Posts tagged alzheimer's disease
Articles and news from the latest research reports.
Human Stem Cells Predict Efficacy of Alzheimer Drugs
Researchers from the University of Bonn use reprogrammed patient neurons for drug testing
Why do certain Alzheimer medications work in animal models but not in clinical trials in humans? A research team from the University of Bonn and the biomedical enterprise LIFE & BRAIN GmbH has been able to show that results of established test methods with animal models and cell lines used up until now can hardly be translated to the processes in the human brain. Drug testing should therefore be conducted with human nerve cells, conclude the scientists. The results are published by Cell Press in the journal “Stem Cell Reports”.
In the brains of Alzheimer patients, deposits form that consist essentially of beta-amyloid and are harmful to nerve cells. Scientists are therefore searching for pharmaceutical compounds that prevent the formation of these dangerous aggregates. In animal models, certain non-steroidal anti-inflammatory drugs (NSAIDs) were found to a reduced formation of harmful beta-amyloid variants. Yet, in subsequent clinical studies, these NSAIDs failed to elicit any beneficial effects.
"The reasons for these negative results have remained unclear for a long time", says Prof. Dr. Oliver Brüstle, Director of the Institute for Reconstructive Neurobiology of the University of Bonn and CEO of LIFE & BRAIN GmbH. "Remarkably, these compounds were never tested directly on the actual target cells – the human neuron", adds lead author Dr. Jerome Mertens of Prof. Brüstle’s team, who now works at the Laboratory of Genetics in La Jolla (USA). This is because, so far, living human neurons have been extremely difficult to obtain. However, with the recent advances in stem cell research it has become possible to derive limitless numbers of brain cells from a small skin biopsy or other adult cell types.
Scientists transform skin cells into nerve cells
Now a research team from the Institute for Reconstructive Neurobiology and the Department of Neurology of the Bonn University Medical Center together with colleagues from the LIFE & BRAIN GmbH and the University of Leuven (Belgium) has obtained such nerve cells from humans. The researchers used skin cells from two patients with a familial form of Alzheimer’s Disease to produce so-called induced pluripotent stem cells (iPS cells), by reprogramming the body’s cells into a quasi-embryonic stage. They then transformed the resulting so-called “jack-of-all-trades cells” into nerve cells.
Using these human neurons, the scientists tested several compounds in the group of non-steroidal anti-inflammatory drugs. As control, the researchers used nerve cells they had obtained from iPS cells of donors who did not have the disease. Both in the nerve cells obtained from the Alzheimer patients and in the control cells, the NSAIDs that had previously tested positive in the animal models and cell lines typically used for drug screening had practically no effect: The values for the harmful beta-amyloid variants that form the feared aggregates in the brain remained unaffected when the cells were treated with clinically relevant dosages of these compounds.
Metabolic processes in animal models differ from humans
"In order to predict the efficacy of Alzheimer drugs, such tests have to be performed directly on the affected human nerve cells", concludes Prof. Brüstle’s colleague Dr. Philipp Koch, who led the study. Why do NSAIDs decrease the risk of aggregate formation in animal experiments and cell lines but not in human neurons? The scientists explain this with differences in metabolic processes between these different cell types. "The results are simply not transferable", says Dr. Koch.
The scientists now hope that in the future, testing of potential drugs for the treatment of Alzheimer’s disease will be increasingly conducted using neurons obtained from iPS cells of patients. “The development of a single drug takes an average of ten years”, says Prof. Brüstle. “By using patient-specific nerve cells as a test system, investments by pharmaceutical companies and the tedious search for urgently needed Alzheimer medications could be greatly streamlined”.
(Source: www3.uni-bonn.de)
Study Treats Alzheimer’s by Delivering Protein Across Blood-Brain Barrier
The body is structured to ensure that any invading organisms have a tough time reaching the brain, an organ obviously critical to survival. Known as the blood-brain barrier, cells that line the brain and spinal cord are tightly packed, making it difficult for anything besides very small molecules to cross from the bloodstream into the central nervous system. While beneficial, this blockade also stands in the way of delivering drugs intended to treat neurological disorders, such as Alzheimer’s.
In a new study published in the journal Molecular Therapy, University of Pennsylvania researchers have found a way of traversing the blood-brain barrier, as well as a similar physiological obstacle in the eye, the retinal-blood barrier. By pairing a receptor that targets neurons with a molecule that degrades the main component of Alzheimer’s plaques, the biologists were able to substantially dissolve these plaques in mice brains and human brain tissue, offering a potential mechanism for treating the debilitating disease, as well as other conditions that involve either the brain or the eyes.
The work was led by Henry Daniell, a professor in Penn’s School of Dental Medicine’s departments of biochemistry and pathology and director of translational research. The research team included Penn Dental Medicine’s Neha Kohli, Donevan R. Westerveld, Alexandra C. Ayache and Sich L. Chan. Co-authors at the University of Florida College of Medicine, including Amrisha Verma, Pollob Shil, Tuhina Prasad, Ping Zhu and Quihong Li, analyzed retinal tissues.
The researchers began their work by considering how they might breach the blood-brain barrier. Daniell hypothesized that a molecule might be permitted to cross if it was attached to a carrier that is able to pass over, as a sort of molecular crossing guard. The protein cholera toxin B, or CTB, a non-toxic carrier currently approved for use in humans by the Food and Drug Administration, is used in this study to traverse the blood-brain barrier.
They next identified a protein that could clear the plaques that are found in the brains of Alzheimer’s patients. These plaques, which are believed to cause the dementia associated with the disease, are made up of tangles of amyloid beta (Aβ), a protein that is found in soluble form in healthy individuals. Noting that myelin basic protein (MBP) has been shown to degrade Aβ chains, the team decided to couple it with CTB to see if MBP would be permitted to cross.
“These tangles of beta amyloid are known to be the problem in Alzheimer’s,” says Daniell. “So our idea was to chop the protein back to their normal size so they wouldn’t form these tangles.”
To test this idea, the Penn-led team first exposed healthy mice to the CTB-MBP compound by feeding them capsules of freeze-dried leaves that had been genetically engineered to express the fused proteins, a method developed and perfected by Daniell over many years as a means of orally administering various drugs and vaccines. Adding a green-fluorescent protein to the CTB carrier, the researchers tracked the “glow” to see where the mice took up the protein. They found the glowing protein in both the brain and retina.
“When we found the glowing protein in the brain and the retina we were quite thrilled,” said Daniell. “If the protein could cross the barrier in healthy mice, we thought it was likely that it could cross in Alzheimer’s patients brains, because their barrier is somewhat impaired.”
When CTB was not part of the fused protein, they did not see this expression, suggesting that their carrier protein, the crossing guard, was an essential part of delivering their protein of interest.
To then see what MBP would do once it got to the brain, Daniell and colleagues exposed the CTB-MBP protein to the brains of mice bred to have an Alzheimer’s disease. They used a stain that binds to the brain plaques and found that exposure to the CTB-MBP compound resulted in reductions of staining up to 60 percent, indicating that the plaques were dissolving.
Gaining confidence that their compound was appropriately targeting the plaques, the researchers worked with the National Institutes of Health to obtain brain tissue from people who died of Alzheimer’s and performed the same type of staining. Their results showed a 47 percent decrease in staining in the inferior parietal cortex, a portion of the brain found to play an important role in the development of Alzheimer’s-associated dementia.
As a final step, the researchers fed the CTB-MBP-containing capsules to 15-month-old mice, the equivalent of 80 or more human years, bred to develop Alzheimer’s disease. After three months of feeding, the mice had reductions in Aβ plaques of up to 70 percent in the hippocampus and up to 40 percent in the cortex, whereas mice fed capsules that contained lettuce leaves without CTB-MBP added and mice that were not fed any capsules did not have any reduction in evidence of brain plaques.
Because Alzheimer’s patients have also been found to have plaques in their eyes, the researchers examined the eyes of the mice fed the protein. They found that, indeed, the Alzheimer’s-mice did have retinal plaques, but those fed the CBP-MBP compound had undetectable Aβ plaques in their retinae.
“Really no one knows whether the memory problems that people who have Alzheimer’s disease are due to the dementia or problems with their eyes,” Daniell said. “Here we show it may be both, and that we can dissolve the plaques through an oral route.”
Daniell hopes that this technique of delivering proteins across the blood-brain and blood-retina barriers could serve to treat a variety of diseases beyond Alzheimer’s. Several current clinical trials have failed because of an inability to deliver drugs to the brain. Currently, treatments of some eye conditions must physically penetrate the retina with an injection, an approach that requires anesthesia and risks retinal detachment. Treatment with an ingestible capsule would be safer, easier, and more cost-effective.
As a next step, Daniell hopes to collaborate with Alzheimer’s experts at Penn to advance these studies and add a behavioral component to determine whether the CBP-MBP compound not only removes plaques but also improves the memory and functioning of mice with the Alzheimer’s disease.
Alzheimer’s drug discovery: Looking under the right ROCK
A discovery by Emory Alzheimer’s Disease Research Center and Scripps Research Institute scientists could lead to drugs that slow Alzheimer’s disease progression.
A straightforward drug strategy against Alzheimer’s is to turn down the brain’s production of beta-amyloid, the key component of the disease’s characteristic plaques. A toxic fragment of a protein found in healthy brains, beta-amyloid accumulates in the brains of people affected by the disease.
The enzyme that determines how much beta-amyloid brain cells generate is called BACE (beta-secretase or beta-site APP cleaving enzyme). Yet finding drugs that inhibit that elusive enzyme has been far from straightforward.
Now researchers have identified a way to shut down production of beta-amyloid by diverting BACE to a different part of the cell and inhibiting its activity. The results were published this week in Journal of Neuroscience.
"This is an indirect but highly effective way of blocking BACE, which controls the chokepoint step in beta-amyloid production," says lead author Jeremy Herskowitz, PhD, instructor in neurology at Emory’s Alzheimer’s Disease Research Center.
"Jeremy has found a promising approach toward reducing beta-amyloid production and potentially modifying Alzheimer’s disease progression, something for which there is immense need," says senior author James Lah, MD, PhD, associate professor of neurology at Emory University School of Medicine and director of the Cognitive Neurology program. "Drugs that reduce beta-amyloid production would probably be mostly preventive. However, since amyloid-beta is toxic, such drugs could have some immediate effect on cognitive impairment."
In the paper, Herskowitz and his colleagues demonstrate that a specific inhibitor of the enzyme ROCK2 can cut beta-amyloid production in brain cells by more than 75 percent. Co-author Yangbo Feng, PhD, associate director of medicinal chemistry at Scripps Research Institute in Florida, previously discovered the ROCK2 inhibitor, called SR3677.
Alzheimer’s researchers were already interested in ROCK2 and a related enzyme, ROCK1, because of a connection with NSAIDs (non-steroid anti-inflammatory drugs) such as ibuprofen. Some NSAIDS can inhibit production of a particularly toxic form of beta-amyloid, and scientists believed NSAIDs were exerting their effects through the ROCKs.
Herskowitz first showed that in cultured cells, “knocking down” the ROCK2 gene reduced beta-amyloid production, but knocking down ROCK1 had the opposite effect.
"This says that anytime you’re hitting both ROCKs at once, the effects cancel each other out," he says.
The known drugs that affect the ROCKs seemed to affect both and thus have diminished effects. In contrast, SR3677 inhibits ROCK2 much more effectively than ROCK1, and it offered a way around the obstacle. Herskowitz found that by inhibiting ROCK2, SR3677 diverts BACE to a different part of the cell, where it is less likely to act on beta-amyloid’s parent protein.
He and ADRC colleagues found that ROCK2 levels are higher than usual in tissue samples from brains of patients with Alzheimer’s, including those with mild cognitive impairment, thought to be a precursor stage of the disease.
"There is plenty of ROCK2 in the brain, and its levels are elevated in Alzheimer’s patients, indicating that it’s an excellent drug target," Herskowitz says. "We are eager to pursue more extensive studies of this strategy in animal models of Alzheimer’s."
SR3677 can substantially inhibit beta-amyloid production in an animal model of Alzheimer’s, but so far, this effect has been observed when the drug is injected directly into the brain. More studies are required to learn if SR3677 or related drugs can pass the blood-brain barrier and thus be given by injection or orally, and what side effects could appear. ROCK inhibitors are also being investigated for treating other conditions such as glaucoma, hypertension and multiple sclerosis.
(Source: news.emory.edu)
Omega-3 dietary supplements pass the blood-brain barrier
New research from Karolinska Institutet shows that omega-3 fatty acids in dietary supplements can cross the blood brain barrier in people with Alzheimer’s disease, affecting known markers for both the disease itself and inflammation. The findings are presented in the Journal of Internal Medicine, and strengthen the evidence that omega-3 may benefit certain forms of this seriously debilitating disease.
"Earlier population studies indicate that omega-3 can protect against Alzheimer’s disease, which makes it interesting to study the effects of dietary supplements containing this group of fatty acids in patients who have already developed the disease," says the study’s lead author Dr Yvonne Freund-Levi.
Omega-3 and other essential polyunsaturated fatty acids accumulate in the central nervous system (CNS) during gestation. It has been assumed that these acids are continually replaced throughout life, but little is known about how this occurs and whether changes in diet can affect the transport of important fatty acids across the blood-brain barrier. The blood-brain barrier serves to protect the brain from harmful chemicals existing naturally in the blood, but also blocks the delivery of drug substances to the brain.
Several diseases can affect the fatty acid profile of the CNS; in patients with Alzheimer’s disease, for example, previous research has observed lower than normal brain concentrations of docosahexaenoic acid (DHA), an omega-3 fatty acid.
In the present study, part of the larger OmegAD project, scientists examined whether omega-3 dietary supplements change the fatty acid profile of the CNS in patients with mild Alzheimer’s disease. Thirty-three patients participated in the study, 18 of whom received a daily omega-3 supplement and 15 a placebo for six months. The results show that the first group had higher levels of both DHA and eicosapentaenoic acid (EPA, another omega-3 fatty acid) in their cerebrospinal fluid (which surrounds the CNS) and blood. No such change was seen in the placebo group.
Moreover, they also found that levels of DHA correlated directly with the degree of change in Alzheimer’s disease and inflammatory markers in the cerebrospinal fluid. Researchers in the field have long been interested in this link between Alzheimer’s disease and inflammation, but attempts to treat the disease using traditional anti-inflammatory drugs have failed to produce any improvements in memory function.
"In animals, DHA dietary supplements can lead to an increase in DHA concentrations in the CNS," says Professor Jan Palmblad, who initiated the study. "Here we show that the same applies to humans, which suggests that omega-3 fatty acids in dietary supplements cross the blood-brain barrier. However, much work remains to be done before we know how these fatty acids can be used in the treatment of Alzheimer’s disease to halt memory loss."
Alzheimer’s risk gene may begin to affect brains as early as childhood
People who carry a high-risk gene for Alzheimer’s disease show changes in their brains beginning in childhood, decades before the illness appears, new research from the Centre for Addiction and Mental Health (CAMH) suggests.
The gene, called SORL1, is one of a number of genes linked to an increased risk of late-onset Alzheimer’s disease, the most common form of the illness. SORL1 carries the gene code for the sortilin-like receptor, which is involved in recycling some molecules in the brain before they develop into beta-amyloid a toxic Alzheimer protein. SORL1 is also involved in lipid metabolism, putting it at the heart of the vascular risk pathway for Alzheimer’s disease as well.
“We need to understand where, when and how these Alzheimer’s risk genes affect the brain, by studying the biological pathways through which they work,” says Dr. Aristotle Voineskos, head of the Kimel Family Translational Imaging-Genetics Laboratory at CAMH, who led the study. “Through this knowledge, we can begin to design interventions at the right time, for the right people.” The study was recently published online in Molecular Psychiatry with Dr. Voineskos’s graduate student, Daniel Felsky as first author, and was a collaborative effort with the Zucker Hillside Hospital/Feinstein Institute in New York and the Rush Alzheimer’s Disease Center in Chicago.
To understand SORL1’s effects across the lifespan, the researchers studied individuals both with and without Alzheimer’s disease. Their approach was to identify genetic differences in SORL1, and see if there was a link to Alzheimer’s-related changes in the brain, using imaging as well as post-mortem tissue analysis.
In each approach, a link was confirmed.
In the first group of healthy individuals, aged eight to 86, researchers used a brain imaging technique called diffusion tensor imaging (DTI). Even among the youngest participants in the study, those with a specific copy of SORL1 showed a reduction in white matter connections in the brain important for memory performance and executive function.
The second sample included post-mortem brain tissue from 189 individuals less than a year old to 92 years, without Alzheimer’s disease. Among those with that same copy of the SORL1 gene, the brain tissue showed a disruption in the process by which the gene translated its code to become the sortilin-like receptor.
Finally, the third set of post-mortem brains came from 710 individuals, aged 66 to 108, of whom the majority had mild cognitive impairment or Alzheimer’s. In this case, the SORL1 risk gene was linked with the presence of amyloid-beta, a protein found in Alzheimer’s disease.
Dr. Voineskos notes that risk for Alzheimer’s disease results from a combination of factors – unhealthy diet, lack of exercise, smoking, high blood pressure combined with a person’s genetic profile – which all contribute to the development of the illness. “The gene has a relatively small effect, but the changes are reliable, and may represent one ‘hit’, among a pathway of hits required to develop Alzheimer’s disease later in life”.
While it’s too early to provide interventions that may target these changes, “individuals can take measures in their own lifestyle to reduce the risk of late-onset Alzheimer’s disease.” Determining whether there is an interaction with this risk gene and lifestyle factors will be one important next step.
In order to develop genetically-based interventions to prevent Alzheimer’s disease, the biological pathways of other risk genes also need to be systematically analyzed, the researchers note.
This research does, however, build on a previous CAMH imaging-genetics study on another gene related to Alzheimer’s disease. That study showed that a genetic variation of brain-derived neurotrophic factor (BDNF) affected brain structures in Alzheimer’s.
“The interesting connection is that BDNF may have important therapeutic value. But there is data to suggest that the effects of BDNF won’t work unless SORL1 is present, so there is the possibility that if you boost the activity of one gene, the other will increase,” says Dr. Voineskos, adding that BDNF therapeutics are in development. A next stage in the research, he says, is to look at the interaction of BDNF and SORL1.
(Source: camh.ca)
New compound for slowing the aging process can lead to novel treatments for brain diseases
A successful joint collaboration between researchers at the Hebrew university of Jerusalem and the startup company TyrNovo may lead to a potential treatment of brain diseases. The researchers found that TyrNovo’s novel and unique compound, named NT219, selectively inhibits the process of aging in order to protect the brain from neurodegenerative diseases, without affecting lifespan. This is a first and important step towards the development of future drugs for the treatment of various neurodegenerative maladies.
Human neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s diseases share two key features: they stem from toxic protein aggregation and emerge late in life. The common temporal emergence pattern exhibited by these maladies proposes that the aging process negatively regulates protective mechanisms that prevent their manifestation early in life, exposing the elderly to disease. This idea has been the major focus of the work in the laboratory of Dr. Ehud Cohen of the Department of Biochemistry and Molecular Biology, at the Institute for Medical Research Israel-Canada in the Hebrew University of Jerusalem’s Faculty of Medicine.
Cohen’s first breakthrough in this area occurred when he discovered, working with worms, that reducing the activity of the signaling mechanism conveyed through insulin and the growth hormone IGF1, a major aging regulating pathway, constituted a defense against the aggregation of the Aβ protein which is mechanistically-linked with Alzheimer’s disease. Later, he found that the inhibition of this signaling route also protected Alzheimer’s-model mice from behavioral impairments and pathological phenomena typical to the disease. In these studies, the path was reduced through genetic manipulation, a method not applicable in humans.
Dr. Hadas Reuveni, the CEO of TyrNovo, a startup company formed for the clinical development of NT219, and Prof. Alexander Levitzki from the Department of Biological Chemistry at the Hebrew University, with their research teams, discovered a new set of compounds that inhibit the activity of the IGF1 signaling cascade in a unique and efficient mechanism, primarily for cancer treatment, and defined NT219 as the leading compound for further development.
Now, in a fruitful collaboration Dr. Cohen and Dr. Reuveni, together with Dr. Cohen’s associates Tayir El-Ami and Lorna Moll, have demonstrated that NT219 efficiently inhibits IGF1 signaling, in both worms and human cells. The inhibition of this signaling pathway by NT219 protected worms from toxic protein aggregation that in humans is associated with the development of Alzheimer’s or Huntington’s disease.
The discoveries achieved during this project, which was funded by the Rosetrees Trust of Britain, were published this week in the journal Aging Cell (“A novel inhibitor of the insulin/IGF signaling pathway protects from age-onset, neurodegeneration-linked proteotoxicity”). The findings strengthen the notion that the inhibition of the IGF1 signaling pathway has a therapeutic potential as a treatment for neurodegenerative disorders. They also point at NT219 as the first compound that provides protection from neurodegeneration-associated toxic protein aggregation through a selective manipulation of aging.
Cohen, Reuveni and Levitzki have filed a patent application that protects the use of NT219 as a treatment for neurodegenerative maladies through Yissum, the technology transfer company of the Hebrew University. Dr. Gil Pogozelich, chairman of Goldman Hirsh Partners Ltd., which holds the controlling interest in TyrNovo, says that he sees great importance in the cooperation on this project with the Hebrew University, and that TyrNovo represents a good example of how scientific and research initiatives can further health care together with economic benefits.
Recently, Dr. Cohen’s laboratory obtained an ethical approval to test the therapeutic efficiency of NT219 as a treatment in Alzheimer’s-model mice, hoping to develop a future treatment for hitherto incurable neurodegenerative disorders.
Study Suggests Low Vitamin D Causes Damage to Brain
A new study led by University of Kentucky researchers suggests that a diet low in vitamin D causes damage to the brain.
In addition to being essential for maintaining bone health, newer evidence shows that vitamin D serves important roles in other organs and tissue, including the brain. Published in Free Radical Biology and Medicine, the UK study showed that middle-aged rats that were fed a diet low in vitamin D for several months developed free radical damage to the brain, and many different brain proteins were damaged as identified by redox proteomics. These rats also showed a significant decrease in cognitive performance on tests of learning and memory.
"Given that vitamin D deficiency is especially widespread among the elderly, we investigated how during aging from middle-age to old-age how low vitamin D affected the oxidative status of the brain," said lead author on the paper Allan Butterfield, professor in the UK Department of Chemistry, director of the Center of Membrane Sciences, faculty of Sanders-Brown Center on Aging, and director of the Free Radical Biology in Cancer Core of the Markey Cancer Center. “Adequate vitamin D serum levels are necessary to prevent free radical damage in brain and subsequent deleterious consequences."
Previously, low levels of vitamin D have been associated with Alzheimer’s disease, and it’s also been linked to the development of certain cancers and heart disease. In both the developed world and in areas of economic hardship where food intake is not always the most nutritious, vitamin D levels in humans are often low, particularly in the elderly population. Butterfield recommends persons consult their physicians to have their vitamin D levels determined, and if low that they eat foods rich in vitamin D, take vitamin D supplements, and/or get at least 10-15 minutes of sun exposure each day to ensure that vitamin D levels are normalized and remain so to help protect the brain.
(Source: uknow.uky.edu)
Brain imaging differences in infants at genetic risk for Alzheimer’s
Researchers from Brown University and Banner Alzheimer’s Institute have found that infants who carry a gene associated with increased risk for Alzheimer’s disease tend to have differences in brain development compared to children without the gene. The study, published in JAMA Neurology, demonstrates some of the earliest developmental differences associated with a gene variant called APOE ε4, a common genotype and a known risk factor for late-onset Alzheimer’s.
The researchers imaged the brains of 162 healthy infants between the ages of two months and 25 months. All of the infants had DNA tests to see which variant of the APOE gene they carried. Sixty of them had the ε4 variant that has been linked to an increased risk of Alzheimer’s. Using a specialized MRI technique, the researchers compared the brains of ε4 carriers with non-carriers. They found that children who carry the APOE ε4 gene tended to have increased brain growth in areas in the frontal lobe, and decreased growth in areas in several areas in the middle and rear of the brain. The decreased growth was found in areas that tend to be affected in elderly patients who have Alzheimer’s disease.
Researchers emphasized that the findings do not mean that any of the children in the study are destined to develop Alzheimer’s or that the brain changes detected are the first clinical signs of the disease. What the findings do suggest, however, is that brains of APOE ε4 carriers tend to develop differently from those of non-ε4 carriers beginning very early in life. It is possible that these early changes provide a “foothold” for the later pathologies that lead to Alzheimer’s symptoms, the researchers say. Information from this study may be an important step toward understanding how this gene confers risk for Alzheimer’s, something that is not currently well understood.
“This work is about understanding how this gene influences brain development,” said Sean Deoni, who oversees Brown University’s Advanced Baby Imaging Lab and was one of the study’s senior authors. “These results do not establish a direct link to the changes seen in Alzheimer’s patients, but with more research they may tell us something about how the gene contributes to Alzheimer’s risk later in life.”
The APOE ε4 variant linked to Alzheimer’s is present in about 25 percent of the U.S. population. Not everyone who carries the gene gets Alzheimer’s, but 60 percent of people who develop the disease have at least one copy of the ε4 gene.
The gene is thought to have several different roles in the blood and brain, some of which remain to be clarified. For instance, it has been shown to participate in regulation of cholesterol, a molecule that is involved in the development of gray matter and white matter brain cells. It has also been shown to participate in the regulation of amyloid, a brain protein that accumulates in Alzheimer’s and is now being targeted by investigational treatments. Studies are needed to clarify the ways in which APOE, human development, aging and other risk factors may conspire to produce the brain changes involved in Alzheimer’s disease.
The researchers used an MRI technique developed at Brown’s Advanced Baby Imaging Lab. The technique quiets the MRI machine to a whisper, enabling the brains of healthy babies to be imaged while they sleep without medication. The technique also enables imaging of both gray matter — the part of the brain that contains neurons and nerve fibers — and white matter, which contains the fatty material that insulates the nerve fibers. Both gray and white matter are thought to have a role in Alzheimer’s. White matter growth begins shortly after birth and is an important measure of brain development.
“We’re in a good spot to be able to investigate how this gene influences development in healthy infants,” said Deoni, assistant professor of engineering at Brown. “These infants are not medicated and not showing any cognitive decline — quite the opposite, actually; they’re developing normally.”
There is no reason to believe that the children won’t continue to develop normally, Deoni said. There is no consistent evidence to suggest that ε4 carriers suffer any cognitive problems or developmental delay. And the areas of increased growth raise the possibility that the gene might actually confer some advantages to infants early on. Utimately the researchers hope the findings could lead to new strategies for preventing a disease that currently affects more than 5.2 million people in the U.S. alone.
“It may sound scary that we could detect these brain differences in infants,” said Dr. Eric Reiman, executive director of the Banner Alzheimer’s Institute in Arizona and another senior author on the paper. “But it is our sincere hope that an understanding of the earliest brain changes involved in the predisposition to Alzheimer’s will help researchers find treatments to prevent the clinical onset of Alzheimer’s disease — and do so long before these children become senior citizens.”
Study reveals how variant forms of APOE protein impact risk of Alzheimer’s disease
Carrying a particular version of the gene for apolipoprotein E (APOE) is the major known genetic risk factor for the sporadic, late-onset form of Alzheimer’s disease, but exactly how that variant confers increased risk has been controversial among researchers. Now an animal study led by Massachusetts General Hospital (MGH) investigators shows that even low levels of the Alzheimer’s-associated APOE4 protein can increase the number and density of amyloid beta (A-beta) brain plaques, characteristic neuronal damage, and the amount of toxic soluble A-beta within the brain in mouse models of the disease. Introducing APOE2, a rare variant that has been associated with protection from developing Alzheimer’s disease, into the brains of animals with established plaques actually reduced A-beta deposition, retention and neurotoxicity, suggesting the potential for gene-therapy-based treatment.
"Using a technique developed by our collaborators at the University of Iowa, we were able to get long-term expression of these human gene variants in the fluid that bathes the entire brain," says Bradley Hyman, MD, PhD, of the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND), senior author of the report in the Nov. 20 Science Translational Medicine. “Our results suggest that strategies aimed at decreasing levels of APOE4, the harmful form of the protein, and increasing concentrations of protective variant APOE2 could be helpful to patients.”
The association between the APOE4 variant and increased Alzheimer’s risk was first made more than 20 years ago. Subsequent research has established that carrying two copies of the harmful variant increases risk 12 times compared with having two copies of the more common form, APOE3. Inheriting the APOE2 variant, however, appears to cut the risk in half. The extremely rare gene variants that directly cause the familial forms of the disease all participate in the production and deposition of A-beta, but exactly how APOE variants contribute to the process has been poorly understood.
Secreted by certain brain cells, APOE is known to regulate cholesterol metabolism within the brain and can bind to A-beta peptides, suggesting that the different forms of the protein may affect whether and how toxic A-beta plaques form. While previous investigations into the protein’s effects have used either mice in which gene expression was knocked out or transgenic animals that expressed human gene variants throughout their lifetimes, the MGH-MIND-led study used a different approach to investigate the effects of introducing the variant forms of the protein into brains in which plaque formation had already begun. They directly injected into the cerebrospinal fluid of a mouse model of Alzheimer’s – adult animals in which plaques were well established – viral vectors carrying genes for one of the three APOE variants or a control protein.
Two month after the vectors had been injected, about 10 percent of the APOE in the brains of animals that received one of the variants was found to be the introduced human version. At five months after injection, examination of brain tissue revealed that the A-beta plaques in mice that received APOE4 injections were more numerous and significantly denser than those of mice receiving APOE2. The growth of plaques in animals receiving APOE3 was intermediate between that of the other two groups and similar to what was seen in control animals. Levels of A-beta in the blood of mice that received APOE2 were higher than in the other groups, suggesting that the protective variant had increased clearance of A-beta from the brain.
In a group of animals in which tiny implanted windows allowed direct imaging of brain tissue, the progression of A-beta plaque deposition was fastest in animals receiving APOE4 and slowest, sometimes even appearing to regress, in mice injected with APOE2. Signs of neuronal damage around plaques also varied depending on the APOE variant the animals received, and experiments in a different Alzheimer’s model in which plaques appear more slowly showed that injection of APOE4 increased levels of free, soluble A-beta in the fluid that bathes the brain.
"This study has allowed us to sort out, in mice, which effects of the different types of APOE were most important to variation in amyloid plaque deposition," says Eloise Hudry, PhD, of MGH-MIND, lead author of the Science Translational Medicine report. “Our results imply that APOE-based therapeutic approaches may help to alleviate the progression of Alzheimer’s disease. More study is needed to pursue that possibility and to investigate the potential use of this gene transfer technology to introduce other protective proteins into the brain.”
(Source: massgeneral.org)
Image: Mice lacking autophagy and with high levels of Aβ (right) have degenerated brain structures compared with normal mice (left).
The benefits of a spotless mind
Alzheimer’s disease is an age-related memory disorder characterized by the accumulation of clumps of the toxic amyloid-β (Aβ) protein fragment in the extracellular space around neurons in the brain. Drugs that help to ‘clean up’ cells by inducing autophagy—the degradation of unnecessary cellular components—are known to lower Aβ levels within cells and have been shown to rescue memory deficits in mice. A team of researchers including Per Nilsson and Takaomi Saido from the RIKEN Brain Science Institute have now found that autophagy also plays an important role in secreting Aβ from the cell into the extracellular space.
The researchers set out to investigate what would happen to extracellular Aβ aggregates, called plaques, when genetic methods were used to eliminate the autophagy process. They started with transgenic mice commonly used as a model for Alzheimer’s disease. These mice have high levels of Aβ and Aβ plaque accumulation in their brains, and display learning and memory deficits. Surprisingly, in genetically engineered variants of these mice lacking autophagy-related gene 7 (Atg7), which is required for normal autophagy, the researchers found fewer extracellular Aβ plaques in the brain; instead, the Aβ seemed to accumulate inside the neurons. Conversely, increasing the expression of the Atg7 protein in neurons grown in cell culture resulted in an increase in the release of Aβ from the cells into the tissue culture medium. The findings suggest that autophagy is required for the secretion of Aβ from neurons into the extracellular environment.
Mice with an elevated expression of Aβ but defective autophagy seemed to have degenerated brain structures, as well as sicker neurons—as defined by their expression of markers of cell death—and worse learning and memory functions than mice with high Aβ expression but normal autophagy. This result indicates that autophagy is important for maintaining normal neuronal function and cognition in Alzheimer’s disease. Moreover, because autophagy lowers Aβ levels within the cell, the researchers deduced that intracellular Aβ may be more toxic than extracellular Aβ with respect to inducing neuronal dysfunction and memory impairment.
The findings suggest that the effectiveness of therapeutic strategies for Alzheimer’s disease may be improved by targeting the elimination of intracellular Aβ deposits rather than extracellular plaques. “Intraneuronal Aβ accumulation is seen in early Alzheimer’s disease in humans, similar to what we found upon autophagy deletion in mice,” explains Nilsson. “Targeting this pool of Aβ may therefore offer a potential treatment for Alzheimer’s disease,” he says.