Posts tagged beta amyloid
Articles and news from the latest research reports.
Novel culture system replicates course of Alzheimer’s disease, confirms amyloid hypothesis
An innovative laboratory culture system has succeeded, for the first time, in reproducing the full course of events underlying the development of Alzheimer’s disease. Using the system they developed, investigators from the Genetics and Aging Research Unit at Massachusetts General Hospital (MGH) now provide the first clear evidence supporting the hypothesis that deposition of beta-amyloid plaques in the brain is the first step in a cascade leading to the devastating neurodegenerative disease. They also identify the essential role in that process of an enzyme, inhibition of which could be a therapeutic target.
"Originally put forth in the mid-1980s, the amyloid hypothesis maintained that beta-amyloid deposits in the brain set off all subsequent events – the neurofibrillary tangles that choke the insides of neurons, neuronal cell death, and inflammation leading to a vicious cycle of massive cell death," says Rudolph Tanzi, PhD, director of the MGH Genetics and Aging Research Unit and co-senior author of the report receiving advance online publication in Nature. “One of the biggest questions since then has been whether beta-amyloid actually triggers the formation of the tangles that kill neurons. In this new system that we call ‘Alzheimer’s-in-a-dish,’ we’ve been able to show for the first time that amyloid deposition is sufficient to lead to tangles and subsequent cell death.”
While the mouse models of Alzheimer’s disease that express the gene variants causing the inherited early-onset form of the disease do develop amyloid plaques in their brains and memory deficits, the neurofibrillary tangles that cause most of the damage do not appear. Other models succeed in producing tangles but not plaques. Cultured neurons from human patients with Alzheimer’s exhibit elevated levels of the toxic form of amyloid found in plaques and the abnormal version of the tau protein that makes up tangles, but not actual plaques and tangles.
Genetics and Aging Research Unit investigator Doo Yeon Kim, PhD, co-senior author of the Nature paper, realized that the liquid two-dimensional systems usually used to grow cultured cells poorly represent the gelatinous three-dimensional environment within the brain. Instead the MGH team used a gel-based, three-dimensional culture system to grow human neural stem cells that carried variants in two genes – the amyloid precursor protein and presenilin 1 – known to underlie early-onset familial Alzheimer’s Disease (FAD). Both of those genes were co-discovered in Tanzi’s laboratory.
After growing for six weeks, the FAD-variant cells were found to have significant increases in both the typical form of beta-amyloid and the toxic form associated with Alzheimer’s. The variant cells also contained the neurofibrillary tangles that choke the inside of nerve cells causing cell death. Blocking steps known to be essential for the formation of amyloid plaques also prevented the formation of the tangles, confirming amyloid’s role in initiating the process. The version of tau found in tangles is characterized by the presence of excess phosphate molecules, and when the team investigated possible ways of blocking tau production, they found that inhibiting the action of an enzyme called GSK3-beta – known to phosphorylate tau in human neurons – prevented the formation of tau aggregates and tangles even in the presence of abundant beta-amyloid and amyloid plaques
"This new system – which can be adapted to other neurodegenerative disorders – should revolutionize drug discovery in terms of speed, costs and physiologic relevance to disease," says Tanzi. "Testing drugs in mouse models that typically have brain deposits of either plaques or tangles, but not both, takes more than a year and is very costly. With our three-dimensional model that recapitulates both plaques and tangles, we now can screen hundreds of thousands of drugs in a matter of months without using animals in a system that is considerably more relevant to the events occurring in the brains of Alzheimer’s patients."
Protein that Causes Frontotemporal Dementia also Implicated in Alzheimer’s Disease
Researchers at the Gladstone Institutes have shown that low levels of the protein progranulin in the brain can increase the formation of amyloid-beta plaques (a hallmark of Alzheimer’s disease), cause neuroinflammation, and worsen memory deficits in a mouse model of this condition. Conversely, by using a gene therapy approach to elevate progranulin levels, scientists were able to prevent these abnormalities and block cell death in this model.
Progranulin deficiency is known to cause another neurodegenerative disorder, frontotemporal dementia (FTD), but its role in Alzheimer’s disease was previously unclear. Although the two conditions are similar, FTD is associated with greater injury to cells in the frontal cortex, causing behavioral and personality changes, whereas Alzheimer’s disease predominantly affects memory centers in the hippocampus and temporal cortex.
Earlier research showed that progranulin levels were elevated near plaques in the brains of patients with Alzheimer’s disease, but it was unknown whether this effect counteracted or exacerbated neurodegeneration. The new evidence, published today in Nature Medicine, shows that a reduction of the protein can severely aggravate symptoms, while increases in progranulin may be the brain’s attempt at fighting the inflammation associated with the disease.
According to first author S. Sakura Minami, PhD, a postdoctoral fellow at the Gladstone Institutes, “This is the first study providing evidence for a protective role of progranulin in Alzheimer’s disease. Prior research had shown a link between Alzheimer’s and progranulin, but the nature of the association was unclear. Our study demonstrates that progranulin deficiency may promote Alzheimer’s disease, with decreased levels rendering the brain vulnerable to amyloid-beta toxicity.”
In the study, the researchers manipulated several different mouse models of Alzheimer’s disease, genetically raising or lowering their progranulin levels. Reducing progranulin markedly increased amyloid-beta plaque deposits in the brain as well as memory impairments. Progranulin deficiency also triggered an over-active immune response in the brain, which can contribute to neurological disorders. In contrast, increasing progranulin levels via gene therapy effectively lowered amyloid beta levels, protecting against cell toxicity and reversing the cognitive deficits typically seen in these Alzheimer’s models.
These effects appear to be linked to progranulin’s involvement in phagocytosis, a type of cellular house-keeping whereby cells “eat” other dead cells, debris, and large molecules. Low levels of progranulin can impair this process, leading to increased amyloid beta deposition. Conversely, increasing progranulin levels enhanced phagocytosis, decreasing the plaque load and preventing neuron death.
“The profound protective effects of progranulin against both amyloid-beta deposits and cell toxicity have important therapeutic implications,” said senior author Li Gan, PhD, an associate investigator at Gladstone and associate professor of neurology at the University of California, San Francisco. “The next step will be to develop progranulin-enhancing approaches that can be used as potential novel treatments, not only for frontotemporal dementia, but also for Alzheimer’s disease.”
(Source: gladstoneinstitutes.org)
Down syndrome helps researchers understand Alzheimer’s disease
The link between a protein typically associated with Alzheimer’s disease and its impact on memory and cognition may not be as clear as once thought, according to a new study from the University of Wisconsin-Madison’s Waisman Center. The findings are revealing more information about the earliest stages of the neurodegenerative disease.
The researchers — including lead study author Sigan Hartley, UW-Madison assistant professor of human development and family studies, and Brad Christian, UW-Madison associate professor of medical physics and psychiatry and director of PET Physics in the Waisman Laboratory for Brain Imaging and Behavior — looked at the role of the brain protein amyloid-β in adults living with Down syndrome, a genetic condition that leaves people more susceptible to developing Alzheimer’s. They published their findings in the September issue of the journal Brain.
"Our hope is to better understand the role of this protein in memory and cognitive function," says Hartley. "With this information we hope to better understand the earliest stages in the development of this disease and gain information to guide prevention and treatment efforts."
However, the findings of their study not only may help scientists better understand the condition as it impacts those living with Down syndrome, but they are also relevant to adults without the genetic syndrome.
"There are many unanswered questions about at what point amyloid-β, together with other brain changes, begins to take a toll on memory and cognition and why certain individuals may be more resistant than others," says Hartley.
The UW-Madison scientists, along with collaborators at the University of Pittsburgh, studied 63 healthy adults with Down syndrome, aged 30 to 53, who did not exhibit clinical signs of Alzheimer’s or other forms of dementia. They found that many adults with Down syndrome had high levels of amyloid-β protein but did not suffer the expected negative consequences of the elevated protein.
Alzheimer’s disease is the sixth leading cause of death in the U.S. People with Down syndrome are born with an extra copy of the 21st chromosome, where the gene that codes for the amyloid-β protein resides.
For the study, which was conducted over the course of two days, researchers used magnetic resonance imaging (MRI) and positron emission tomography (PET) scans to capture images of the participants’ brains. Twenty-two of the 63 participants had elevated levels of amyloid-β but showed no evidence of diminished memory or cognitive function when compared to those without elevated levels of the protein. The researchers controlled for differences in age and intellectual level.
Similarly, when assessed as a continuous measure, amyloid-β levels were not tied to differences in memory or cognitive ability, such as changes in visual and verbal memory, attention and language.
(Source: news.wisc.edu)
Researchers Reveal Pathway that Contributes to Alzheimer’s Disease
Researchers at Jacksonville’s campus of Mayo Clinic have discovered a defect in a key cell-signaling pathway they say contributes to both overproduction of toxic protein in the brains of Alzheimer’s disease patients as well as loss of communication between neurons — both significant contributors to this type of dementia.
Their study, in the online issue of Neuron, offers the potential that targeting this specific defect with drugs “may rejuvenate or rescue this pathway,” says the study’s lead investigator, Guojun Bu, Ph.D., a neuroscientist at Mayo Clinic, Jacksonville, Fla.
“This defect is likely not the sole contributor to development of Alzheimer’s disease, but our findings suggest it is very important, and could be therapeutically targeted to possibly prevent Alzheimer’s or treat early disease,” he says.
The pathway, Wnt signaling, is known to play a critical role in cell survival, embryonic development and synaptic activity — the electrical and chemical signals necessary for learning and memory. Any imbalance in this pathway (too much or too little activity) leads to disease — the overgrowth of cells in cancer is one example of overactivation of this pathway.
While much research on Wnt has focused on diseases involved in overactive Wnt signaling, Dr. Bu’s team is one of the first to demonstrate the link between suppressed Wnt signaling and Alzheimer’s disease.
“Our finding makes sense, because researchers have long known that patients with cancer are at reduced risk of developing Alzheimer’s disease, and vice versa,” Dr. Bu says. “What wasn’t known is that Wnt signaling was involved in that dichotomy.”
Using a new mouse model, the investigators discovered the key defect that leads to suppressed Wnt signaling in Alzheimer’s. They found that the low-density lipoprotein receptor-related protein 6 (LRP6) is deficient, and that LRP6 regulates both production of amyloid beta, the protein that builds up in the brains of AD patients, and communication between neurons. That means lower than normal levels of LRP6 leads to a toxic buildup of amyloid and impairs the ability of neurons to talk to each other.
Mice without LRP6 had impaired Wnt signaling, cognitive impairment, neuroinflammation and excess amyloid.
The researchers validated their findings by examining postmortem brain tissue from Alzheimer’s patients — they found that LRP6 levels were deficient and Wnt signaling was severely compromised in the human brain they examined.
The good news is that specific inhibitors of this pathway are already being tested for cancer treatment. “Of course, we don’t want to inhibit Wnt in people with Alzheimer’s or at risk for the disease, but it may be possible to use the science invested in inhibiting Wnt to figure out how to boost activity in the pathway,” Dr. Bu says.
“Identifying small molecule compounds to restore LRP6 and the Wnt pathway, without inducing side effects, may help prevent or treat Alzheimer’s disease,” he says. “This is a really exciting new strategy — a new and fresh approach.”
(Image caption: Shown are fMRI scans across all subjects in the study. The yellow and red areas in Section A represent parts of the brain that are activated while subjects are forming “gist memories” of pictures viewed. Section B represents areas of increased activation, shown in yellow and red, as detailed memories are being formed. Credit: Image courtesy of Jagust Lab)
Researchers find neural compensation in people with Alzheimer’s-related protein
The human brain is capable of a neural workaround that compensates for the buildup of beta-amyloid, a destructive protein associated with Alzheimer’s disease, according to a new study led by UC Berkeley researchers.
The findings, published today (Sunday, Sept. 14) in the journal Nature Neuroscience, could help explain how some older adults with beta-amyloid deposits in their brain retain normal cognitive function while others develop dementia.
“This study provides evidence that there is plasticity or compensation ability in the aging brain that appears to be beneficial, even in the face of beta-amyloid accumulation,” said study principal investigator Dr. William Jagust, a professor with joint appointments at UC Berkeley’s Helen Wills Neuroscience Institute, the School of Public Health and Lawrence Berkeley National Laboratory.
Previous studies have shown a link between increased brain activity and beta-amyloid deposits, but it was unclear whether the activity was tied to better mental performance.
The study included 22 healthy young adults and 49 older adults who had no signs of mental decline. Brain scans showed that 16 of the older subjects had beta-amyloid deposits, while the remaining 55 adults did not.
The researchers used functional magnetic resonance imaging (fMRI) to track the brain activity of subjects in the process of memorizing pictures of various scenes. Afterwards, the researchers tested the subjects’ “gist memory” by asking them to confirm whether a written description of a scene – such as a boy doing a handstand – corresponded to a picture previously viewed. Subjects were then asked to confirm whether specific written details of a scene – such as the color of the boy’s shirt – were true.
“Generally, the groups performed equally well in the tasks, but it turned out that for people with beta-amyloid deposits in the brain, the more detailed and complex their memory, the more brain activity there was,” said Jagust. “It seems that their brain has found a way to compensate for the presence of the proteins associated with Alzheimer’s.”
What remains unclear, said Jagust, is why some people with beta-amyloid deposits are better at using different parts of their brain than others. Previous studies suggest that people who engage in mentally stimulating activities throughout their lives have lower levels of beta-amyloid.
“I think it’s very possible that people who spend a lifetime involved in cognitively stimulating activity have brains that are better able to adapt to potential damage,” said Jagust.
New technique could benefit Alzheimer’s diagnosis
Swinburne researchers have developed a technique to create a highly sensitive surface for measuring the concentration of a peptide that is a biomarker for early stage Alzheimer’s disease.
(Image caption: Ultrashort-laser pulses were used to write ripples on the surface of sapphire. The self-organised nano-structure of ripples (seen in the image) is a perfect sensing surface after coating with a nanometre-thin layer of gold made by evaporation or sputtering. Such surface ripples were used in the study of amyloid detection.)
Alzheimer’s disease was first recorded more than 100 years ago, but there is still no effective therapy to stop or slow the progression of the disease. Sufferers can lose up to 60 per cent of their neuronal cells before a diagnosis is obtained.
Diagnosis at the very early stages before neuronal degeneration has begun is vital for testing and developing new treatments.
Abnormality of the beta amyloid peptide in cerebrospinal fluid appears to be the earliest and most significant marker of Alzheimer’s. Currently there are no standardised tests to detect these biomarkers.
The researchers have developed a sensor based on nanotechnology that outperforms commercial sensors and demonstrates fast and reliable measurement of beta amyloid oligomers at low concentrations.
The key to the high sensitivity is the laser nano-textured gold coated surface. This sensor can identify concentrations of beta amyloid in a quantitative manner for the first time.
“We showed that sensors based on light scattering can indeed deliver QUANTATIVE measurements and they can be made fast,” Professor of Nanophotonics Saulius Juodkazis said.
“The sensor platform we developed by laser nano-texturing of surfaces is delivering results of the highest sensitivity and repeatability.
“The challenge is to create fast and efficient fabrication of sensors based on nanotechnology and develop new analytical methods of detection. This means we should be able to detect markers of diseases at far lower levels.”
Surface enhanced Raman spectroscopy (SERS) is one of the most sensitive and highly specific label-free detection methods which may evolve as a detection technique for different forms of beta amyloid or as a rapid, low cost technique to validate new biomarkers before developing standard assays for enzyme-linked immunosorbent assays (ELISAs).
This research is a PhD project work of Dr Ricardas Buividas who received his doctorate in May 2014. It was published in the Journal of Biophotonics.
(Source: swinburne.edu.au)
How Alzheimer’s Peptides Shut Down Cellular Powerhouses
The failing in the work of nerve cells: An international team of researchers led by Prof. Dr. Chris Meisinger from the Institute of Biochemistry and Molecular Biology of the University of Freiburg has discovered how Alzheimer’s disease damages mitochondria, the powerhouses of the cell. For several years researchers have known that the cellular energy supply of brain cells is impaired in Alzheimer’s patients. They suspect this to be the cause of premature death of nerve cells that occurs in the course of the disease. Little is known about the precise cause of this neuronal cell death, and many approaches and attempts to find an effective therapy have failed to make an impact. What is certain is that a tiny protein fragment by the name of “amyloid-beta” plays a key role in the process. Meisinger, a member of the Cluster of Excellence BIOSS Centre for Biological Signalling Studies of the University of Freiburg, and his team have now demonstrated how this protein fragment blocks the maturation of protein machines that are responsible for the production of energy inside the cellular powerhouses. The researchers demonstrated this with the help of model organisms and with brain samples from Alzheimer’s patients. “The elucidation of this key component of the disease mechanism will enable us to develop new therapies and improve diagnostics in the future,” explains Meisinger. The findings were published in the journal Cell Metabolism.
Mitochondria are made up of around 1500 different proteins. Most of them need to migrate to the cellular powerhouses before taking up their work. This import is facilitated by a so-called signaling sequence – tiny protein extensions that transport the protein into the mitochondria. Once the protein is inside, the signaling sequence is normally removed. Dirk Mossmann and Dr. Nora Vögtle from Meisinger’s research team have now discovered that the amyloid-beta peptide prevents mitochondria from removing these signaling sequences. As a consequence, incomplete proteins accumulate in the mitochondria. Since the signaling sequences remain attached, the proteins are unstable and can no longer adequately carry out their function in energy metabolism. The researchers demonstrated that modified yeast cells producing the amyloid-beta protein generate less energy and accumulate more harmful substances.
In the brain, the mechanism probably leads to the death of nerve cells: The brain shrinks and the patient suffers from dementia. The researchers are currently developing an Alzheimer’s blood test to detect the accumulation of mitochondrial precursor proteins. They suspect that the mitochondrial alterations observed in nerve cells will also be detected in the blood cells of Alzheimer’s patients.
(Source: pr.uni-freiburg.de)
Marijuana compound may offer treatment for Alzheimer’s disease
Extremely low levels of the compound in marijuana known as delta-9-tetrahydrocannabinol, or THC, may slow or halt the progression of Alzheimer’s disease, a recent study from neuroscientists at the University of South Florida shows.
Findings from the experiments, using a cellular model of Alzheimer’s disease, were reported online in the Journal of Alzheimer’s Disease.
Researchers from the USF Health Byrd Alzheimer’s Institute showed that extremely low doses of THC reduce the production of amyloid beta, found in a soluble form in most aging brains, and prevent abnormal accumulation of this protein — a process considered one of the pathological hallmarks evident early in the memory-robbing disease. These low concentrations of THC also selectively enhanced mitochondrial function, which is needed to help supply energy, transmit signals, and maintain a healthy brain.
“THC is known to be a potent antioxidant with neuroprotective properties, but this is the first report that the compound directly affects Alzheimer’s pathology by decreasing amyloid beta levels, inhibiting its aggregation, and enhancing mitochondrial function,” said study lead author Chuanhai Cao, PhD and a neuroscientist at the Byrd Alzheimer’s Institute and the USF College of Pharmacy.
“Decreased levels of amyloid beta means less aggregation, which may protect against the progression of Alzheimer’s disease. Since THC is a natural and relatively safe amyloid inhibitor, THC or its analogs may help us develop an effective treatment in the future.”
The researchers point out that at the low doses studied, the therapeutic benefits of THC appear to prevail over the associated risks of THC toxicity and memory impairment.
Neel Nabar, a study co-author and MD/PhD candidate, recognized the rapidly changing political climate surrounding the debate over medical marijuana.
“While we are still far from a consensus, this study indicates that THC and THC-related compounds may be of therapeutic value in Alzheimer’s disease,” Nabar said. “Are we advocating that people use illicit drugs to prevent the disease? No. It’s important to keep in mind that just because a drug may be effective doesn’t mean it can be safely used by anyone. However, these findings may lead to the development of related compounds that are safe, legal, and useful in the treatment of Alzheimer’s disease.”
The body’s own system of cannabinoid receptors interacts with naturally-occurring cannabinoid molecules, and these molecules function similarly to the THC isolated from the cannabis (marijuana) plant.
Dr. Cao’s laboratory at the Byrd Alzheimer’s Institute is currently investigating the effects of a drug cocktail that includes THC, caffeine as well as other natural compounds in a cellular model of Alzheimer’s disease, and will advance to a genetically-engineered mouse model of Alzheimer’s shortly.
“The dose and target population are critically important for any drug, so careful monitoring and control of drug levels in the blood and system are very important for therapeutic use, especially for a compound such as THC,” Dr. Cao said.
Smell and eye tests show potential to detect Alzheimer’s early
A decreased ability to identify odors might indicate the development of cognitive impairment and Alzheimer’s disease, while examinations of the eye could indicate the build-up of beta-amyloid, a protein associated with Alzheimer’s, in the brain, according to the results of four research trials reported today at the Alzheimer’s Association International Conference® 2014 (AAIC® 2014) in Copenhagen.
In two of the studies, the decreased ability to identify odors was significantly associated with loss of brain cell function and progression to Alzheimer’s disease. In two other studies, the level of beta-amyloid detected in the eye (a) was significantly correlated with the burden of beta-amyloid in the brain and (b) allowed researchers to accurately identify the people with Alzheimer’s in the studies.
Beta-amyloid protein is the primary material found in the sticky brain “plaques” characteristic of Alzheimer’s disease. It is known to build up in the brain many years before typical Alzheimer’s symptoms of memory loss and other cognitive problems.
"In the face of the growing worldwide Alzheimer’s disease epidemic, there is a pressing need for simple, less invasive diagnostic tests that will identify the risk of Alzheimer’s much earlier in the disease process," said Heather Snyder, Ph.D., Alzheimer’s Association director of Medical and Scientific Operations. "This is especially true as Alzheimer’s researchers move treatment and prevention trials earlier in the course of the disease."
"More research is needed in the very promising area of Alzheimer’s biomarkers because early detection is essential for early intervention and prevention, when new treatments become available. For now, these four studies reported at AAIC point to possible methods of early detection in a research setting to choose study populations for clinical trials of Alzheimer’s treatments and preventions," Snyder said.
With the support of the Alzheimer’s Association and the Alzheimer’s community, the United States created its first National Plan to Address Alzheimer’s Disease in 2012. The plan includes the critical goal, which was adopted by the G8 at the Dementia Summit in 2013, of preventing and effectively treating Alzheimer’s by 2025. It is only through strong implementation and adequate funding of the plan, including an additional $200 million in fiscal year 2015 for Alzheimer’s research, that we’ll meet that goal. For more information and to get involved, visit http://www.alz.org.
Clinically, at this time it is only possible to detect Alzheimer’s late in its development, when significant brain damage has already occurred. Biological markers of Alzheimer’s disease may be able to detect it at an earlier stage. For example, using brain PET imaging in conjunction with a specialized chemical that binds to beta-amyloid protein, the buildup of the protein as plaques in the brain can be revealed years before symptoms appear. These scans can be expensive and are not available everywhere. Amyloid can also be detected in cerebrospinal fluid through a lumbar puncture where a needle is inserted between two bones (vertebrae) in your lower back to remove a sample of the fluid that surrounds your brain and spinal cord.
(Image: Getty Images)
Research Links Alzheimer’s Disease to Brain Hyperactivity
Patients with Alzheimer’s disease run a high risk of seizures. While the amyloid-beta protein involved in the development and progression of Alzheimer’s seems the most likely cause for this neuronal hyperactivity, how and why this elevated activity takes place hasn’t yet been explained — until now.
A new study by Tel Aviv University researchers, published in Cell Reports, pinpoints the precise molecular mechanism that may trigger an enhancement of neuronal activity in Alzheimer’s patients, which subsequently damages memory and learning functions. The research team, led by Dr. Inna Slutsky of TAU’s Sackler Faculty of Medicine and Sagol School of Neuroscience, discovered that the amyloid precursor protein (APP), in addition to its well-known role in producing amyloid-beta, also constitutes the receptor for amyloid-beta. According to the study, the binding of amyloid-beta to pairs of APP molecules triggers a signalling cascade, which causes elevated neuronal activity.
Elevated activity in the hippocampus — the area of the brain that controls learning and memory — has been observed in patients with mild cognitive impairment and early stages of Alzheimer’s disease. Hyperactive hippocampal neurons, which precede amyloid plaque formation, have also been observed in mouse models with early onset Alzheimer’s disease. “These are truly exciting results,” said Dr. Slutsky. “Our work suggests that APP molecules, like many other known cell surface receptors, may modulate the transfer of information between neurons.”
With the understanding of this mechanism, the potential for restoring memory and protecting the brain is greatly increased.
Building on earlier research
The research project was launched five years ago, following the researchers’ discovery of the physiological role played by amyloid-beta, previously known as an exclusively toxic molecule. The team found that amyloid-beta is essential for the normal day-to-day transfer of information through the nerve cell networks. If the level of amyloid-beta is even slightly increased, it causes neuronal hyperactivity and greatly impairs the effective transfer of information between neurons.
In the search for the underlying cause of neuronal hyperactivity, TAU doctoral student Hilla Fogel and postdoctoral fellow Samuel Frere found that while unaffected “normal” neurons became hyperactive following a rise in amyloid-beta concentration, neurons lacking APP did not respond to amyloid-beta. “This finding was the starting point of a long journey toward decoding the mechanism of APP-mediated hyperactivity,” said Dr. Slutsky.
The researchers, collaborating with Prof. Joel Hirsch of TAU’s Faculty of Life Sciences, Prof. Dominic Walsh of Harvard University, and Prof. Ehud Isacoff of University of California Berkeley, harnessed a combination of cutting-edge high-resolution optical imaging, biophysical methods and molecular biology to examine APP-dependent signalling in neural cultures, brain slices, and mouse models. Using highly sensitive biophysical techniques based on fluorescence resonance energy transfer (FRET) between fluorescent proteins in close proximity, they discovered that APP exists as a dimer at presynaptic contacts, and that the binding of amyloid-beta triggers a change in the APP-APP interactions, leading to an increase in calcium flux and higher glutamate release — in other words, brain hyperactivity.
A new approach to protecting the brain
"We have now identified the molecular players in hyperactivity," said Dr. Slutsky. "TAU postdoctoral fellow Oshik Segev is now working to identify the exact spot where the amyloid-beta binds to APP and how it modifies the structure of the APP molecule. If we can change the APP structure and engineer molecules that interfere with the binding of amyloid-beta to APP, then we can break up the process leading to hippocampal hyperactivity. This may help to restore memory and protect the brain."
Previous studies by Prof. Lennart Mucke’s laboratory strongly suggest that a reduction in the expression level of “tau” (microtubule-associated protein), another key player in Alzheimer’s pathogenesis, rescues synaptic deficits and decreases abnormal brain activity in animal models. “It will be crucial to understand the missing link between APP and ‘tau’-mediated signalling pathways leading to hyperactivity of hippocampal circuits. If we can find a way to disrupt the positive signalling loop between amyloid-beta and neuronal activity, it may rescue cognitive decline and the conversion to Alzheimer’s disease,” said Dr. Slutsky.
(Source: aftau.org)