Category Archives: Research News (General)

Scientists know that faulty proteins can cause harmful deposits or “aggregates” in neurological disorders such as Alzheimer’s and Parkinson’s disease. Although the causes of these protein deposits remain a mystery, it is known that abnormal aggregates can result when cells fail to
transmit proper genetic information to proteins.

Researchers from the University of California San Diego first highlighted this cause of brain disease more than 10 years ago. Today, they have identified a gene, Ankrd16, that prevents the protein aggregates they originally observed. Usually, the information transfer from gene to protein is carefully controlled — biologically “proofread” and corrected — to avoid the production of improper proteins.
Recent research identified that Ankrd16 rescued specific neurons — called Purkinje cells — that die when proofreading fails. Without normal levels of Ankrd16, these nerve cells, located in the cerebellum, incorrectly activate the amino acid serine, which is then improperly incorporated into proteins, causing protein aggregation.

The levels of Ankrd16 are normally low in Purkinje cells, making these neurons vulnerable to proofreading defects. Raising the level of Ankrd16 protects these cells from dying, while removing Ankrd16 from other neurons in mice with a proofreading deficiency caused widespread buildup of abnormal proteins and ultimately neuronal death. The researchers note that only a few modifier genes of disease mutations such as Ankrd16 have been identified and a modifier-based mechanism for understanding the underlying pathology of neurodegenerative diseases may be a promising route to understanding disease development.

Paper: “ANKRD16 prevents neuron loss caused by an editing-defective tRNA synthetase.”

Reprinted by materials provided by: The University of California – San Diego

Moderate to high intensity exercise does not slow cognitive impairment in older people with dementia, a trial published by The BMJ finds. The view that exercise might slow cognitive decline has gained popularity, however, recent reviews of trials of exercise training in people with dementia have shown conflicting results.

A team of UK researchers decided to estimate the effect of a moderate to high intensity aerobic and strength exercise training programme on cognitive impairment and other outcomes in people with dementia. 494 people with mild to moderate dementia living in the community across 15 regions of England were involved. Participants were randomly assigned to either a supervised exercise and support programme or to usual care. The main outcome was an Alzheimer’s disease assessment score (ADAS-cog) at 12 months. Other (secondary) outcomes included activities of daily living, number of falls, and quality of life.

Compliance with exercise was good and participants were assessed again at six and 12 months. The researchers found that cognitive impairment declined over the 12-month follow-up in both groups. The exercise group showed improved physical fitness in the short term, but higher ADAS-cog scores at 12 months (25.2 v 23.8) compared with the usual care group, indicating worse cognitive impairment.

Paper: “Dementia And Physical Activity (DAPA) trial of moderate to high intensity exercise training for people with dementia: randomised controlled trial”

Reprinted by materials provided by The BMJ

Lifetime risks of developing Alzheimer’s disease dementia vary considerably by age, gender and the presence of any signs or symptoms of dementia, a new study by Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association reports.

These are the first lifetime risk estimates for Alzheimer’s that take into account what are believed to be biological changes in the brain that occur 10 to 20 years before memory and thinking symptoms appear. These early changes are referred to as preclinical Alzheimer’s disease.

Researchers provide the example of a 90-year-old female with amyloid plaques having a lifetime risk of Alzheimer’s disease of only 8.4 percent, compared to a 65-year-old female with amyloid plaques who has a lifetime risk of 29.3 percent. The shorter life expectancy of the older person explains the lower lifetime risk for this person over that of the 65 year old.

That same 65-year-old with amyloid plaques has a 10-year risk of Alzheimer’s disease dementia of 2.5 percent. Lifetime risks for females are generally higher than males because they live longer. The authors state that the lifetime and 10-year risks are an indication of the potential that someone will develop Alzheimer’s disease dementia based on their age and screenings for amyloid deposits, neurodegeneration and presence or absence of MCI or any combination of those three.

Paper: “Estimation of lifetime risks of Alzheimer’s disease dementia using biomarkers for preclinical disease”

Reprinted by materials provided by the Alzheimer’s Association

Enhanced lifestyle counselling prevents cognitive decline even in people who are carriers of the APOE4 gene, a common risk factor of Alzheimer’s disease, according to a new study published in JAMA Neurology.

The two-year FINGER trial involved 60–77 year-old people living in Finland with risk factors for memory disorders. The study participants were divided into two groups: one of the groups was given regular lifestyle counselling and the other enhanced lifestyle counselling. Enhanced counselling involved nutrition counselling, physical and cognitive exercises and support in managing the risk of cardiovascular diseases.

Earlier findings from the FINGER trial have shown that the regular lifestyle counselling group had a significantly increased risk of cognitive and functional impairment compared to the intervention group, i.e. the group receiving enhanced counselling.

Now the researchers analysed whether the presence of the APOE4 gene affected the intervention results. The analysis included 1,109 persons of whom 362 were carriers of the APOE4 gene.

The findings show that enhanced lifestyle counselling prevented cognitive decline despite the presence of the risk gene. Analyses carried out within the groups also indicate that the intervention results might even be better in carriers of the APOE4 gene.

Paper: “Effect of the Apolipoprotein E Genotype on Cognitive Change During a Multidomain Lifestyle Intervention”

Reprinted from materials provided by the University of Eastern Finland. 

New research sheds light on how a breakdown in the brain’s vascular system predates the accumulation of toxic plaques and tangles in the brain that bring about Alzheimer’s disease.

Nearly 50 percent of all dementias, including Alzheimer’s, begins with the breakdown of the smallest blood vessels in the brain and their protective “gatekeeper cells,” according to the study, published in Nature Medicine.

That catastrophe causes a communications failure called small vessel disease. Many people with that disease also have white matter disease, the wearing away of fatty myelin that allows neurons to transfer messages within the brain network. In an animal model, researchers found that brain deterioration associated with dementia may start as early 40 in humans.

For more than 25 years, scientists have known that white matter disease impedes a person’s ability to learn or remember new things, slows thinking and causes people to fall more often due to balance issues. They identified a link between crippled small blood vessels in the brain and white matter disease but didn’t know what started that process until now.

The study explains that pericytes, gatekeeper cells that surround the brain’s smallest blood vessels, play a critical role in white matter health and disease via fibrinogen, a protein that circulates in blood. Fibrinogen develops blood clots so wounds can heal. When gatekeeper cells are compromised, an unhealthy amount of fibrinogen slinks into the brain and causes white matter and brain structures, including axons (nerve fibers) and oligodendrocytes (cells that produces myelin), to die.

In a mouse model, the researchers used an enzyme known to reduce fibrinogen in blood and the brain. White matter volume in the mice returned to 90 percent of their normal state, and white matter connections were back to 80 percent productivity, the study found.

Paper: “Pericyte degeneration causes white matter dysfunction in the mouse central nervous system”

Reprinted from materials provided by USC.

ALS and frontotemporal dementia (FTD) are two neurodegenerative diseases with a toxic relationship, according to a new paper published in Nature Medicine. The study describes how a mutation in a gene, called C9ORF72, leads to toxicity in nerve cells—causing 10 percent of all cases of ALS, and an additional 10 percent of FTD.

To understand how this happens, the researchers extracted blood from ALS patients carrying the C9ORF72 mutation, and reprogrammed these blood cells into the motor nerve cells that degenerate and die in the disease. They also extracted blood from healthy patients, reprogrammed these blood cells into motor nerve cells, and used gene editing to delete the C9ORF72 gene.

Whether patient-derived or gene-edited, all motor nerve cells with the mutation had reduced amounts of the protein normally made by the C9ORF72 gene. Furthermore, by adding supplemental C9ORF72 protein, the researchers could stop the motor nerve cells from degenerating.

Through a series of experiments, the researchers revealed that the motor nerve cells use C9ORF72 protein to build lysosomes—which are cellular compartments used to engulf and break down toxic proteins and other garbage.

Without enough lysosomes, the cells accumulate two key types of garbage. The first type is a large, toxic protein produced by the mutated C9ORF72 gene itself. The second type is an excessive number of receptors, or molecules that receive signals from a neurotransmitter known as glutamate. These receptors respond to glutamate by causing the motor nerve cell to activate. Too much activation can kill a motor nerve cell.

The researchers are now using patient-derived motor nerve cells to test potential drugs—with a focus on those that affect lysosomes.

Paper: “Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons”

Reprinted from materials provided by the Keck School of Medicine at USC.

A team has developed a system to model Huntington’s in human embryonic stem cells for the first time. In a report published in Development, they describe early abnormalities in the way Huntington’s neurons look, and how these cells form larger structures that had not previously been associated with the disease.

Huntington’s is one of the few diseases with a straightforward genetic culprit: One hundred percent of people with a mutated form of the Huntingtin (HTT) gene develop the disease. The mutation takes the form of extra DNA, and causes the gene to produce a longer-than-normal protein.

Research on Huntington’s has thus far relied heavily on animal models of the disease. Suspecting that the disease works differently in humans, the researchers developed a cell-based human system for their research. They used the gene editing technology CRISPR to engineer a series of human embryonic stem cell lines, which were identical apart from the number of DNA repeats that occurred at the ends of their HTT genes.

When cells divide, they typically each retain one nuclei. However, some of these mutated cells flaunted up to 12 nuclei—suggesting that neurogenesis, or the generation of new neurons, was affected.

Treatments for Huntington’s have typically focused on blocking the activity of the mutant HTT protein. However, this research shows that the brain disruption may actually be due to a lack of HTT protein activity. The researchers created cell lines that completely lacked the HTT protein. These cells turned out to be very similar to those with Huntington’s pathology, corroborating the idea that a lack of the protein—not an excess of it—is driving the disease.

Article:  “Chromosomal instability during neurogenesis in Huntington’s disease.”
Reprinted from materials provided by Rockefeller University.

People with Alzheimer’s disease are known to have disturbances in their internal body clocks that affect sleep/wake cycle and may increase their risk of developing the disorder. Now, new research published in JAMA Neurology indicates that such circadian rhythm disruptions also occur much earlier in people whose memories are intact but whose brain scans show early, preclinical evidence of Alzheimer’s disease.

Previous studies conducted in people and in animals have found that levels of amyloid fluctuate in predictable ways during the day and night. Amyloid levels decrease during sleep, and several studies have shown that levels increase when sleep is disrupted or when people don’t get enough deep sleep.

The researchers tracked circadian rhythms in 189 cognitively normal, older adults with an average age of 66. Of the participants, 139 had no evidence of the amyloid protein that signifies preclinical Alzheimer’s. Most had normal sleep/wake cycles, although several had circadian disruptions that were linked to advanced age, sleep apnea or other causes.

But among the other 50 subjects — who either had abnormal brain scans or abnormal cerebrospinal fluid — all experienced significant disruptions in their internal body clocks, determined by how much rest they got at night and how active they were during the day. Disruptions in the sleep/wake cycle remained even after the researchers statistically controlled for sleep apnea, age and other factors.

By tracking activity during the day and night, the researchers could tell how scattered rest and activity were throughout 24-hour periods. Subjects who experienced short spurts of activity and rest during the day and night were more likely to have evidence of amyloid buildup in their brains, the researchers said.

Paper: “Circadian Rest-Activity Pattern Changes in Aging and Preclinical  Alzheimer Disease”
Reprinted from materials provided by Washington University School of Medicine.

A new study published in Scientific Reports shows that low levels of alcohol consumption may tamp down inflammation and help the brain clear away toxins, including those associated with Alzheimer’s disease.

The research focused on the glymphatic system, the brain’s unique cleaning process that was first described by the same researchers in 2012. They showed how cerebral spinal fluid (CSF) is pumped into brain tissue and flushes away waste, including the proteins beta amyloid and tau that are associated with Alzheimer’s disease and other forms of dementia. Subsequent research has shown that the glymphatic system is more active while we sleep, can be damaged by stroke and trauma, and improves with exercise.

The new study, which was conducted in mice, looked at the impact of both acute and chronic alcohol exposure.  When they studied the brains of animals exposed to high levels of alcohol over a long period of time, the researchers observed high levels of a molecular marker for inflammation, particularly in cells called astrocytes which are key regulators of the glymphatic system.  They also noted impairment of the animal’s cognitive abilities and motor skills.

Animals that were exposed to low levels of alcohol consumption, analogous to approximately 2 ½ drinks per day, actually showed less inflammation in the brain and their glymphatic system was more efficient in moving CSF through the brain and removing waste, compared to control mice who were not exposed to alcohol.  The low dose animals’ performance in the cognitive and motor tests was identical to the controls.

Paper: “Beneficial effects of low alcohol exposure, but adverse effects of high alcohol intake on glymphatic function.”

Reprinted from materials provided by the University of Rochester Medical Center