is still exciting to see that amyloid deposits can be scrubbed by the introduction of an artificial agent that tricks the immune system into attacking the amyloid deposits. Researchers assume that the antibody most likely initiated activation of microglia cells in the brain which took on the task of removing amyloid deposits. The clearing away of amyloid plaque was so thorough that when comparing the scans of the group receiving the highest dose of aducanumab to scans of individuals without amyloid there was practically no difference. The amount of reduction of amyloid was tied to the dosage over the year-long study.

Cognitive Decline Was Slowed

Aducanumab performed similar to nilvadipine, which also reduces buildup of amyloid, in that cases transitioning from mild cognitive impairment to Alzheimer’s was reduced. Nilvadipine is in phase III trials in nine European countries. The drug is being developed by Archer Pharmaceutical. The advantage of Nilvadipine is that it can be administered orally, and only once a day, whereas Aducanumab, once approved, would be administered intravenously once a month.

Adverse Effects Not AlarmingBrain_Synap.jpg

While patients who received the highest doses of aducanumab, which was 10 mg per kilogram, experienced the best results, they also suffered the most severe adverse reactions. Over the course of the year, cognitive decline was observed. Those receiving a placebo showed a decline of slightly under two points on the clinical dementia sum of boxes (CDR-SB). Those receiving the highest dose showed a decline of slightly more than 0.5 point. In general, study commentators found serious adverse effects to be low, however, the 10 mg per kilogram group exhibited adverse rates of 38%, which would present significant challenges to patient management. Lower doses produced an adverse reaction rate of less than 15%, with only 10% of cases being discontinued due to serious side effects, which is similar to the rates seen with other treatments that have already been approved. Also of note is the fact that no patients needed to be hospitalized for ARIA. Nevertheless, MRIs would need to be repeated and constantly monitored to avoid this extremely threatening complication.

In the final analysis, the Biogen study gives cause for optimism about the efficiency of antibody agents to remove amyloid oligomers. With the evidence that reduced amyloid also led to reduced cognitive decline, the strategy of amyloid clearance as a therapy for treating or preventing Alzheimer’s becomes more of a reality.

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Researchers Discover a Control Switch That Serves to Relieve Cellular Stress

A new discovery by University of San Diego researchers could be the key to opening new doors of understanding and treating a number of neurodegenerative disorders such as, Alzheimer’s, Parkinson’s, and ALS, as well as diabetes, cancer and inflammatory disorders. The ramifications are significant and could vastly improve the process of developing new drug therapies to treat these conditions.

Cell death

The normal process when the body undergoes stress is that the endoplasmic reticulum, where all proteins are stored and shaped, experiences a buildup of unfolded or not properly folded proteins. In order to function properly, proteins must be three-dimensional. When there is stress, the protein shaping process is impacted, producing misshapen proteins. The unfolded protein response (UPR), a cellular stress relief mechanism, senses the problem, and begins to correct the cellular process. If not successful, then the UPR sends a signal to the cell to destroy itself.

A new control switch for the unfolded protein response (UPR) 

According to the study published in EMBO Reports by researchers at the University of California, San Diego School of Medicine, two pathways are involved in cell stress response, the UPR and a nonsense-mediated RNA decay pathway (NMD). Dr. Miles, senior author of the paper, said that the two pathways intersect at some point when there is cell stress, indicating that NMD acts to control UPR so that it does not overreact to mild stress.

Diseases such as cancers, diabetes, Parkinson’s and Alzheimer’s are known to cause significant cell stress at a level that typically triggers a self-destruct signal from the UPR. Without a control mechanism, the resulting acceleration of cell death can lead to a rapid deterioration in the health of the patient. According to the researchers, the intersecting NMD is crucial to normalizing the UPR activities, thus protecting the patient from extreme levels of cell death.

 

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Can the GLUT1 protein Help Alzheimer’s Patients?

Posted by MullanMichael on June 21, 2015

Degenerative GLUT1 protein is a causal factor in neurological degeneration


The GLUT1 protein serves as a driver of glucose across the blood-brain barrier. The blood-brain barrier separates the brain from the circulatory system and protects it from harmful chemicals. It is a highly sophisticated network of dynamic cellular barriers. Glucose, which is vital to the healthy functioning of the body is carried across this blood-brain barrier by GLUT1, a protein whose job it is to ensure a good flow of blood through the brain’s capillaries.

A new study by Keck School of Medicine published recently in “Nature Neuroscience” sought to build on previous research proving that patients exhibiting a higher genetic risk to Alzheimer’s also have low levels of glucose in their systems. This glucose deficiency was found to be due to abnormalities in GLUT1. Researchers found that rather than glucose deficiencies being a result of Alzheimer’s, it was actually the cause of the neurological deterioration so common in Alzheimer’s patients.

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New research study confirms earlier findings


Keck researchers found that when GLUT1 is not at normal levels, glucose movement across the blood-brain barrier is impeded, and cognitive functioning of Alzheimer’s is negatively impacted. This would seem to indicate that if one can manipulate the protein, perhaps there is a chance to retard or stop the progression of neurological decline.

Using a research study pool of mice, Keck School of Medicine researches set out to establish the degree of GLUT1’s role in ensuring a healthy flow of blood in the brain, as well as maintaining the well-being of the blood-brain barrier. The study confirmed that when GLUT1 was at an imperfect level, glucose flow across the blood-brain barrier was reduced. More importantly, after six months of reduced glucose absorption, the mice subjects began to exhibit abnormal behavior patterns, neural dysfunction and neurological degeneration. Additionally, abnormal levels of amyloid-beta were found in their systems.
Researchers have more investigation ahead of them, but thus far the results offer promise for early intervention for Alzheimer’s patients.

 

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In a nationwide study conducted last year, Georgetown University neurologist R. Scott Turner, MD, PhD, and director of the University’s Medical Center’s Memory Disorders Program; when he began enrolling individuals with mild to moderate Alzheimer’s disease, he expected only to find a handful of participants that had undiagnosed glucose intolerance, as all of the study’s patients were under doctor’s care, and all individuals with known diabetes were excluded from the study. The results shocked Turner as to how many individuals came back with undiagnosed pre-diabetes. Turner’s study examined resveratrol, a compound found in red grapes and wine, and was tested to see if it would change the glucose levels in patients with Alzheimer’s disease. Resveratrol is thought to act on proteins in the brain in a way that would mimic effects of a low-calorie diet.

                  In order to join Turner’s study, participants were first given a fasting glucose tolerance test in order to establish a baseline level, and then retested two hours after eating. During the digestion process, the blood sugar level rises, and in response the pancreas produces insulin to lower it. A high blood sugar level after two hours of digestion revealed glucose intolerance (pre-diabetes), and higher levels revealed full-blown diabetes. The results of the study showed that four percent, or five individuals, out of the one hundred and twenty-eight participants showed impaired fasting glucose levels while 2 percent, or three individuals had blood sugar levels at the type-2 diabetes mark.

            Of the 125 individuals who completed the glucose tolerance test, 38 individuals had glucose intolerance, and 16 others had levels consistent with diabetes. What proved shocking to Turner was the fact that the overall prevalence of impaired glucose tolerance, or diabetes, at the two-hour mark after eating was 43 percent of the individuals involved in the study, The results lead Turner to further question testing methods, and whether or not all patients with early Alzheimer’s should be tested for glucose tolerance. While it is an unusual test ordered by neurologists, it could help provide much-needed clues about the diseases and would provide researchers and doctors with critical health information.

                  Source:

1)     Georgetown University Medical Center (2013, July 14). Undiagnosed pre-diabetes highly prevalent in early Alzheimer's disease study. ScienceDaily. Retrieved July 15, 2013, from http://www.sciencedaily.com­ /releases/2013/07/130714160840.htm

 

The Roskamp Institute is a 501(c)3 research facility dedicated to translating the efforts of its qualified research staff into real-world results for those suffering from neurological diseases. To learn more about our programs and to get information about donating, visit www.rfdn.org.

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Unlocking Stem Cell Potential to Repair Brain Damage

Posted by MullanMichael on August 01, 2014

Rachel Okolicsanyi from the Genomics Research Centre at QUT’s Institute of Health and Biomedical Innovation, is attempting to unlock potential for stem cells to repair neural damage in the brain. Brain cells are unable to divide and replicate like most other cells, and once they die, the damage seemed to be irreversible. Okolicsanyi is currently working on manipulating adult stem cells from bone marrow to produce populations of bells which can be used to treat brain damage. Her research has been published in the Developmental Biology journal, and outlines her work of taking stem cells from bone marrow and manipulating them into neural cells, or precursor cells with the potential to repair damage. She is focusing her research on whether the stem cells from the bone marrow can differentiate, or mature into neural cells.

Neural cells are from the brain and can make up the structure of the brain, and every connection for movements, voice, hearing, and sight to be possible. Okolicsanyi targeted her research for heparin sulfate proteoglycans, which are a family of proteins that are found on the surface of all cells in the body. She hopes that by manipulating this family of proteins, it would then be possible to encourage the stem cells to show a higher percentage of neural markers, which would indicate the cells maturing into neural cells. Ordinarily, the cells on their own would mature into bone, cartilage, and fats. The cells would be manipulated by modifying the surrounding environment. Chemicals like complex salts and commonly found biological substances would feed the cells, and either inhibit or encourage cell processes. The cells could react differently to various chemicals, and the research could determine if the chemicals could increase or decrease the neural markers within the cells. The proteins have a core protein that is attached to the cell surface and have heparin sulfate chains branching off from the core. The chemicals would influence the stem cell in different ways, and the interactions between the proteins and the changes in the cell could be better understood.

Sources

  1. Rachel K. Okolicsanyi, Lyn R. Griffiths, Larisa M. Haupt. Mesenchymal stem cells, neural lineage potential, heparan sulfate proteoglycans and the matrix.Developmental Biology, 2014; 388 (1): 1 DOI: 10.1016/j.ydbio.2014.01.024

2)  Queensland University of Technology. (2014, June 4). Unlocking the potential of stem cells to repair brain damage. ScienceDaily. Retrieved June 5, 2014 from www.sciencedaily.com/releases/2014/06/140604094127.htm

 

By Lauren Horne

 

The Roskamp Institute is a 501(c)3 research facility dedicated to translating the efforts of its qualified research staff into real-world results for those suffering from neurological diseases. To learn more about our programs and to get information about donating, visit www.rfdn.org.

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Physical Activity and Hippocampus Health

Posted by MullanMichael on July 30, 2014

Researchers from the University of Maryland School of Public Health have published a study in Frontiers in Aging Neuroscience exploring the relationship between exercise and brain health. 

The results show that adults with an increased risk for Alzheimer’s disease who partake in moderate physical activity are helping to stave off shrinkage of the hippocampus, the brain region responsible for memory and spatial orientation.  While everyone loses brain volume as they age, those with a heightened genetic risk for Alzheimer’s typically show greater hippocampal atrophy over time.  The scientists found physical activity can preserve the volume of the hippocampus in those with increased risk, meaning they can possibly delay cognitive decline and the onset of the disease.  

The study tracked four groups of adults aged 65-89, all of whom had normal cognitive abilities, for an eighteen-month period.  The volume of the hippocampus was measured using an MRI at both the beginning and end of this period.  The groups were then classified as low or high risk of Alzheimer’s, based on the absence of presence of ApoE4, and for low or high physical activity levels.

Of the four groups studied, those with high genetic risk who did not exercise experienced a decrease in hippocampal volume by around three percent.  All other groups, including those at high risk who did exercise, maintained the volume of their hippocampus 

"Our study provides additional evidence that exercise plays a protective role against cognitive decline and suggests the need for future research to investigate how physical activity may interact with genetics and decrease Alzheimer's risk,” said Dr. Smith, lead author of the study.

Sources:

1)   University of Maryland. (2014, April 23). Physical activity keeps hippocampus healthy in people at risk for Alzheimer's disease. ScienceDaily. Retrieved April 25, 2014 from www.sciencedaily.com/releases/2014/04/140423102746.htm

2)   J. Carson Smith, Kristy A. Nielson, John L. Woodard, Michael Seidenberg, Sally Durgerian, Kathleen E. Hazlett, Christina M. Figueroa, Cassandra C. Kandah, Christina D. Kay, Monica A. Matthews, Stephen M. Rao. Physical activity reduces hippocampal atrophy in elders at genetic risk for Alzheimer's disease. Frontiers in Aging Neuroscience, 2014; 6 DOI: 10.3389/fnagi.2014.00061

By Emma Henson 

 

The Roskamp Institute is a 501(c)3 research facility dedicated to translating the efforts of its qualified research staff into real-world results for those suffering from neurological diseases. To learn more about our programs and to get information about donating, visit www.rfdn.org.

 

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Antibodies Effectively Treat Alzheimer's-like Disease

Posted by MullanMichael on July 21, 2014

Drs. David Holtzman and Mac Diamond of the Washington University School of Medicine recently published research in Neuron that outlined the process of studying mice for potential tau protein tangle treatment avenues.             

Tau is a toxic component of Alzheimer's and other neurodegenerative diseases, due to the protein’s tendency to amass in tangles.  The aggregates, called neurofibrillary tangles, are believed to interfere with brain function and ultimately lead to cognitive decline.  The study followed mice models with a neurodegenerative disease called frontotemporal dementia, whose tau proteins have similar pathology to those present in the brains of Alzheimer's patients.  The scientists used advanced screening methods to sort through anti-bodies and identify the few that could stop uptake of accumulated tau by cellular interaction, therefore ending intracellular tau tangles.  The researchers then infused three anti-tau antibodies into mice brains.  The results showed mice with the anti-tau antibodies had reduced tau accumulation and increased cognition, while mice infused with control antibodies experienced no change. 

The first study to deal with infusing antibodies directly into the brain, Washington University's research not only suggests a path of action, but solidifies the spread of tau aggregates between cells as a crucial step in tau-mediated diseases like Alzheimer's.  Dr. Diamond says that their research could lead to the creation of therapies designed to target the aggregation of tau proteins. 

Sources:

1) Kiran Yanamandra, Najla Kfoury, Hong Jiang, Thomas E. Mahan, Shengmei Ma, Susan E. Maloney, David F. Wozniak, Marc I. Diamond, David M. Holtzman.  Anti-tau Antibodies Block Tau Aggregates.  September 26, 2013. 10.1016/j.neuron.2013.07.046.

2) Washington University (September 26, 2013). Antibodies Effectively Treat Alzheimer's-like Disease in Mice. Retrieved October  1, 2013 from http://www.sciencedaily.com/releases/2013/09/130926123326.htm     

 

By Emma Henson

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Traumatic Brain Injury and Risk for Alzheimer's Disease

Posted by MullanMichael on July 24, 2013

Recently, there has been increasing interest in the role of sports head injuries and subsequent cognitive decline. For instance, American football players are being scrutinized more closely because of new research suggesting close links between repeated concussion and decline in cognitive abilities. However, over the last three decades, there has been much work on the relationship between head injury (usually single head injury) and Alzheimer's disease (AD) and other dementias. Many well designed, population based studies have suggested a link between head injury and the development of AD and other dementias. However, there are many discrepancies between these studies and the risk attributed to head injury has varied widely between them. Several key factors are often examined in these studies to try to understand better the relationship between traumatic brain injury (TBI) and AD. One of the areas that has been studied extensively is the effect of gender. Despite the many case control and cohort studies, none have shown an increased risk for AD after TBI for women. Although many TBI studies focus on the male population who are more at risk (for instance, in contact sports or in the military) the finding that women are at no increased risk of AD after TBI suggests that there may be a protective effect of female hormones against the development of AD after head injury. Another area that is extensively studied is the relationship between the degree of injury and the subsequent development of AD or related disorders. Few studies have adequately assessed the degree of injury and so information in this area is limited but, the studies that have, in general, suggest that more moderate or severe injuries predispose to dementia later in life. For instance, one study divided TBI into mild, moderate, and severe categories:  injuries with loss of consciousness (LOC) or post-traumatic amnesia (PTA) of less than 30 minutes (mild); of more than 30 minutes but less than 24 hours (moderate); and of more than 24 hours (severe). Most studies suggested moderate and severe disease is more related to AD and that full recovery of cognitive loss can be regained after mild TBI.

 

Another key area of interest is the relationship between time of injury to the development of subsequent dementia. This has been studied in large populations and there are good data to suggest that TBI in old age is associated with worsening of outcome compared to TBI at a younger age. Nevertheless, even individuals that have TBI in early adulthood (if the injury is severe enough) are at increased risk of AD and other dementias as many as five decades later.

One key question is how the brain "remembers" the injury for so many years and why there may be no signs of cognitive impairment soon after the injury for many decades until AD onsets. The question of the molecular underpinnings of TBI and how the brain continues to register that an injury has occurred is an area of intense study. One such candidate for molecular memory is amyloid, the molecule that is increased in the brains of AD sufferers and occurs early in the pathological sequence that leads to full-blown AD. However, not all TBI victims have increased amyloid in their brain at autopsy, most studies showing that only about a third do so. And, although amyloid is produced acutely after TBI, much of that amyloid does not stay in the brain but is degraded in the weeks and months following injury. Another pathological molecule central to the AD process is tau. Although tau has been implicated in TBI, again, there are inconsistent data between studies -- some showing no increased involvement of tau while others show hyperphosphorylation and/or aggregation of tau. More recently in repetitive head injury (for instance, those occurring in American football) tau has been implicated as it has been seen particularly around blood vessels in the brain.

Whatever the ultimate underlying cause of the link between TBI  and the subsequent development of AD, we can expect that once those links are fully uncovered, they will become new targets for the prevention of AD following TBI.

One other area that deserves attention is the genetic risk for poor recovery after TBI and subsequent risk for AD. Although it is generally accepted that APOE4 is a risk factor for AD, some studies of head injury have been equivocal in demonstrating that APOE4 acts synergistically with TBI to increase risk for AD. However, given the plethora of data on the negative roles of APOE4 in the brain after TBI, it is safe to assume that individuals who carry the E4 are most probably at greater risk for developing AD than those who do not. It has been advocated that those individuals carrying an APOE4 allele should not engage in professions or pastimes with increased risk of TBI. Much more work is needed in this area; but, at this stage, as a precaution, this is probably a position that can be easily endorsed.

 

By Dr. Michael Mullan

CEO of Roskamp Institute

President of Sci-Brain

 

 

 


Effects of an experimental drug, (Val8)GLP-1

Posted by MullanMichael on September 21, 2012

Researchers at the Biomedical Science Institute (BMSRI) recently had their study published in the September 14 edition of Brain Research. This study focused on the effects of an experimental drug, (Val8)GLP-1, on cell growth in the hippocampus, an area of the brain that plays an important role in memory. This experimental drug is designed to treat diabetes II, a disease that does increase the risk of Alzheimer’s disease. Therefore, the researchers at BMSRI believed the drug would be effective for the treatment of Alzheimer’ disease.

            (Val8)GLP-1 controls blood sugar levels in the body by stimulating GLP-1. When the scientists tested (Val8)GLP-1 on healthy mice, they found that the drug could easily cross the blood-brain barrier with little side-effects. The presence of GLP-1 incited the production of nerve cells in the hippocampus, but caused the mice to perform poorly on memory tests when its effects were inhibited.

            Further studies have to be conducted to test the validity of these results, but these findings indicate that GLP-1 could be a potential target for treating Alzheimer’s disease. (Moore)

 

 


Researchers Discover a Control Switch That Serves to Relieve Cellular Stress

A new discovery by University of San Diego researchers could be the key to opening new doors of understanding and treating a number of neurodegenerative disorders such as, Alzheimer’s, Parkinson’s, and ALS, as well as diabetes, cancer and inflammatory disorders. The ramifications are significant and could vastly improve the process of developing new drug therapies to treat these conditions.

Cell death

The normal process when the body undergoes stress is that the endoplasmic reticulum, where all proteins are stored and shaped, experiences a buildup of unfolded or not properly folded proteins. In order to function properly, proteins must be three-dimensional. When there is stress, the protein shaping process is impacted, producing misshapen proteins. The unfolded protein response (UPR), a cellular stress relief mechanism, senses the problem, and begins to correct the cellular process. If not successful, then the UPR sends a signal to the cell to destroy itself.

A new control switch for the unfolded protein response (UPR) 

According to the study published in EMBO Reports by researchers at the University of California, San Diego School of Medicine, two pathways are involved in cell stress response, the UPR and a nonsense-mediated RNA decay pathway (NMD). Dr. Miles, senior author of the paper, said that the two pathways intersect at some point when there is cell stress, indicating that NMD acts to control UPR so that it does not overreact to mild stress.

Diseases such as cancers, diabetes, Parkinson’s and Alzheimer’s are known to cause significant cell stress at a level that typically triggers a self-destruct signal from the UPR. Without a control mechanism, the resulting acceleration of cell death can lead to a rapid deterioration in the health of the patient. According to the researchers, the intersecting NMD is crucial to normalizing the UPR activities, thus protecting the patient from extreme levels of cell death.