Yearly Archives: 2018

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.

JPND’s database of experimental models for Parkinson’s disease has recently been updated with 29 additional new pages on in-vivo mammalian models.

The database,  which was first made available to the community in 2017, is a unique collection aimed at presenting and fostering scientific discussion around the experimental models currently available to study Parkinson’s disease.

The database is continuously updated to reflect developments from the scientific literature and is a major effort by JPND to help researchers in the field. Together with an exhaustive description of each model and the studies that have already been done, there is a section for comments. You are welcome to add your comments to any of the models you have had experience with or to present alternative models.

We hope that you will join this growing community of scientists. To consult the database and add your contributions, please visit: http://www.neurodegenerationresearch.eu/models-for-parkinsons-disease/.

If you’d like any additional information, don’t hesitate to contact us directly at experimentalmodels@jpnd.eu.

 

 

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.