Posts tagged amyloid precursor protein
Articles and news from the latest research reports.
Study finds potential genetic link between epilepsy and neurodegenerative disorders
A recent scientific discovery showed that mutations in prickle genes cause epilepsy, which in humans is a brain disorder characterized by repeated seizures over time. However, the mechanism responsible for generating prickle-associated seizures was unknown.
A new University of Iowa study, published online July 14 in the Proceedings of the National Academy of Sciences, reveals a novel pathway in the pathophysiology of epilepsy. UI researchers have identified the basic cellular mechanism that goes awry in prickle mutant flies, leading to the epilepsy-like seizures.
“This is to our knowledge the first direct genetic evidence demonstrating that mutations in the fly version of a known human epilepsy gene produce seizures through altered vesicle transport,” says John Manak, senior author and associate professor of biology in the College of Liberal Arts and Sciences and pediatrics in the Carver College of Medicine.
Seizure suppression in flies
A neuron has an axon (nerve fiber) that projects from the cell body to different neurons, muscles, and glands. Information is transmitted along the axon to help a neuron function properly.
Manak and his fellow researchers show that seizure-prone prickle mutant flies have behavioral defects (such as uncoordinated gait) and electrophysiological defects (problems in the electrical properties of biological cells) similar to other fly mutants used to study seizures. The researchers also show that altering the balance of two forms of the prickle gene disrupts neural information flow and causes epilepsy.
Further, they demonstrate that reducing either of two motor proteins responsible for directional movement of vesicles (small organelles within a cell that contain biologically important molecules) along tracks of structural proteins in axons can suppress the seizures.
“The reduction of either of two motor proteins, called Kinesins, fully suppressed the seizures in the prickle mutant flies,” says Manak, faculty member in the Interdisciplinary Graduate Programs in Genetics, Molecular and Cellular Biology, and Health Informatics. “We were able to use two independent assays to show that we could suppress the seizures, effectively ‘curing’ the flies of their epileptic behaviors.”
Genetic link between epilepsy and Alzheimer’s
This new epilepsy pathway was previously shown to be involved in neurodegenerative diseases, including Alzheimer’s and Parkinson’s.
Manak and his colleagues note that two Alzheimer’s-associated proteins, amyloid precursor protein and presenilin, are components of the same vesicle, and mutations in the genes encoding these proteins in flies affect vesicle transport in ways that are strikingly similar to how transport is impacted in prickle mutants.
“We are particularly excited because we may have stumbled upon one of the key genetic links between epilepsy and Alzheimer’s, since both disorders are converging on the same pathway,” Manak says. “This is not such a crazy idea. In fact, Dr. Jeff Noebels, a leading epilepsy researcher, has presented compelling evidence suggesting a link between these disorders. Indeed, patients with inherited forms of Alzheimer’s disease also present with epilepsy, and this has been documented in a number of published studies.”
Manak adds, “If this connection is real, then drugs that have been developed to treat neurodegenerative disorders could potentially be screened for anti-seizure properties, and vice versa.”
Manak’s future research will involve treating seizure-prone flies with such drugs to see if he can suppress their seizures.
(Source: now.uiowa.edu)
New Amyloid-Reducing Compound Could Be a Preventive Measure Against Alzheimer’s
Scientists at NYU Langone Medical Center have identified a compound, called 2-PMAP, in animal studies that reduced by more than half levels of amyloid proteins in the brain associated with Alzheimer’s disease. The researchers hope that someday a treatment based on the molecule could be used to ward off the neurodegenerative disease since it may be safe enough to be taken daily over many years.
“What we want in an Alzheimer’s preventive is a drug that modestly lowers amyloid beta and is also safe for long term use,” says Martin J. Sadowski, MD, PhD, associate professor of neurology, psychiatry, and biochemistry and molecular pharmacology, who led the research to be published online June 3 in the journal Annals of Neurology. “Statin drugs that lower cholesterol appear to have those properties and have made a big impact in preventing coronary artery disease. That’s essentially what many of us envision for the future of Alzheimer’s medicine.”
The 2-PMAP molecule that Dr. Sadowski’s team identified is non-toxic in mice, gets easily into the brain, and lowers the production of amyloid beta and associated amyloid deposits.
The prime target for Alzheimer’s prevention is amyloid beta. Decades before dementia begins, this small protein accumulates in clumps in the brain. Modestly lowering the production of amyloid beta in late middle age, and thus removing some of the burden from the brain’s natural clearance mechanisms, is believed to be a good prevention strategy. Researchers two years ago reported that something like this happens naturally in about 0.5 percent of Icelanders, due to a mutation they carry that approximately halves amyloid beta production throughout life. These fortunate people show a slower cognitive decline in old age, live longer, and almost never get Alzheimer’s.
Prevention of Alzheimer’s dementia is now considered more feasible than stopping it after it has begun, when brain damage is already severe. Every prospective Alzheimer’s drug in clinical trials has failed even to slow the disease process at that late stage. “The key is to prevent the disease process from going that far,” Dr. Sadowski says.
Dr. Sadowski and colleagues screened a library of compounds and found that 2-PMAP reduced the production of amyloid beta’s mother protein, known as amyloid precursor protein (APP). The APP protein normally is cut by enzymes in a way that leaves amyloid beta as one of the fragments. Dr. Sadowski’s team found that 2-PMAP, even at low, non-toxic concentrations, significantly reduced APP production in test cells, lowering amyloid beta levels by 50 percent or more.
The scientists subsequently found that 2-PMAP had essentially the same impact on APP and amyloid beta in the brains of living mice. The mice were engineered to have the same genetic mutations found in Alzheimer’s patients with a hereditary form of the disease, causing overproduction of APP and Alzheimer’s-like amyloid deposits. A five-day treatment with 2-PMAP lowered brain levels of APP and, even more so, levels of amyloid beta. Four months of treatment sharply reduced the amyloid deposits and prevented the cognitive deficits that are normally seen in these transgenic mice as they get older.
Dr. Sadowski and his laboratory are now working to make chemical modifications to the compound to improve its effectiveness. But 2-PMAP already seems to have advantages over other amyloid-lowering compounds, he says. One is that it can cross efficiently from the bloodstream to the brain, and thus doesn’t require complex modifications that might compromise its effects on APP.
The compound also appears to have a highly selective effect on APP production, by interfering with the translation of APP’s gene transcript into the APP protein itself. The best known candidates for Alzheimer’s preventives lower amyloid by inhibiting the secretase enzymes that cleave amyloid beta from APP, tending to cause unwanted side-effects via their off target interference with the processing of other client proteins cleaved by these enzymes. A clinical trial of one secretase inhibitor was halted in 2010 after it was found to worsen dementia and cause a higher incidence of skin cancer.
Alzheimer’s disease, the most common form of dementia, currently afflicts more than five million Americans, according to the Alzheimer’s Association. Unless preventive drugs or treatments are developed, the prevalence of Alzheimer’s is expected to triple by 2050.
(Source: communications.med.nyu.edu)
(Image caption: Researchers have identified a new class of compounds—pharmacologic chaperones—that can stabilize the retromer protein complex (the blue and orange structure shows part of the complex). Retromer plays a vital role in keeping amyloid precursor from being cleaved and producing the toxic byproduct amyloid beta, which contributes to the development of Alzheimer’s. The study found that when the chaperone named R55 (the multicolored molecule) was added to neurons in cell culture, it bound to and stabilized retromer, increasing retromer levels and lowering amyloid-beta levels. Credit: Nature Chemical Biology and lab of Scott A. Small, MD/Columbia University Medical Center.)
“Chaperone” Compounds Offer New Approach to Alzheimer’s Treatment
A team of researchers from Columbia University Medical Center (CUMC), Weill Cornell Medical College, and Brandeis University has devised a wholly new approach to the treatment of Alzheimer’s disease involving the so-called retromer protein complex. Retromer plays a vital role in neurons, steering amyloid precursor protein (APP) away from a region of the cell where APP is cleaved, creating the potentially toxic byproduct amyloid-beta, which is thought to contribute to the development of Alzheimer’s.
Using computer-based virtual screening, the researchers identified a new class of compounds, called pharmacologic chaperones, that can significantly increase retromer levels and decrease amyloid-beta levels in cultured hippocampal neurons, without apparent cell toxicity. The study was published today in the online edition of the journal Nature Chemical Biology.
“Our findings identify a novel class of pharmacologic agents that are designed to treat neurologic disease by targeting a defect in cell biology, rather than a defect in molecular biology,” said Scott Small, MD, the Boris and Rose Katz Professor of Neurology, Director of the Alzheimer’s Disease Research Center in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at CUMC, and a senior author of the paper. “This approach may prove to be safer and more effective than conventional treatments for neurologic disease, which typically target single proteins.”
In 2005, Dr. Small and his colleagues showed that retromer is deficient in the brains of patients with Alzheimer’s disease. In cultured neurons, they showed that reducing retromer levels raised amyloid-beta levels, while increasing retromer levels had the opposite effect. Three years later, he showed that reducing retromer had the same effect in animal models, and that these changes led to Alzheimer’s-like symptoms. Retromer abnormalities have also been observed in Parkinson’s disease.
In discussions at a scientific meeting, Dr. Small and co-senior authors Gregory A. Petsko, DPhil, Arthur J. Mahon Professor of Neurology and Neuroscience in the Feil Family Brain and Mind Research Institute and Director of the Helen and Robert Appel Alzheimer’s Disease Research Institute at Weill Cornell Medical College, and Dagmar Ringe, PhD, Harold and Bernice Davis Professor in the Departments of Biochemistry and Chemistry and in the Rosenstiel Basic Medical Sciences Research Center at Brandeis University, began wondering if there was a way to stabilize retromer (that is, prevent it from degrading) and bolster its function. “The idea that it would be beneficial to protect a protein’s structure is one that nature figured out a long time ago,” said Dr. Petsko. “We’re just learning how to do that pharmacologically.”
Other researchers had already determined retromer’s three-dimensional structure. “Our challenge was to find small molecules—or pharmacologic chaperones—that could bind to retromer’s weak point and stabilize the whole protein complex,” said Dr. Ringe.
This was accomplished through computerized virtual, or in silico, screening of known chemical compounds, simulating how the compounds might dock with the retromer protein complex. (In conventional screening, compounds are physically tested to see whether they interact with the intended target, a costlier and lengthier process.) The screening identified 100 potential retromer-stabilizing candidates, 24 of which showed particular promise. Of those, one compound, called R55, was found to significantly increase the stability of retromer when the complex was subjected to heat stress.
The researchers then looked at how R55 affected neurons of the hippocampus, a key brain structure involved in learning and memory. “One concern was that this compound would be toxic,” said Dr. Diego Berman, assistant professor of clinical pathology and cell biology at CUMC and a lead author. “But R55 was found to be relatively non-toxic in mouse neurons in cell culture.”
More important, a subsequent experiment showed that the compound significantly increased retromer levels and decreased amyloid-beta levels in cultured neurons taken from healthy mice and from a mouse model of Alzheimer’s. The researchers are currently testing the clinical effects of R55 in the actual mouse model .
“The odds that this particular compound will pan out are low, but the paper provides a proof of principle for the efficacy of retromer pharmacologic chaperones,” said Dr. Petsko. “While we’re testing R55, we will be developing chemical analogs in the hope of finding compounds that are more effective.”
Researchers discover novel function of protein linked to Alzheimer’s disease
A research team led by the National Neuroscience Institute (NNI) has uncovered a novel function of the Amyloid Precursor Protein (APP), one of the main pathogenic culprits of Alzheimer’s disease. This discovery may help researchers understand how the protein goes awry in the brains of Alzheimer’s disease patients, and potentially paves the way for the development of innovative therapeutics to improve the brain function of dementia patients.
The findings were published in the prestigious scientific research journal Nature Communications last month. The study, which is led by Dr Zeng Li and her team from NNI, involved investigators from Duke-NUS Graduate Medical School and the Agency for Science and Technology (A*STAR).
Alzheimer’s disease is the most common form of dementia, which is set to rise significantly from the current 28,000 cases to 80,000 cases in 2030 among Singaporeans aged 60 and above. With a rapidly aging population, the burden of the disease will be profound affecting not just the person afflicted, but also the caregiver and family. While the exact cause of Alzheimer’s disease remains unknown, one of its pathological hallmarks is clear – the clumping of APP product in the brain when the protein is abnormally processed.
Finding out more about APP can help researchers gain a better understanding of the disease, and potentially identify biomarkers and therapeutic targets for it. However up till this point, little was known about the APP’s primary function in the brain.
(Source: eurekalert.org)
New insight into SIDS deaths points to lack of oxygen
Research at the University of Adelaide has shed new light onto the possible causes of sudden infant death syndrome (SIDS), which could help to prevent future loss of children’s lives.
In a world-first study, researchers in the University’s School of Medical Sciences have found that telltale signs in the brains of babies that have died of SIDS are remarkably similar to those of children who died of accidental asphyxiation.
"This is a very important result. It helps to show that asphyxia rather than infection or trauma is more likely to be involved in SIDS deaths," says the leader of the project, Professor Roger Byard AO, Marks Professor of Pathology at the University of Adelaide and Senior Specialist Forensic Pathologist with Forensic Science SA.
The study compared 176 children who died from head trauma, infection, drowning, asphyxia and SIDS.
Researchers were looking at the presence and distribution of a protein called β-amyloid precursor protein (APP) in the brain. This “APP staining”, as it’s known, could be an important tool for showing how children have died. This is the first time a detailed study of APP has been undertaken in SIDS cases.
"All 48 of the SIDS deaths we looked at showed APP staining in the brain," Professor Byard says.
"The staining by itself does not necessarily tell us the cause of death, but it can help to clarify the mechanism.
"The really interesting point is that the pattern of APP staining in SIDS cases - both the amount and distribution of the staining - was very similar to those in children who had died from asphyxia."
Professor Byard says that in one case, the presence of APP staining in a baby who had died of SIDS led to the identification of a significant sleep breathing problem, or apnoea, in the deceased baby’s sibling.
"This raised the possibility of an inherited sleep apnoea problem, and this knowledge could be enough to help save a child’s life," Professor Byard says.
"Because of the remarkable similarity in SIDS and asphyxia cases, the question is now: is there an asphyxia-based mechanism of death in SIDS? We don’t know the answer to that yet, but it looks very promising."
This study was conducted at the University of Adelaide by visiting postdoctoral researcher Dr Lisbeth Jensen from Aarhus University Hospital, Denmark, and was funded by SIDS and Kids South Australia. The results have been published in the journal Neuropathology and Applied Neurobiology.
"This work also fits in very well with collaborative research that is currently being undertaken between the University of Adelaide and Harvard University, on chemical changes in parts of the brain that control breathing," Professor Byard says.
(Source: adelaide.edu.au)
New mouse model could revolutionize research in Alzheimer’s disease
In a study published today in Nature Neuroscience, a group of researchers led by Takaomi Saido of the RIKEN Brain Science Institute in Japan have reported the creation of two new mouse models of Alzheimer’s disease that may potentially revolutionize research into this disease.
Alzheimer’s disease, the primary cause of dementia in the elderly, imposes a tremendous social and economic burden on modern society. In Japan, the burden of the disease in 2050 is estimated to be a half a trillion US dollars, a figure equivalent to the government’s annual revenues.
Unfortunately, it has proven very difficult to develop drugs capable of ameliorating the disease. After a tremendous burst of progress in the 1990s, the pace of discoveries has slowed. Dr. Saido believes that part of the difficulty is the inadequacy of current mouse models to replicate the real conditions of Alzheimer’s disease and allow an understanding of the underlying mechanisms that lead to neurodegeneration. In fact, much of the research in Alzheimer’s disease over the past decade may be flawed, as it was based on unrealistic models.
The problem with older mouse models is that they overexpress a protein called amyloid precursor protein, or APP, which gives rise to the amyloid-beta (Abeta) peptides that accumulate in the brain, eventually leading to the neurodegeneration that characterizes Alzheimer’s disease. However, in mice the overexpression of APP gives rise to effects which are not seen in human Alzheimer’s disease.
For example, the APP mutant mice often die of unknown causes at a young age, and the group believes this may be related to the generation of toxic fragments of APP, such as CTF-beta. In addition, some of the fragments of APP could be neuroprotective, making it difficult to judge whether drugs are being effective due to their effect on Abeta peptides, which are known to be involved in human AD, or whether it is due to other effects that would not be seen in human disease. In addition, the gene for expressing APP is inserted in different places in the genome, and may knock out other genes, creating artifacts that are not seen in humans.
With this awareness, more than a decade ago Dr. Saido launched a project to develop a new mouse model that would allow more accurate evaluation of therapies for the disease. One of the major hurdles involved a part of the gene, intron 16, which they discovered was necessary for creating more specific models.
The first mice model they developed (NL-F/NL-F) was knocked in with two mutations found in human familial Alzheimer’s disease. The mice showed early accumulation of Abeta peptides, and importantly, were found to undergo cognitive dysfunction similar to the progression of AD seen in human patients. A second model, with the addition of a further mutation that had been discovered in a family in Sweden, showed even faster initiation of memory loss.
These new models could help in two major areas. The first model, which expresses high levels of the Abeta peptides, seems to realistically model the human form of AD, and could be used for elucidating the mechanism of Abeta deposition. The second model, which demonstrates AD pathology very early on, could be used to examine factors downstream of Abeta-40 and Abeta-42 deposition, such as tauopathy, which are believed to be involved in the neurodegeneration. These results may eventually contribute to drug development and to the discovery of new biomarkers for Alzheimer’s disease. The group is currently looking at several proteins, using the new models, which have potential to be biomarkers.
According to Dr. Saido, “We have a social responsibility to make Alzheimer’s disease preventable and curable. The generation of appropriate mouse models will be a major breakthrough for understanding the mechanism of the disease, which will lead to the establishment of presymptomatic diagnosis, prevention and treatment of the disease.”
Key Molecular Pathways Leading to Alzheimer’s Identified
Key molecular pathways that ultimately lead to late-onset Alzheimer’s disease, the most common form of the disorder, have been identified by researchers at Columbia University Medical Center (CUMC). The study, which used a combination of systems biology and cell biology tools, presents a new approach to Alzheimer’s disease research and highlights several new potential drug targets. The paper was published today in the journal Nature.
Much of what is known about Alzheimer’s comes from laboratory studies of rare, early-onset, familial (inherited) forms of the disease. “Such studies have provided important clues as to the underlying disease process, but it’s unclear how these rare familial forms of Alzheimer’s relate to the common form of the disease,” said study leader Asa Abeliovich, MD, PhD, associate professor of pathology and cell biology and of neurology in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at CUMC. “Most important, dozens of drugs that ‘work’ in mouse models of familial disease have ultimately failed when tested in patients with late-onset Alzheimer’s. This has driven us, and other laboratories, to pursue mechanisms of the common form of the disease.”
Non-familial Alzheimer’s is complex; it is thought to be caused by a combination of genetic and environmental risk factors, each having a modest effect individually. Using so-called genome-wide association studies (GWAS), prior reports have identified a handful of common genetic variants that increase the likelihood of Alzheimer’s. A key goal has been to understand how such common genetic variants function to impact the likelihood of Alzheimer’s.
In the current study, the CUMC researchers identified key molecular pathways that link such genetic risk factors to Alzheimer’s disease. The work combined cell biology studies with systems biology tools, which are based on computational analysis of the complex network of changes in the expression of genes in the at-risk human brain.
More specifically, the researchers first focused on the single most significant genetic factor that puts people at high risk for Alzheimer’s, called APOE4 (found in about a third of all individuals). People with one copy of this genetic variant have a three-fold increased risk of developing late-onset Alzheimer’s, while those with two copies have a ten-fold increased risk. “In this study,” said Dr. Abeliovich, “we initially asked: If we look at autopsy brain tissue from individuals at high risk for Alzheimer’s, is there a consistent pattern?”
Surprisingly, even in the absence of Alzheimer’s disease, brain tissue from individuals at high risk (who carried APOE4 in their genes) harbored certain changes reminiscent of those seen in full-blown Alzheimer’s disease,” said Dr. Abeliovich. “We therefore focused on trying to understand these changes, which seem to put people at risk. The brain changes we considered were based on ‘transcriptomics’—a broad molecular survey of the expression levels of the thousands of genes expressed in brain.”
Using the network analysis tools mentioned above, the researchers then identified a dozen candidate “master regulator” factors that link APOE4 to the cascade of destructive events that culminates in Alzheimer’s dementia. Subsequent cell biology studies revealed that a number of these master regulators are involved in the processing and trafficking of amyloid precursor protein (APP) within brain neurons. APP gives rise to amyloid beta, the protein that accumulates in the brain cells of patients with Alzheimer’s. In sum, the work ultimately connected the dots between a common genetic factor that puts individuals at high risk for Alzheimer’s, APOE4, and the disease pathology.
Among the candidate “master regulators” identified, the team further analyzed two genes, SV2A and RFN219. “We were particularly interested in SV2A, as it is the target of a commonly used anti-epileptic drug, levetiracetam. This suggested a therapeutic strategy. But more research is needed before we can develop clinical trials of levetiracetam for patients with signs of late-onset Alzheimer’s disease.”
The researchers evaluated the role of SV2A, using human-induced neurons that carry the APOE4 genetic variant. (The neurons were generated by directed conversion of skin fibroblasts from individuals at high risk for Alzheimer’s, using a technology developed in the Abeliovich laboratory.) Treating neurons that harbor the APOE4 at-risk genetic variant with levetiracetam (which inhibits SV2A) led to reduced production of amyloid beta. The study also showed that RFN219 appears to play a role in APP-processing in cells with the APOE4 variant.
Rare genomic mutations found in 10 families with early-onset, familial Alzheimer’s disease
Although a family history of Alzheimer’s disease is a primary risk factor for the devastating neurological disorder, mutations in only three genes – the amyloid precursor protein and presenilins 1 and 2 – have been established as causative for inherited, early-onset Alzheimer’s, accounting for about half of such cases. Now Massachusetts General Hospital (MGH) researchers have discovered a type of mutation known as copy-number variants (CNVs) – deletions, duplications, or rearrangements of human genomic DNA – in affected members of 10 families with early-onset Alzheimer’s. Notably, different genomic changes were identified in the Alzheimer’s patients in each family.
The study was conducted as part of the Alzheimer’s Genome Project – directed by Rudolph Tanzi, PhD, director of the Genetics and Aging Research Unit at Massachusetts General Hospital (MGH) and a co-discoverer of the first three early-onset genes – and was supported by the Cure Alzheimer’s Fund and the National Institute of Mental Health (NIMH).
"We found that the Alzheimer’s-afflicted members of these families had duplications or deletions in genes with important roles in brain function, while their unaffected siblings had unaltered copies of those genes," says Basavaraj Hooli, PhD, of the Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, lead author of a report that has been published online in Molecular Psychiatry. “Since our preliminary review of the affected genes has provided strong clues to a range of pathways associated with Alzheimer’s disease and other forms of dementia, we believe that further research into the functional effects of these CNVs will provide new insights into Alzheimer’s pathogenesis.” Hooli is a research fellow in Neurology at Harvard Medical School.
Most studies searching for genes contributing to Alzheimer’s risk have looked for variants in a single nucleotide, and while thousands of such changes have been identified, each appears to have a very small impact on disease risk. Recently research has found that CNVs – in which DNA segments of varying lengths are deleted or duplicated – have a greater impact on genomic diversity than do single-nucleotide changes. This led Tanzi and his team to search for large CNVs in affected members of families with inherited Alzheimer’s disease. “These are the first new early-onset familial Alzheimer’s disease gene mutations to be reported since 1995, when we co-discovered the presenilins. As with those original genes, we hope to use the information gained from studies of the new Alzheimer’s mutations to guide the development of novel therapies aimed at preventing and treating this devastating disease.” Tanzi explains.
The investigators reviewed genomic data from two sources – the NIMH Alzheimer’s Disease Genetics Initiative and the National Cell Repository for Alzheimer’s Disease – and focused on 261 families with at least one member who developed Alzheimer’s before the age of 65. Using a novel algorithm they had developed for analyzing CNVs, the researchers identified deletions or duplications that appeared only in affected members of these families. Two of these families had CNVs that included the well-established amyloid precursor protein gene, but 10 others were found to have novel Alzheimer’s-associated CNVs, with different gene segments being affected in each family.
While none of the novel variants have previously been associated with Alzheimer’s disease, most of them affect genes believed to be essential to normal neuronal function, and several have been previously associated with other forms of dementia. For example, one of the identified CNVs involves deletion of a gene called CHMP2B, mutations of which can cause ALS. In another family, affected members had three copies of the gene MAPT, which encodes the tau protein found in the neurofibrillary tangles characteristic of Alzheimer’s. Mutations in MAPT also cause frontotemporal dementia.
Hooli explains, “Potential clinical application of the findings of this study are not yet clear and require two additional pieces of information: similar studies in larger groups of families with inherited Alzheimer’s to establish the prevalence of these CNVs and whether the presence of one ensures development of the disease, and a better understanding of how these variants affect neuronal pathways leading to the early-onset form of Alzheimer’s disease.”
"In a broader sense," Tanzi adds, "the advent of affordable, advanced whole-genome sequencing will lead to the identification of novel, rare mutations that lead to many human disorders. In the future, diagnosis and prognosis may rely more on disease genetics than on traditional laboratory results and behavioral effects. If knowing the exact genetic causes of these disorders leads to more effective and efficient treatment strategies targeted to specific defects, the consequences of this approach would be enormous."
Menzies’ Alzheimer’s disease research gains momentum
New research focuses on brain protein thought to be bad
Research conducted by Menzies Research Institute Tasmania, an institute of the University of Tasmania, is shedding new light on the biology of Alzheimer’s disease, in particular a protein in the brain that is indirectly responsible for causing Alzheimer’s disease.
Dementia is on the rise in Australia. There will be 75,000 baby boomers with dementia by 2020 and dementia will be the third largest source of health and residential care costs by 2030.*
Approximately 278,700 Australians were living with dementia in 2012. Without a medical breakthrough, the number of people with dementia in Australia is expected to be around 942,620 by 2050.*
Tasmania had over 7,000 people with dementia in 2012; this is projected to increase to 20,650 people by 2050.*
A brain protein known as the amyloid precursor protein (APP) has previously been considered to be mostly bad, in the sense that APP is indirectly responsible for causing Alzheimer’s disease.
Specifically, APP breaks down in the brain to produce a protein called Abeta, which is the direct cause of the disease. However, Menzies researchers have recently discovered that APP has a positive function.
Senior member of Menzies, Professor David Small, said the study discovered that APP is responsible for the growth of new neurons (nerve cells) in the brain.
"In addition to its role in causing Alzheimer’s disease, APP may also be part of a solution to the disease," Professor Small said.
"We may be able to use APP to encourage the brain to replace damaged neurons.
"Dissecting out the yin and yang of APP’s actions may be a key to the treatment of Alzheimer’s disease as well as a number of other similar diseases.
Our recent findings already present us with several avenues for developing new treatment strategies,” he said.
The study was recently published in the prestigious journal, Journal of Biological Chemistry.
(Source: utas.edu.au)
A new strategy required in the search for Alzheimer’s drugs?
In the search for medication against Alzheimer’s disease, scientists have focused – among other factors – on drugs that can break down Amyloid beta (A-beta). After all, it is the accumulation of A-beta that causes the known plaques in the brains of Alzheimer’s patients. Starting point for the formation of A-beta is APP. Alessia Soldano and Bassem Hassan (VIB/KU Leuven) were the first to unravel the function of APPL – the fruit-fly version of APP – in the brain of healthy fruit flies. (PLoS Biology)
Alessia Soldano (VIB/KU Leuven): “We have discovered that APPL ensures that brain cells form a good network. We now have to ask ourselves the question whether this function of APPL is also relevant to Alzheimer’s disease.”
Bassem Hassan (VIB/KU Leuven): “Since we show that APP and APPL show similar activities in cultured cells, we suspect that APP in the human brain functions in the same manner as APPL in the brain of fruit flies. Hopefully we can use this to ask and eventually answer the question whether A-beta or APP itself is the better target for new drugs.”
Plaques in the brain: cause or effect
The brain of a person with Alzheimer’s disease is very recognizable due to the so-called plaques. A plaque is an accumulation of proteins that are primarily made up of Amyloid beta (A-beta), a small structure that splits off from the Amyloid Precursor Protein (APP). We have been dreaming for a long time of a drug that can break down A-beta, but we should be asking ourselves whether this is really the best strategy. After all, it is not yet clear whether the plaques are a cause or effect of Alzheimer’s disease. In order to answer this question, it is important to determine the function of APP in healthy brains.
Optimum communication between brain cells
Alessia Soldano and Bassem Hassan study APPL, the fruit-fly version of APP. APPL is found throughout the fruit-fly brain, but primarily in the so-called alpha-beta neurons that are vital to learning processes and memory. The alpha-beta neurons must form functional axons for optimum functioning. Axons are tendrils projecting from the neuron, which are essential for communication between neurons. The VIB scientists had previously shown that APPL is important for memory in flies. Now, they have discovered that – in the developing brain of a fruit fly – APPL ensures that the axons are long enough and grow in the correct direction. APPL is therefore essential in the formation of a good network of neurons. The question is whether or not it is a good strategy to target a protein with such an important function in the brain in order to combat Alzheimer’s disease. (PLoS Biology)