Yearly Archives: 2017

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.