Reporting in two companion papers in the October 19 issue of the Journal of Neuroscience, investigators from the Gladstone Institute of Neurological Disease show in genetically engineered mouse models of the disease that the accumulation of Alzheimer-related neurotoxic amyloid-beta (A??) peptides can deplete key proteins in a specific memory center of the brain. They also report that this process can be worsened by increased activity of an enzyme called Fyn.
The inability of Alzheimer's patients to remember events from a few days ago may be linked to the lack of proteins that strengthen the contact points, or synapses, between neurons in the brain, according to study findings.
Much research points to the idea that, far from having a single cause, Alzheimer's disease is typically brought on by a combination of risk factors. In keeping with that model, these papers show that the depletion of memory proteins can require the interaction of different disease-promoting molecules, explains GIND Director Lennart Mucke, MD, the Joseph B. Martin Distinguished Professor in Neuroscience at the University of California, San Francisco, and senior author of the papers.
The researchers found that memory proteins can be depleted not only by high levels of A?? but also by low levels of A?? in combination with high levels of Fyn activity.
"Like partners in crime, A?? and Fyn appear to cooperate to cause Alzheimer-like changes in the brain," says Mucke. The findings may eventually help identify novel therapeutic targets and biomarkers for emerging treatments.
Scientists in Mucke's laboratory were among the first to generate genetically engineered mice that produce human A??, providing a powerful tool to study the devastating disease. Using a technique called gene expression imaging to profile molecular changes in millions of neurons throughout the brain, they unexpectedly found Ab-induced deficits in a very specific neuronal population in the hippocampus, a brain region that serves as a gateway to the complex system that helps lay down new memories.
"The most striking changes within the brain were found in hippocampal granule cells, the specialized neurons that help convert new information into a format for long-term storage," says Jorge J. Palop, PhD, lead author of one of the papers. "That conversion requires proteins that help strengthen the synapses between neurons." These important proteins, which included two called Arc and Fos, were found to be depleted in mice that produced Alzheimer's-related Ab peptides in the brain.
The investigators have good leads on exactly how the memory proteins are depleted in Alzheimer's disease, adds Jeannie Chin, PhD, lead author of the companion paper. They have discovered that changing the activity of the enzyme Fyn can drastically alter the susceptibility of granule cells to the Ab-induced depletion of memory proteins.
"Fyn is strategically located at the synapses, where it regulates the activity of several memory-related proteins," explains Chin. The scientists found that increases in Fyn activity markedly enhanced the susceptibility of granule cells to the A??-induced depletion of memory proteins and, in fact, triggered prominent deficits in memory retention, even in mice with low levels of human A??.
Further studies are now underway to determine whether treatments aimed at A?? and at Fyn-related pathways will together enhance the level and function of memory proteins, thereby providing synergistic benefit in the fight against Alzheimer's disease.
Palop, Chin and Mucke will present their work at Neuroscience 2005, the Society for Neuroscience's 35th Annual Meeting, to be held in Washington, DC, November 12-16.
The research was supported in part by grants from the National Institutes of Health and by fellowships from the John Douglas French Alzheimer's Foundation and the Academy of Finland.
One paper is titled "Vulnerability of Dentate Granule Cells to Disruption of Arc Expression in Human Amyloid Precursor Protein Transgenic Mice." Co-authors are GIND staff members Jorge J. Palop, Jeannie Chin, Nga Bien-Ly, Catherine Massaro, Bertrand Z. Yeung, Gui-Qiu Yu and Lennart Mucke.
The companion paper is titled "Fyn Kinase Induces Synaptic and Cognitive Impairments in a Transgenic Mouse Model of Alzheimer's Disease." Co-authors are GIND staff members Chin, Palop, Jukka Puoliv?li, Massaro, Bien-Ly, Hilary Gerstein, Kimberly Scearce-Levie, and Mucke, as well as Eliezer Masliah of the UC San Diego Department of Neurosciences and Pathology.
Palop, Chin, and Mucke are additionally associated with the UCSF Department of Neurology, and Massaro and Mucke are associated with the UCSF Neuroscience Program.
The Gladstone Institute of Neurological Disease is one of three research institutes of The J. David Gladstone Institutes, a private, nonprofit biomedical research institution. It is affiliated with UCSF, a leading university that consistently defines health care worldwide by conducting advanced biomedical research, educating graduate students in the life sciences, and providing complex patient care. For further information, visit gladstone.ucsf and ucsf.
John Watson
jwatsongladstone.ucsf
415-734-2019
Gladstone Institutes
gladstone.ucsf
вторник, 7 июня 2011 г.
понедельник, 6 июня 2011 г.
Alzheimer Patients Brain Tracked By PET Scanner During Disease And After Death
For the first time the brain of a patient with Alzheimer's disease who displayed detectable amyloids with a PET scanner was regularly scanned as his disease progressed, and then his brain was analyzed after he died, researchers from the Karolinska Institutet, Sweden, reveal in the medical journal Brain. The authors say their study reveals important data on the pathological course of Alzheimer's disease.
Alzheimer's disease, also known as SDAT (Senile Dementia of the Alzheimer Type), or simply Alzheimer's, is a progressive neurologic brain disease which leads to irreversible loss of neurons and intellectual abilities, including reasoning and memory. Eventually, the patient is unable to function professionally, socially or independently. Plaques or tangles develop within the structure of the brain during the course of the disease, causing brain cells to die. The accumulation in the brain of beta-amyloid proteins form amyloid plaques.
The authors explain that we do not know how the plaques form in the brain in the early stages of the disease. We don't even know whether the plaques are the primary cause of Alzheimer's, and what the pathogenic impact might be of other alterations in the brain.
In 2002, Professor Professor Agneta Nordberg carried out the first PET scan ever of amyloid plaque on a living patient with 11C-PIB, an amyloid-binding compound. It was performed at the Karolinska Institutet on a patient with Alzheimer's disease; he was 56 years old at the time. The progression of his disease was tracked with periodic PET scans and memory tests. After death, the researchers performed neurochemical and pathological analyses of his brain tissue.
Their findings provide us with a detailed picture of how Alzheimer's develops. During the early stages of the disease, when the patient experienced only slight memory loss, high concentrations of amyloid plaques were detected. Amyloid plaque levels, in fact, did not change as the disease progressed, right until the patient died. However, the PET scans were able to show that his brain's metabolism declined with time. The decline in brain metabolism occurred in parallel to his rate of memory loss.
The scientists also discovered that an accumulation of plaque is accompanied by a fall in the brain's neuronal nicotinic receptors, which are key for the proper functioning of memory. We now know that these receptors are affected during the early stages of Alzheimer's.
The scientists also believe that inflammation of parts of the brain of a patient with Alzheimer's may have a different cause and occur at different times from the accumulation of amyloid. They found brain inflammation in areas of the brain with low levels of plaques. The authors inform that further research with living patients on this subject is currently underway.
Over 1,000 individuals have undergone PET scans to see what amyloid concentrations they have in their brains. The American Alzheimer's Association in its latest diagnostic guidelines includes PIB-PET as a recommended early clinical diagnostic biomarker for discovering Alzheimer's disease.
In order to fully understand the importance of the PET scans, a follow-up examination of brain tissue should be carried out after the patient has died, the researchers wrote.
Professor Nordberg said:
"If we combine different examinations, we will be able to affirm that complex changes take place at the same time in the brain during the development of Alzheimer's disease. Our study shows that new, modern imaging technology known as molecular imaging makes it possible to discover the disease at an early stage. This opens up new opportunities for early diagnosis and for understanding the causes of the disease and identifying patients who can be expected to respond well to future Alzheimer's therapy."
"Positron emission tomography imaging and clinical progression in relation to molecular pathology in the first Pittsburgh Compound B positron emission tomography patient with Alzheimer's disease"
Ahmadul Kadir,Amelia Marutle, Daniel Gonzalez, Michael Sch?¶ll, Ove Almkvist, Malahat Mousavi, Tamanna Mustafiz, Taher Darreh-Shori, Inger Nennesmo and Agneta Nordberg
Brain (2010) doi: 10.1093/brain/awq349
Written by
Alzheimer's disease, also known as SDAT (Senile Dementia of the Alzheimer Type), or simply Alzheimer's, is a progressive neurologic brain disease which leads to irreversible loss of neurons and intellectual abilities, including reasoning and memory. Eventually, the patient is unable to function professionally, socially or independently. Plaques or tangles develop within the structure of the brain during the course of the disease, causing brain cells to die. The accumulation in the brain of beta-amyloid proteins form amyloid plaques.
The authors explain that we do not know how the plaques form in the brain in the early stages of the disease. We don't even know whether the plaques are the primary cause of Alzheimer's, and what the pathogenic impact might be of other alterations in the brain.
In 2002, Professor Professor Agneta Nordberg carried out the first PET scan ever of amyloid plaque on a living patient with 11C-PIB, an amyloid-binding compound. It was performed at the Karolinska Institutet on a patient with Alzheimer's disease; he was 56 years old at the time. The progression of his disease was tracked with periodic PET scans and memory tests. After death, the researchers performed neurochemical and pathological analyses of his brain tissue.
Their findings provide us with a detailed picture of how Alzheimer's develops. During the early stages of the disease, when the patient experienced only slight memory loss, high concentrations of amyloid plaques were detected. Amyloid plaque levels, in fact, did not change as the disease progressed, right until the patient died. However, the PET scans were able to show that his brain's metabolism declined with time. The decline in brain metabolism occurred in parallel to his rate of memory loss.
The scientists also discovered that an accumulation of plaque is accompanied by a fall in the brain's neuronal nicotinic receptors, which are key for the proper functioning of memory. We now know that these receptors are affected during the early stages of Alzheimer's.
The scientists also believe that inflammation of parts of the brain of a patient with Alzheimer's may have a different cause and occur at different times from the accumulation of amyloid. They found brain inflammation in areas of the brain with low levels of plaques. The authors inform that further research with living patients on this subject is currently underway.
Over 1,000 individuals have undergone PET scans to see what amyloid concentrations they have in their brains. The American Alzheimer's Association in its latest diagnostic guidelines includes PIB-PET as a recommended early clinical diagnostic biomarker for discovering Alzheimer's disease.
In order to fully understand the importance of the PET scans, a follow-up examination of brain tissue should be carried out after the patient has died, the researchers wrote.
Professor Nordberg said:
"If we combine different examinations, we will be able to affirm that complex changes take place at the same time in the brain during the development of Alzheimer's disease. Our study shows that new, modern imaging technology known as molecular imaging makes it possible to discover the disease at an early stage. This opens up new opportunities for early diagnosis and for understanding the causes of the disease and identifying patients who can be expected to respond well to future Alzheimer's therapy."
"Positron emission tomography imaging and clinical progression in relation to molecular pathology in the first Pittsburgh Compound B positron emission tomography patient with Alzheimer's disease"
Ahmadul Kadir,Amelia Marutle, Daniel Gonzalez, Michael Sch?¶ll, Ove Almkvist, Malahat Mousavi, Tamanna Mustafiz, Taher Darreh-Shori, Inger Nennesmo and Agneta Nordberg
Brain (2010) doi: 10.1093/brain/awq349
Written by
воскресенье, 5 июня 2011 г.
Study On Antioxidants And Memory Concerns Underway At Rush University Medical Center
Rush University Medical Center is conducting a clinical trial to evaluate whether taking Cerefolin®NAC reduces the inflammation and oxidative stress that is associated with memory decline in older persons. Cerefolin NAC is a commercially available food supplement available by prescription. It is a combination of high dose vitamin B12, B6, and folic acid along with n-acetylcysteine, an antioxidant.
Researchers will evaluate whether taking Cerefolin NAC causes a greater reduction in homocysteine, oxidative stress, and inflammation blood marker levels than a standard multivitamin. Homocysteine is an amino acid associated with inflammation.
"Finding treatments with the ability to reduce inflammation responses in the brain may help delay the onset of Alzheimer's disease," Said Dr. Raj Shah, medical director of the Rush Alzheimer's Disease Center. "The results of this study will help determine how to design future studies to see if Cerefolin NAC can make a difference in maintaining memory."
Rush University Medical Center will be the only site conducting this study. The study seeks 100 participants over age 60 with memory concerns who have a slightly higher risk for having an elevated homocysteine level. Participants must not have a diagnosis of Mild Cognitive Impairment, Alzheimer's disease, or a dementia.
One-half of participants will receive Cerefolin NAC and one-half will receive a placebo. All participants will receive a multivitamin. During the six month double-blind clinical trial, investigators will measure blood markers, will assess memory, walking, mood, and functional abilities, and will monitor side-effects over the course of four study visits with the participant.
"Alzheimer's disease is a public health crisis now and in the future. Alzheimer's disease currently affects over 4.5 million persons in the United States and over 200,000 in Illinois alone," said Shah. "It is projected to affect over 13 million persons by 2050 if nothing can be found to prevent the symptoms of the disease."
rush
Researchers will evaluate whether taking Cerefolin NAC causes a greater reduction in homocysteine, oxidative stress, and inflammation blood marker levels than a standard multivitamin. Homocysteine is an amino acid associated with inflammation.
"Finding treatments with the ability to reduce inflammation responses in the brain may help delay the onset of Alzheimer's disease," Said Dr. Raj Shah, medical director of the Rush Alzheimer's Disease Center. "The results of this study will help determine how to design future studies to see if Cerefolin NAC can make a difference in maintaining memory."
Rush University Medical Center will be the only site conducting this study. The study seeks 100 participants over age 60 with memory concerns who have a slightly higher risk for having an elevated homocysteine level. Participants must not have a diagnosis of Mild Cognitive Impairment, Alzheimer's disease, or a dementia.
One-half of participants will receive Cerefolin NAC and one-half will receive a placebo. All participants will receive a multivitamin. During the six month double-blind clinical trial, investigators will measure blood markers, will assess memory, walking, mood, and functional abilities, and will monitor side-effects over the course of four study visits with the participant.
"Alzheimer's disease is a public health crisis now and in the future. Alzheimer's disease currently affects over 4.5 million persons in the United States and over 200,000 in Illinois alone," said Shah. "It is projected to affect over 13 million persons by 2050 if nothing can be found to prevent the symptoms of the disease."
rush
суббота, 4 июня 2011 г.
How Stroke And Head Injury Can Increase Risk Of Alzheimer's Disease, Outlined By Study
Researchers from the MassGeneral Institute for Neurodegenerative Disorders (MGH-MIND) have discovered how the death of brain cells caused by a stroke or head injury may cause generation of amyloid-beta protein - the key component of senile plaques seen in the brains of patients with Alzheimer's disease. Their report appears in the journal Neuron.
"We have discovered how a stroke can trigger a series of biochemical events that increase amyloid-beta production in the brain," says Giuseppina Tesco, MD, PhD, of the MGH-MIND Genetics and Aging Research Unit, the paper's lead author. "These findings raise the prospect of novel therapies that could interfere with this process and reduce the risk of Alzheimer's disease in stroke or head trauma patients."
It has been known for several years that strokes and head injuries can increase the risk of Alzheimer's disease, but the mechanism underlying that increased risk has not been understood. Alzheimer's disease is characterized by plaques within the brain of amyloid-beta protein, which is toxic to brain cells. Amyloid-beta is formed when the larger amyloid precursor protein (APP) is clipped by two enzymes - beta-secretase, also known as BACE, and gamma-secretase - which releases the amyloid-beta fragment. The usual processing of APP by an enzyme called alpha-secretase produces an alternative, non-toxic protein.
The MGH-MIND team previously reported that cellular BACE levels are normally controlled by the enzyme's breakdown in compartments called lysosomes, a process that is disrupted if a molecular signal on the enzyme is altered. That signal binds to GGA proteins, which are required for the transport of several types of enzymes into lysosomes. One of these proteins, GGA3, can be degraded by caspase, an enzyme takes part in the cell-death process called apoptosis.
In a series of experiments the MGH-MIND researchers revealed how cell death caused by a brain injury, including a stroke, can lead to the production of amyloid-beta. Damaged brain cells undergo apoptosis, releasing caspase which also breaks down GGA3. Without enough GGA3 to help transport BACE to lysosomes, levels of BACE rise and lead to increased amyloid-beta production. Amyloid-beta itself is toxic to brain cells, so it may cause further apoptosis, leading to a vicious cycle of continued cell death and amyloid-beta production.
The importance of GGA3's control of BACE levels was supported by the observation that, in brain tissue from Alzheimer's patients, reductions in GGA3 corresponded with elevations in BACE, particularly in those areas most affected by the disease.
"Our findings also shed new light on how the aged brain becomes more vulnerable to AD, since any insult to the brain - head injury, stroke, or the mini-strokes called TIAs - can set off this process and turn up BACE activity," says Rudolph Tanzi, PhD, director of the Genetics and Aging Research Unit and senior author of the Neuron paper. "Therapies that protect GGA3 from caspase cleaving might be able to reduce the risk of AD or the more transient type of dementia that can occur after such injuries." Tanzi is a professor of Neurology at Harvard Medical School, where Tesco is an assistant professor.
The research was supported by grants from the National Institute of Health, the National Institute of Mental Health, the American Health Assistance Foundation, the Cure Alzheimer's Fund, and the John French Douglas Foundation Fellowship. Additional co-authors of the Neuron paper are Young Ho Koh, PhD, Eugene Kang, MPH, Andrew Cameron, Shinjita Das, and Mikko Hiltunen, PhD, of MGH-MIND; Miguel Sena-Esteves, PhD, MGH Neuroscience Center; Shao-Hua Yang, MD, PhD, and James Simpkins, PhD, University of North Texas; and Zhenyu Zhong, PhD, and Yong Shen, MD, PhD, Sun Health Research Institute.
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine. MGH and Brigham and Women's Hospital are founding members of Partners HealthCare HealthCare System, a Boston-based integrated health care delivery system.
Contact: Sue McGreevey
Massachusetts General Hospital
"We have discovered how a stroke can trigger a series of biochemical events that increase amyloid-beta production in the brain," says Giuseppina Tesco, MD, PhD, of the MGH-MIND Genetics and Aging Research Unit, the paper's lead author. "These findings raise the prospect of novel therapies that could interfere with this process and reduce the risk of Alzheimer's disease in stroke or head trauma patients."
It has been known for several years that strokes and head injuries can increase the risk of Alzheimer's disease, but the mechanism underlying that increased risk has not been understood. Alzheimer's disease is characterized by plaques within the brain of amyloid-beta protein, which is toxic to brain cells. Amyloid-beta is formed when the larger amyloid precursor protein (APP) is clipped by two enzymes - beta-secretase, also known as BACE, and gamma-secretase - which releases the amyloid-beta fragment. The usual processing of APP by an enzyme called alpha-secretase produces an alternative, non-toxic protein.
The MGH-MIND team previously reported that cellular BACE levels are normally controlled by the enzyme's breakdown in compartments called lysosomes, a process that is disrupted if a molecular signal on the enzyme is altered. That signal binds to GGA proteins, which are required for the transport of several types of enzymes into lysosomes. One of these proteins, GGA3, can be degraded by caspase, an enzyme takes part in the cell-death process called apoptosis.
In a series of experiments the MGH-MIND researchers revealed how cell death caused by a brain injury, including a stroke, can lead to the production of amyloid-beta. Damaged brain cells undergo apoptosis, releasing caspase which also breaks down GGA3. Without enough GGA3 to help transport BACE to lysosomes, levels of BACE rise and lead to increased amyloid-beta production. Amyloid-beta itself is toxic to brain cells, so it may cause further apoptosis, leading to a vicious cycle of continued cell death and amyloid-beta production.
The importance of GGA3's control of BACE levels was supported by the observation that, in brain tissue from Alzheimer's patients, reductions in GGA3 corresponded with elevations in BACE, particularly in those areas most affected by the disease.
"Our findings also shed new light on how the aged brain becomes more vulnerable to AD, since any insult to the brain - head injury, stroke, or the mini-strokes called TIAs - can set off this process and turn up BACE activity," says Rudolph Tanzi, PhD, director of the Genetics and Aging Research Unit and senior author of the Neuron paper. "Therapies that protect GGA3 from caspase cleaving might be able to reduce the risk of AD or the more transient type of dementia that can occur after such injuries." Tanzi is a professor of Neurology at Harvard Medical School, where Tesco is an assistant professor.
The research was supported by grants from the National Institute of Health, the National Institute of Mental Health, the American Health Assistance Foundation, the Cure Alzheimer's Fund, and the John French Douglas Foundation Fellowship. Additional co-authors of the Neuron paper are Young Ho Koh, PhD, Eugene Kang, MPH, Andrew Cameron, Shinjita Das, and Mikko Hiltunen, PhD, of MGH-MIND; Miguel Sena-Esteves, PhD, MGH Neuroscience Center; Shao-Hua Yang, MD, PhD, and James Simpkins, PhD, University of North Texas; and Zhenyu Zhong, PhD, and Yong Shen, MD, PhD, Sun Health Research Institute.
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine. MGH and Brigham and Women's Hospital are founding members of Partners HealthCare HealthCare System, a Boston-based integrated health care delivery system.
Contact: Sue McGreevey
Massachusetts General Hospital
пятница, 3 июня 2011 г.
Alzheimer's Society Comment On New Research Into The Effects Of Amyloid On Blood Clots In Alzheimer's
Research published in the journal Neuron has shown that the amyloid protein, a hallmark of Alzheimer's disease, increases the likelihood of the formation of blood clots.
The study worked with mouse models of the disease to determine how the presence of the amyloid protein affected accumulation of fibrinogen, a key component of blood clots.
People with Alzheimer's disease are more susceptible to stroke and bleeding in the brain. Previous research has shown that amyloid is found in the lining of blood vessels in the brain, causing the vessels to become more fragile. This new study provides new information about how amyloid affects the blood vessels, and increases the risk of stroke in people with Alzheimer's disease.
Alzheimer's Society comment:
'Many people with Alzheimer's disease actually have a condition called mixed dementia, a combination of Alzheimer's disease and vascular dementia, which is linked to interruptions in the blood flow to the brain. We already know that the amyloid protein is found in blood vessels in the brain in Alzheimer's, and that it increases the risk of stroke and bleeding in the brain.'
'This study provides a better understanding of how this amyloid might also be linked to the formation of blood clots, which increase the chance of damage to nerve cells. However, there is much we still do not understand. Research into dementia is drastically underfunded. We must invest more if we are to move forward in our understanding and treatment of this devastating condition.'
Professor Clive Ballard
Director of Research
Source
Alzheimer's Society
The study worked with mouse models of the disease to determine how the presence of the amyloid protein affected accumulation of fibrinogen, a key component of blood clots.
People with Alzheimer's disease are more susceptible to stroke and bleeding in the brain. Previous research has shown that amyloid is found in the lining of blood vessels in the brain, causing the vessels to become more fragile. This new study provides new information about how amyloid affects the blood vessels, and increases the risk of stroke in people with Alzheimer's disease.
Alzheimer's Society comment:
'Many people with Alzheimer's disease actually have a condition called mixed dementia, a combination of Alzheimer's disease and vascular dementia, which is linked to interruptions in the blood flow to the brain. We already know that the amyloid protein is found in blood vessels in the brain in Alzheimer's, and that it increases the risk of stroke and bleeding in the brain.'
'This study provides a better understanding of how this amyloid might also be linked to the formation of blood clots, which increase the chance of damage to nerve cells. However, there is much we still do not understand. Research into dementia is drastically underfunded. We must invest more if we are to move forward in our understanding and treatment of this devastating condition.'
Professor Clive Ballard
Director of Research
Source
Alzheimer's Society
четверг, 2 июня 2011 г.
Biomarkers For Alzheimer's Disease Can Be Trusted In Clinical Trials
The best-established biomarkers for Alzheimer's disease have a low natural variation over two years. The results suggest the inclusion of these biomarkers in clinical trials of novel drugs against Alzheimer's disease.
The results are presented by researchers at the Sahlgrenska Academy at G?¶teborg University, Sweden, in the November 2007 issue of the Journal of Alzheimer's Disease.
"We show that the best-established diagnostic biomarkers for Alzheimer's disease stay at basically the same level during two years in patients with early Alzheimer's disease. This means that the biomarkers could be useful for detecting even minor biochemical changes induced by treatment in the clinical trials of novel drugs against Alzheimer's," says Henrik Zetterberg, Associate Professor at the Sahlgrenska Academy.
Dr Zetterberg and colleagues analyzed cerebrospinal fluid from more than 80 patients with mild cognitive impairment. Some of these patients developed full-blown Alzheimer's disease. The measured levels of the tau and amyloid-b proteins were compared in samples drawn from the same patients two years apart.
"If a novel drug candidate actually stops or slows down the neurodegenerative disease process in Alzheimer's disease, we should expect a normalized tau concentration in cerebrospinal fluid in patients on active treatment. Such a change should be readily detectable also in a small and inexpensive pilot study, given the low intra-individual variation in biomarker levels over time that was detected in our study," Dr Zetterberg says.
Alzheimer's disease is an age-related brain-damaging disorder that results in progressive cognitive impairment and death. Three decades of progress have resulted in a profound understanding of the molecular mechanisms underlying the disease. In the past 10 years, this knowledge has translated into a range of targets for therapy, the most promising of which is amyloid-b.
Journal: Journal of Alzheimer's Disease, 12:3 (November 2007)
Article title: Intra-Individual Stability of CSF Biomarkers for Alzheimer's Disease over Two Years
Authors: Henrik Zetterberg, Mona Pedersen, Karin Lind, Maria Svensson, Sindre Rolstad, Carl Eckerstr?¶m, Steinar Syversen, Ulla-Britt Mattsson, Chrisina Ysander, Niklas Mattsson, Arto Nordlund, Hugo Vanderstichele, Eugeen Vanmechelen, Michael Jonsson, ?…ke Edman, kaj Blennow and Anders Wallin
Source: Associate Professor Henrik Zetterberg
IOS Press
The results are presented by researchers at the Sahlgrenska Academy at G?¶teborg University, Sweden, in the November 2007 issue of the Journal of Alzheimer's Disease.
"We show that the best-established diagnostic biomarkers for Alzheimer's disease stay at basically the same level during two years in patients with early Alzheimer's disease. This means that the biomarkers could be useful for detecting even minor biochemical changes induced by treatment in the clinical trials of novel drugs against Alzheimer's," says Henrik Zetterberg, Associate Professor at the Sahlgrenska Academy.
Dr Zetterberg and colleagues analyzed cerebrospinal fluid from more than 80 patients with mild cognitive impairment. Some of these patients developed full-blown Alzheimer's disease. The measured levels of the tau and amyloid-b proteins were compared in samples drawn from the same patients two years apart.
"If a novel drug candidate actually stops or slows down the neurodegenerative disease process in Alzheimer's disease, we should expect a normalized tau concentration in cerebrospinal fluid in patients on active treatment. Such a change should be readily detectable also in a small and inexpensive pilot study, given the low intra-individual variation in biomarker levels over time that was detected in our study," Dr Zetterberg says.
Alzheimer's disease is an age-related brain-damaging disorder that results in progressive cognitive impairment and death. Three decades of progress have resulted in a profound understanding of the molecular mechanisms underlying the disease. In the past 10 years, this knowledge has translated into a range of targets for therapy, the most promising of which is amyloid-b.
Journal: Journal of Alzheimer's Disease, 12:3 (November 2007)
Article title: Intra-Individual Stability of CSF Biomarkers for Alzheimer's Disease over Two Years
Authors: Henrik Zetterberg, Mona Pedersen, Karin Lind, Maria Svensson, Sindre Rolstad, Carl Eckerstr?¶m, Steinar Syversen, Ulla-Britt Mattsson, Chrisina Ysander, Niklas Mattsson, Arto Nordlund, Hugo Vanderstichele, Eugeen Vanmechelen, Michael Jonsson, ?…ke Edman, kaj Blennow and Anders Wallin
Source: Associate Professor Henrik Zetterberg
IOS Press
среда, 1 июня 2011 г.
Of Mice And Men And Other News Tips From The Journal Of Neuroscience
1. With and without the 3 Mints
Angela Ho, Wade Morishita, Deniz Atasoy, Xinran Liu, Katsuhiko Tabuchi, Robert E. Hammer, Robert C. Malenka, and Thomas C. Sudhof
You can tell a lot about a protein by what it hangs out with. The three Mints (also called X11-like proteins) bind to multiple synaptic proteins, and knock-out studies have suggested that they may indeed be necessary in synaptic transmission. But different isoforms can complement each other's function; thus, it has been difficult to come to firm conclusions using single knock-outs. This week, Ho et al. deleted the Mints using constitutive and conditional knock-out strategies. Deletion of Mint 1 and 2, the two isoforms specifically expressed in neurons, caused most mice to die at birth. The 20% that survived had ataxia and reduced body weight. In the double knock-outs, whole-cell recording of hippocampal neurons revealed lowered synaptic strength, a twofold decrease in the frequency of miniature EPSCs, and enhanced paired-pulse facilitation, indicative of a presynaptic action of Mint 1 and 2. Similar results were obtained with acute ablation of Mint 1/2/3.
2. Born-Again Neurons in Mice and Men
John J. Ohab, Sheila Fleming, Armin Blesch, and S. Thomas Carmichael and Jadranka Macas, Christian Nern, Karl H. Plate, and Stefan Momma
Stroke doesn't only cause cell death, but it also attempts at recovery through neuronal regeneration in tissues near the infarct, according to two separate studies published this week. Using histological analyses in a large collection of postmortem human brains, Macas et al. found increased numbers of neuronal precursor cells, even in patients of advanced age who had suffered ischemia. Because recent studies have coupled neurogenesis to the formation of new blood vessels, Ohab et al. tested the link in a model of focal stroke in mice. These authors showed that stroke induced the long-distance migration of thousands of newly born neuroblasts from the subventricular zone to peri-infarct cortex. The new cells associated with peri-infarct blood vessels in a region of active vascular remodeling. When Ohab et al. added stromal-derived factor 1 and angiopoietin 1, which are produced by the vasculature, the number of newly formed neurons increased.
3. Localizing Vocal Emotions
Jane E. Warren, Disa A. Sauter, Frank Eisner, Jade Wiland, M. Alexander Dresner, Richard J. S. Wise, Stuart Rosen, and Sophie K. Scott
The sound of laughter or cheering typically makes us smile or laugh. Warren et al. wanted to know how this happens. A facial expression showing an emotion can produce a so-called "mirror" response or similar facial expression in an observer. The authors used functional magnetic resonance imaging to determine whether similar mirror responses were also triggered by vocal expressions of emotion. Study participants were asked to listen to human voices conveying positive valence such as amusement and triumph. Listening to these "positive-valence" vocalizations activated specific premotor areas in the left posterior inferior frontal region, an area involved in control of facial movement. The activation was not attributable to facial movement per se. Thus, listening to vocal expressions of emotions appears to automatically engage preparation for orofacial gestures corresponding to the emotional content of the stimulus.
4. Ginkgo biloba and Oligomeric AB in Worms
Yanjue Wu, Zhixin Wu, Peter Butko, Yves Christen, Mary P. Lambert, William L. Klein, Christopher D. Link, and Yuan Luo
Ginkgo biloba, the ancient plant that fed dinosaurs, is widely used in patients with Alzheimer's disease AD). This week, Wu et al. examined the effects of a standard preparation of plant extract, EGb 761, in Caenorhabditis elegans. Nematodes do not express endogenous B amyloid (AB), the peptide that oligomerizes and form deposits in AD brains. Nonetheless, transgenic expression of AB causes striking pathology in C. elegans, such as muscle paralysis and problems with chemotaxis, which were alleviated by EGb 761. Rescue of these behaviors was accompanied by a reduction in AB oligomers. The beneficial effects of G. biloba are thought to result from neuroprotective and antioxidant properties. But in the transgenic C. elegans, reducing oxidative stress with the antioxidant L-ascorbic acid was not nearly as effective in suppressing paralysis as EGb 761. Thus, the beneficial effects of the extract may result from block of AB oligomerization.
Contact: Sara Harris
Society for Neuroscience
Angela Ho, Wade Morishita, Deniz Atasoy, Xinran Liu, Katsuhiko Tabuchi, Robert E. Hammer, Robert C. Malenka, and Thomas C. Sudhof
You can tell a lot about a protein by what it hangs out with. The three Mints (also called X11-like proteins) bind to multiple synaptic proteins, and knock-out studies have suggested that they may indeed be necessary in synaptic transmission. But different isoforms can complement each other's function; thus, it has been difficult to come to firm conclusions using single knock-outs. This week, Ho et al. deleted the Mints using constitutive and conditional knock-out strategies. Deletion of Mint 1 and 2, the two isoforms specifically expressed in neurons, caused most mice to die at birth. The 20% that survived had ataxia and reduced body weight. In the double knock-outs, whole-cell recording of hippocampal neurons revealed lowered synaptic strength, a twofold decrease in the frequency of miniature EPSCs, and enhanced paired-pulse facilitation, indicative of a presynaptic action of Mint 1 and 2. Similar results were obtained with acute ablation of Mint 1/2/3.
2. Born-Again Neurons in Mice and Men
John J. Ohab, Sheila Fleming, Armin Blesch, and S. Thomas Carmichael and Jadranka Macas, Christian Nern, Karl H. Plate, and Stefan Momma
Stroke doesn't only cause cell death, but it also attempts at recovery through neuronal regeneration in tissues near the infarct, according to two separate studies published this week. Using histological analyses in a large collection of postmortem human brains, Macas et al. found increased numbers of neuronal precursor cells, even in patients of advanced age who had suffered ischemia. Because recent studies have coupled neurogenesis to the formation of new blood vessels, Ohab et al. tested the link in a model of focal stroke in mice. These authors showed that stroke induced the long-distance migration of thousands of newly born neuroblasts from the subventricular zone to peri-infarct cortex. The new cells associated with peri-infarct blood vessels in a region of active vascular remodeling. When Ohab et al. added stromal-derived factor 1 and angiopoietin 1, which are produced by the vasculature, the number of newly formed neurons increased.
3. Localizing Vocal Emotions
Jane E. Warren, Disa A. Sauter, Frank Eisner, Jade Wiland, M. Alexander Dresner, Richard J. S. Wise, Stuart Rosen, and Sophie K. Scott
The sound of laughter or cheering typically makes us smile or laugh. Warren et al. wanted to know how this happens. A facial expression showing an emotion can produce a so-called "mirror" response or similar facial expression in an observer. The authors used functional magnetic resonance imaging to determine whether similar mirror responses were also triggered by vocal expressions of emotion. Study participants were asked to listen to human voices conveying positive valence such as amusement and triumph. Listening to these "positive-valence" vocalizations activated specific premotor areas in the left posterior inferior frontal region, an area involved in control of facial movement. The activation was not attributable to facial movement per se. Thus, listening to vocal expressions of emotions appears to automatically engage preparation for orofacial gestures corresponding to the emotional content of the stimulus.
4. Ginkgo biloba and Oligomeric AB in Worms
Yanjue Wu, Zhixin Wu, Peter Butko, Yves Christen, Mary P. Lambert, William L. Klein, Christopher D. Link, and Yuan Luo
Ginkgo biloba, the ancient plant that fed dinosaurs, is widely used in patients with Alzheimer's disease AD). This week, Wu et al. examined the effects of a standard preparation of plant extract, EGb 761, in Caenorhabditis elegans. Nematodes do not express endogenous B amyloid (AB), the peptide that oligomerizes and form deposits in AD brains. Nonetheless, transgenic expression of AB causes striking pathology in C. elegans, such as muscle paralysis and problems with chemotaxis, which were alleviated by EGb 761. Rescue of these behaviors was accompanied by a reduction in AB oligomers. The beneficial effects of G. biloba are thought to result from neuroprotective and antioxidant properties. But in the transgenic C. elegans, reducing oxidative stress with the antioxidant L-ascorbic acid was not nearly as effective in suppressing paralysis as EGb 761. Thus, the beneficial effects of the extract may result from block of AB oligomerization.
Contact: Sara Harris
Society for Neuroscience
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