Category Archives: Research News (General)

In a study of mice and monkeys, researchers have shown that they could prevent and reverse some of the brain injury caused by the toxic form of the protein tau. The results, published in Science Translational Medicine, suggest that the study of compounds, called tau antisense oligonucleotides, that are genetically engineered to block a cell’s assembly line production of tau, might be pursued as an effective treatment for a variety of disorders.

Cells throughout the body normally manufacture tau proteins. In several disorders, toxic forms of tau clump together inside dying brain cells and form neurofibrillary tangles, including Alzheimer’s disease, tau-associated frontotemporal dementia, chronic traumatic encephalopathy and progressive supranuclear palsy. Currently there are no effective treatments for combating toxic tau.

Antisense oligonucleotides are short sequences of DNA or RNA programmed to turn genes on or off. The researchers tested sequences designed to turn tau genes off in mice that are genetically engineered to produce abnormally high levels of a mutant form of the human protein. Tau clusters begin to appear in the brains of 6-month-old mice and accumulate with age. The mice develop neurologic problems and die earlier than control mice.

Injections of the compound into the fluid-filled spaces of the mice brains prevented tau clustering in 6-9 month old mice and appeared to reverse clustering in older mice. The compound also caused older mice to live longer and have healthier brains than mice that received a placebo. In addition, the compound prevented the older mice from losing their ability to build nests.

Currently researchers are conducting early phase clinical trials on the safety and effectiveness of antisense oligonucleotides designed to treat several neurological disorders, including Huntington’s disease and amyotrophic lateral sclerosis (ALS).

Further experiments on non-human primates suggested that the antisense oligonucleotides tested in mice could reach important areas of larger brains and turn off tau. In comparison with a placebo, two spinal tap injections of the compound appeared to reduce tau protein levels in the brains and spinal cords of Cynomologus monkeys. As the researchers saw with the mice, injections of the compound caused almost no side effects.

Nevertheless, the researchers concluded that the compound needs to be fully tested for safety before it can be tried in humans. They are taking the next steps towards translating it into a possible treatment for a variety of tau related disorders.

Paper: “Abnormal neurogenesis and cortical growth in congenital heart disease”
Reprinted from materials provided by NIH/NINDS.

Researchers have discovered a common genetic variant that greatly impacts normal brain aging, starting at around age 65, and may modify the risk for neurodegenerative diseases. The findings could point toward a novel biomarker for the evaluation of anti-aging interventions and highlight potential new targets for the prevention or treatment of age-associated brain disorders such as Alzheimer’s disease.

The study was published online in the journal Cell Systems.

Previous studies have identified individual genes that increase one’s risk for various neurodegenerative disorders, such as apolipoprotein E (APOE) for Alzheimer’s disease. In the current study, researchers analyzed genetic data from autopsied human brain samples taken from 1,904 people without neurodegenerative disease. First, the researchers looked at the subjects’ transcriptomes (the initial products of gene expression), compiling an average picture of the brain biology of people at a given age. Next, each person’s transcriptome was compared to the average transcriptome of people at the same age, looking specifically at about 100 genes whose expression was found to increase or decrease with aging. From this comparison, the researchers derived a measure that they call differential aging: the difference between an individual’s apparent (biological) age and his or her true (chronological) age. The researchers then searched the genome of each individual, looking for genetic variants that were associated with an increase in differential age. Variants of a gene called TMEM106B, the researchers say, appeared to have an impact on the speed of brain aging starting at age 65.

The researchers found a second variant — inside the progranulin gene — that contributes to brain aging, though less so than TMEM106B. Progranulin and TMEM106B are located on different chromosomes but are involved in the same signaling pathway. Both have also been associated with a rare neurodegenerative disease called frontotemporal dementia.

Paper: “Differential Aging Analysis in Human Cerebral Cortex Identifies Variants in TMEM106B and GRN that Regulate Aging Phénotypes”
Reprinted from materials provided by Columbia University Medical Center.

Restorative neuroscience, the study to identify means to replace damaged neurons and recover permanently lost mental or physical abilities, is a rapidly advancing scientific field. Redirecting immature neurons that reside in specific brain areas towards the sites of brain damage is an appealing strategy for the therapy of acute brain injury or stroke. Now, a collaborative research effort has revealed that some mature neurons are able to reconfigure their local microenvironment such that it becomes conducive for adult-born immature neurons to extensively migrate. Thus, a molecular principle emerges that can allow researchers to best mobilize resident cellular reserves in the adult brain and guide immature neurons to the sites of brain damage.

The research was published in the Proceedings of the National Academy of Sciences.

In the aging Western society, acute brain damage and chronic neurodegenerative conditions such as Alzheimer’s and Parkinson’s diseases are amongst the most debilitating diseases, affecting hundreds of millions of people worldwide. Nerve cells are particularly sensitive to microenvironmental insults and their loss clearly manifests as neurological deficit. Since the innate ability of the adult human brain to regenerate is very poor and confined to its few specialized regions, a key question in present-day neurobiology is how to establish efficient strategies that can replace lost neurons, guide competent cells to the sites of injury and facilitate their functional integration to regain lost functionality. “Cell replacement therapy” thus offers frontline opportunities to design potent therapeutic interventions.

Only two regions of the postnatal mammalian brain are known to retain their intrinsic potential to allow the generation of new neurons throughout life: the olfactory system decoding smell and the hippocampus acting as a key hub for memory encoding and storage. In humans, the generation of new neurons in the olfactory system rapidly ceases during early childhood. “Which are the processes that disallow this innate regenerative process in the human brain and how can dormant progenitors be reinstated to produce new neurons and guide those towards brain areas that require repair?” is a central yet unresolved question for brain repair strategies.

For neuronal migration, the widely accepted concept is that support cells called astroglia are of primary importance to promote the movement of adult-born neurons through chemical signals and physical interactions. The new study goes well beyond these known frontiers through the discovery that the migration of new-born neurons requires resident, differentiated nerve cells to “clear their path” by digesting away some of the glue that fills the space between nerve cells. This process is dependent on the activity of resident neurons, thus suggesting the integration of the ancient developmental process of active cell movement with the integrative capacity and activity patterns of the brain.

The realization that differentiated neurons hold the key to directional cell migration is of enormous significance since they are wired into the brain circuitry, receive information from not only adjacent but also far-away regions and are activated by these specific connections at precisely given times. Consequently, migration controlled by the newly described specific neuronal subset can be aligned with brain activity, or conversely, with inactivity as evoked by neuronal loss during brain diseases.

Paper: “Secretagogin-dependent matrix metalloprotease-2 release from neurons regulates neuroblast migration”
Reprinted from materials provided by Medical University of Vienna.

Two new publications outline a transformative approach to defining, studying and treating Parkinson’s disease. Rather than approaching Parkinson’s disease as a single entity, the international cadre of researchers advocates targeting therapies to distinct “nodes or clusters” of patients based on specific symptoms or molecular features of their disease.

The findings appeared in the journals Nature Reviews Neurology and Movement Disorders.

The researchers theorize that Parkinson’s is not one disease but rather several diseases when considered from genetic and molecular perspectives. They acknowledge that viewing Parkinson’s as a single disorder that predominantly involves dopamine-neuron degeneration has been useful in the development of treatments for symptoms, such as tremor and unstable walking, that touch the vast majority of patients. At the same time, this view has yet to deliver a therapy that is effective in slowing, modifying or curing Parkinson’s. One important reason, the researchers say, could be that promising molecular therapies have been tested in large clinical trials of people who share the diagnosis of Parkinson’s, but not to the specific disease subtype most likely to benefit.

The researchers advocate a “precision medicine” approach that is rooted in systems biology, an inter-disciplinary study that focuses on the complex interactions of biological systems.

Neurologists have long observed the many faces of Parkinson’s in their patients. Some progress rapidly in their disease, some slowly. Some develop dementia relatively early, while others do not.

Tests have also revealed that patients develop deposits of alpha-synuclein, a protein, to varying degrees in the brain, colon, heart, skin, and olfactory bulb. But while these deposits have been thought to be common denominators in most individuals with Parkinson’s, they may represent byproducts of a range of biological abnormalities and may not be the best targets of therapy.

The researchers say the field must work to develop an ideal set of biomarkers. The ideal approach, they write, would start with “an assessment of biological processes” in large populations of aging individuals. The assessments would validation of a genetic variant within the protein tyrosine phostphatase receptor-type delta (PTPRD) gene.

Using autopsies from 909 individuals participating in studies of aging, the team of investigators assessed the human genome for evidence that a genetic variant could affect the neurofibrillary tangle (NFT), aggregates of the hyperphosphorylated tau protein and one of the most common forms of pathology in the aging brain. The researchers found a variant of the PTPRD gene – which is very common –  contributes to the accumulation of NFT.

The researchers say that their study, taken together with previous studies in mice and flies showing a link between PTPRD and Tau pathology, suggests that altering the level of PTPRD could be an intriguing new candidate that deserves further evaluation in the search for disease therapies.

Papers: “Precision medicine for disease modification in Parkinson disease” and “Biomarker-driven phenotyping in Parkinson’s disease: A translational missing link in disease-modifying clinical trials”
Reprinted from materials provided by University of Cincinnati.

Investigators reported the discovery of a new gene that is associated with susceptibility to a common form of brain pathology called Tau that accumulates in several different conditions, including Alzheimer’s disease, certain forms of dementia and Parkinsonian syndromes as well as chronic traumatic encephalopathy that occurs with repeated head injuries.

Published in Molecular Psychiatry, the manuscript describes the identification and validation of a genetic variant within the protein tyrosine phosphatase receptor-type delta (PTPRD) gene.

Using autopsies from 909 individuals participating in studies of aging, the team of investigators assessed the human genome for evidence that a genetic variant could affect the neurofibrillary tangle (NFT), aggregates of the hyperphosphorylated tau protein and one of the most common forms of pathology in the aging brain. The researchers found that a variant of the PTPRD gene – which is very common – contributes to the accumulation of NFT.

The researchers say that their study, taken together with previous studies in mice and flies showing a link between PTPRD and Tau pathology, suggests that altering the level of PTPRD could be an intriguing new candidate that deserves further evaluation in the search for disease therapies.

Paper: “Susceptibility to neurofibrillary tangles: role of the PTPRD locus and limited pleiotropy with other neuropathologies”
Reprinted from materials provided by Rush University Medical Center.

By inserting an amyotrophic lateral sclerosis (ALS)-linked human gene called TDP-43 into fruit flies, researchers have discovered a potential role for ‘transposons’ in the disease. Transposons, which are also called ‘jumping genes’ because they jump from place to place within DNA, are virus-like entities that fill most of the spaces between genes in an organism. The new research demonstrates that these transposons are no longer effectively inhibited, resulting in a storm of jumping genes, leading to DNA damage accumulation and cell death. The research, published in PLOS Genetics, may be a clue to the genetic processes of ALS and the idea that anti-transposon systems may collapse in individuals with ALS.

Transposon replication has evolved to the point where almost half of human DNA consists of these jumping gene sequences. But our cells have developed a highly effective immune-like system to stifle the replication of these moving genes in a vast majority of instances. The researchers conducted experiments using transgenic fruit flies and discovered that anti-transposon systems appear to collapse in brains of fruit flies that contain the ALS linked human gene.

In the study, the researchers engineered the fruit flies to contain TDP-43. Just like humans, this gene caused the fruit flies to experience a progressive loss of movement and premature death. Studying the brains of the fruit flies, the team found that not only were certain transposons not inhibited and triggered a storm of the jumping genes, but one fly transposon called ‘gypsy’ appeared to be the lead culprit of the problem. By deactivating gypsy, cell death stopped and the lifespan of the mutant flies improved.

Humans do not have the gypsy transposon but do have a similar one called HERV-K. Previous research has revealed some ALS patients post-mortem had elevated levels of HERV-K.

The next step for the research team is to determine whether jumping genes are similarly activated in ALS patient tissue, and to determine whether they contribute to disease progression.

Paper “Retrotransposon activation contributes to neurodegeneration in a Drosophila TDP-43 model of ALS”
Reprinted from materials provided by Stony Brook University.

Donepezil, a medication that is approved to treat people with Alzheimer’s disease, should not be prescribed for people with mild cognitive impairment without a genetic test, according to a new study published in the Journal of Alzheimer’s Disease. Researchers discovered that for people who carry a specific genetic variation — the K-variant of butyrylcholinesterase, or BChE-K — donezpezil could accelerate cognitive decline.

Mild cognitive impairment is a transitional state between normal age-related changes in cognition and dementia. Because many people with the condition display symptoms similar to those caused by Alzheimer’s disease, some physicians prescribe donepezil, which is the most-prescribed medication for Alzheimer’s.

Donepezil was tested as a possible treatment for mild cognitive impairment in a large, federally funded American study but was not approved. Still, doctors have often prescribed the drug “off-label” — meaning that it is not approved for that specific disorder — for their patients with mild cognitive impairment.

From data collected during the trial, the researchers looked at the association between BChE-K and changes in cognitive function. Using two tests that measure cognitive impairment, the Mini-Mental State Examination and the Clinical Dementia Rating Sum of Boxes, they found that people with the genetic variation who were treated with donepezil had greater changes in their scores than those who took placebos. They also found that those who took donepezil had a faster cognitive decline than those who took the placebo.

Physicians are increasingly using personalized medicine, including pharmacogenetics — the study of how genetics affect a person’s response to a drug — to tailor their patients’ care. The findings reinforce the importance of physicians discussing the possible benefits and risks of this treatment with their patients, the researchers say.

Paper “Butyrylcholinesterase K and Apolipoprotein E-ɛ4 Reduce the Age of Onset of Alzheimer’s Disease, Accelerate Cognitive Decline, and Modulate Donepezil Response in Mild Cognitively Impaired Subjects”
Reprinted from materials provided by University of California – Los Angeles Health Sciences.

There is growing evidence showing a connection between Parkinson’s disease and the composition of the microbiome of the gut. A new study shows that Parkinson’s disease, and medications to treat Parkinson’s, have distinct effects on the composition of the trillions of bacteria that make up the gut microbiome.

The findings were published in Movement Disorders.

The study, which looked at 197 patients with Parkinson’s and 130 controls, indicated that Parkinson’s is accompanied by imbalance in the gut microbiome, with some species of bacteria present in larger numbers than in healthy individuals and other species diminished. Different medications used to treat Parkinson’s also appeared to affect the composition of the microbiome in different ways.

At this point, researchers do not know which comes first: Does having Parkinson’s cause changes in an individual’s gut microbiome, or are changes in the microbiome a predictor or early warning sign of Parkinson’s? What is known is that the first signs of Parkinson’s often arise as gastrointestinal symptoms such as inflammation or constipation.

One function of the microbiome is to help the body rid itself of xenobiotics — chemicals not naturally found in the body often arising from environmental pollutants. The study found evidence that the composition of bacteria responsible for removing those chemicals was different in individuals with Parkinson’s. This may be relevant because exposure to pesticides and herbicides in agricultural settings is known to increase the risk of developing Parkinson’s.

The researchers stress that the study of the microbiome is a relatively new field, and a better understanding of macrobiotics may provide unexpected answers for Parkinson’s disease and potentially other disorders.

Paper: “Parkinson’s disease and Parkinson’s disease medications have distinct signatures of the gut microbiome”
Reprinted from materials provided by University of Alabama Birmingham.

In experiments with a protein called Ephexin5 that appears to be elevated in the brain cells of Alzheimer’s disease patients and mouse models of the disease, researchers say removing it prevents animals from developing Alzheimer’s characteristic memory losses. In a report on the studies, published in The Journal of Clinical Investigation, the researchers say the findings could eventually advance development of drugs that target Ephexin5 to prevent or treat symptoms of the disorder.

The work with Ephexin5 grew out of a paradox about one of Alzheimer’s disease’s defining features, the development of thick plaques in the brain composed of a protein called amyloid beta. Stemming the production of this protein is currently the major focus of efforts to develop new Alzheimer’s treatments, but it isn’t the amount of amyloid beta in patients’ brains that correlates best with the severity of symptoms; rather, it’s the loss of so-called excitatory synapses, a type of cellular structure forged between two brain cells.

Although it’s not clear how amyloid beta and excitatory synapse loss are connected, researchers showed several years ago that Alzheimer’s patients have decreased brain levels of a protein called EphB2. Ephexin5 is a protein regulated by EphB2 and thought to be responsible for inhibiting the development of dendritic spines, small protrusions on the ends of nerve cells that are the location for most excitatory synapses.

In this study, the researchers used genetic engineering techniques that knocked out the gene that makes Ephexin5, thereby developing mouse Alzheimer’s disease models whose brain cells could not produce the protein. Although the animals still developed the characteristic Alzheimer’s amyloid plaques, they didn’t lose excitatory synapses, retaining the same number as healthy animals as they aged.

To see whether this retention of excitatory synapses in turn affected behavior related to memory tasks, the researchers trained healthy mice, mouse models of Alzheimer’s and Alzheimer’s models genetically engineered to lack Ephexin5 in two learning tasks: one that involved the ability to distinguish objects that had moved upon subsequent visits to the same chamber, and another that involved the ability to avoid chambers where they’d previously received a small electric shock.

While the typical Alzheimer’s disease model mice appeared unable to remember the moved objects or the shocks, the Alzheimer’s animals genetically engineered to be Ephexin5-free performed as well as healthy animals on the two tasks.

To better reflect the human scenario, in which the brain is exposed to amyloid beta for some time, probably decades, before any treatments might be administered, the researchers raised mouse models for Alzheimer’s disease into adulthood — allowing their brains to be exposed to excess amyloid beta for weeks — before injecting their brains with a short piece of genetic material that shut down Ephexin5 production. These mice performed just as well on the memory tasks as the healthy mice and those genetically engineered to produce no Ephexin5.

Together, these results suggest that too much Ephexin5 triggered by amyloid beta and reduced EphB2 signaling might be the reason why Alzheimer’s disease patients gradually lose their excitatory synapses, leading to memory loss — and that shutting down Ephexin5 production could slow or halt the disease.

Paper: “Reducing expression of synapse-restricting protein Ephexin5 ameliorates Alzheimer’s-like impairment in mice”
Reprinted from materials provided by Johns Hopkins.

Researchers have identified early biomarkers of Huntington’s disease (HD) during examinations of HD sheep still at a pre-symptomatic stage of the disease. Up until this point, the five-year-old HD sheep displayed no signs of the illness, but this comprehensive study identified clear metabolic changes in the affected animals. These new findings reveal that Huntington’s disease affects important metabolic processes in the body prior to the appearance of physical symptoms.

During this study, blood samples were taken from normal and HD animals every two hours over a 24-hour period and their metabolic profiles assessed using a targeted metabolomics approach. Unlike previous research in this area, which was affected by external environmental factors that impacted upon metabolic profiling, sheep in this study were monitored in a well-controlled setting, negating any outside influences.

Blood measurements found startling differences in the biochemistry of the sheep carrying the HD gene, compared to the normal sheep. Significant changes were observed in 89 of the 130 metabolites measured in their blood, with increased levels of the amino acids, arginine and citrulline, and decreases in sphingolipids and fatty acids that are commonly found in brain and nervous tissue. The alterations in these metabolites, which include key components of the urea cycle and nitric oxide pathways (both vital body processes), suggest that both of these processes are dysregulated in the early stages of Huntington’s disease, and that the illness affects the body long before physical symptoms appear.

The identification of these biomarkers may help to track disease in pre-symptomatic patients, and could help researchers develop strategies to remedy the biochemical abnormalities.

Paper: “Metabolic profiling of presymptomatic Huntington’s disease sheep reveals novel biomarkers”
Reprinted from materials provided by University of Surrey.