Category Archives: Research News (General)

Scientists have identified a mechanism in the molecular machinery of the cell that could help explain how neurons begin to falter in the initial stages of Alzheimer’s disease, even before amyloid clumps appear. This hypothesis centers on human genes critical for the healthy functioning of mitochondria, the energy factories of the cell, which are riddled with mobile chunks of DNA called Alu elements.

The researchers describe their work in a paper published online in Alzheimer’s & Dementia.

If these “jumping genes” lose their normal controls as a person ages, they could start to wreak havoc on the machinery that supplies energy to brain cells — leading to a loss of neurons and ultimately dementia. And if this “Alu neurodegeneration hypothesis” holds up, it could help identify people at risk sooner, before they develop symptoms, or point to new ways to delay onset or slow progression of the disease.

The dominant idea guiding Alzheimer’s research for 25 years has been that the disease results from the abnormal buildup of hard, waxy amyloid plaques in the parts of the brain that control memory. But drug trials using anti-amyloid drugs have failed, leading some researchers to theorize that amyloid buildup is a byproduct of the disease, not a cause.

This study builds on an alternative hypothesis. First proposed in 2004, the “mitochondrial cascade hypothesis” posits that changes in the cellular powerhouses, not amyloid buildup, are what cause neurons to die.

Most mitochondrial proteins are encoded by genes in the cell nucleus before reaching their final destination in mitochondria. In 2009, neurologists identified a non-coding region in a gene called TOMM40 that varies in length. The team of researchers found that the length of this region can help predict a person’s Alzheimer’s risk and age of onset. They wondered if the length variation in TOMM40 was only part of the equation. The researchers analysed the corresponding gene region in gray mouse lemurs, teacup-sized primates known to develop amyloid brain plaques and other Alzheimer’s-like symptoms with age. They found that in mouse lemurs alone, but not other lemur species, the region is loaded with short stretches of DNA called Alus.

Found only in primates, Alus belong to a family of retrotransposons or “jumping genes,” which copy and paste themselves in new spots in the genome. If the Alu copies present within the TOMM40 gene somehow interfere with the path from gene to protein, the scientists could help explain why mitochondria in nerve cells stop working.

The TOMM40 gene encodes a barrel-shaped protein in the outer membrane of mitochondria that forms a channel for molecules — including the precursor to amyloid — to enter. The scientists used 3D modeling to show that Alu insertions within the TOMM40 gene could make the channel protein it encodes fold into the wrong shape, causing the mitochondria’s import machinery to clog and stop working. The researchers say that such processes likely get underway before amyloid builds up, so they could point to new or repurposed drugs for earlier intervention.

The TOMM40 gene is one example, but if Alus disrupt other mitochondrial genes, the same basic mechanism could help explain the initial stages of other neurodegenerative diseases too, including Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis (ALS).

Paper: “The Alu neurodegeneration hypothesis: A primate-specific mechanism for neuronal transcription noise, mitochondrial dysfunction, and manifestation of neurodegenerative disease”
Reprinted from materials provided by Duke.

Researchers have shown for the first time that Amyotrophic Lateral Sclerosis (ALS) and schizophrenia have a shared genetic origin, indicating that the causes of these diverse conditions are biologically linked. The work was published in Nature Communications.

By analyzing the genetic profiles of almost 13,000 ALS cases and over 30,000 schizophrenia cases, the research confirms that many of the genes that are associated with these two very different conditions are the same.

In fact, the research has shown an overlap of 14% in genetic susceptibility to the adult onset neuro-degeneration condition ALS and the developmental neuropsychiatric disorder schizophrenia.
While overlaps between schizophrenia and other neuropsychiatric conditions including bipolar affective disorder and autism have been shown in the past, this is the first time that an overlap in genetic susceptibility between ALS and psychiatric conditions has been shown.

The research was prompted by earlier epidemiological studies that showed that people with ALS were more likely than expected to have other family members with schizophrenia, and to have had another family member who had committed suicide.

The researchers say that they will continue to study the links between ALS and psychiatric conditions using modern genetics, epidemiology and neuroimaging, and in this way will develop new and more effective treatments that are based on stabilizing disrupted brain networks.

Paper: “Genetic correlation between amyotrophic lateral sclerosis and schizophrenia”
Reprinted from materials provided by Trinity College Dublin.

Researchers have found that engaging in mentally stimulating activities, even late in life, may protect against new-onset mild cognitive impairment, which is the intermediate stage between normal cognitive aging and dementia. The study found that cognitively normal people 70 or older who engaged in computer use, craft activities, social activities and playing games had a decreased risk of developing mild cognitive impairment. The results were published in JAMA Neurology.

The researchers followed 1,929 cognitively normal participants for an average duration of four years. After adjusting for sex, age and educational level, researchers discovered that the risk of new-onset mild cognitive impairment decreased by 30 percent with computer use, 28 percent with craft activities, 23 percent with social activities, and 22 percent with playing games.

Researchers conducted a neurocognitive assessment at the time of enrollment in the study, with evaluations every 15 months. Following the assessment, an expert consensus panel made the classification of normal cognition or mild cognitive impairment for each study participant, based on published criteria.

The benefits of being cognitively engaged even were seen among apolipoprotein E (APOE) ε4 carriers. APOE ε4 is a genetic risk factor for mild cognitive impairment and Alzheimer’s dementia. However, for APOE ε4 carriers, only computer use and social activities were associated with a decreased risk of mild cognitive impairment.

Paper: “Association Between Mentally Stimulating Activities in Late Life and the Outcome of Incident Mild Cognitive Impairment, With an Analysis of the APOE ε4 Genotype”
Reprinted from materials provided by Mayo Clinic.

The most common genetic cause of the brain diseases frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is a mutation in the C9orf72 gene. Researchers have demonstrated that if an affected parent passes on this mutation, the children will be affected at a younger age (than the parent). There are no indications that the disease progresses more quickly. These results were published JAMA Neurology.

After Alzheimer’s disease, FTD is the most common form of dementia in young patients. A fraction of FTD patients show symptoms consistent with ALS, a disease in which the nerve cells that control the muscles in the brain and spinal cord are affected. This causes ALS patients to progressively lose muscle mass, resulting in loss of strength in the limbs and problems with speaking, swallowing, and breathing. ALS is more common without FTD symptoms.

The mutation in C9orf72 consists of a repetition of a short DNA sequence GGGGCC which can expand in patients up to several thousands of repetitions. It is not yet known why some patients get FTD and others ALS.

The age at first presentation of disease symptoms ranges in patients from 29 to 82 years, even in patients from the same family. Until recently, there was no explanation for this high variability. The researchers demonstrated in 2016 that the age of onset is determined by the number of GGGGCC repeats: the more repetitions, the earlier the age of onset. In C9orf72 families in which the affected parent had a late age of onset and their affected children an earlier age of onset, the researchers provided evidence that the GGGGCC repeat in the C9orf72 gene expanded from a short sequence of repeats (less than 200 repeats) to a long one (more than a thousand).

In the new study, the researchers looked at the age of onset across multiple generations. They found that in successive generations of C9orf72 families, the age of onset was markedly different. According to the researchers, most of the patients from the later generations — i.e., the children or grandchildren of the oldest subjects – showed disease symptoms at a younger age, even as the disease was shown to progress no more quickly than in older generations.

Paper: “Children of patients with C9orf72 mutations are at a greater risk of frontotemporal dementia or ALS at a younger age”
Reprinted from materials provided by VIB – Flander Interuniversity Institute for Institute for biotechnology.

In a paper published in the journal Cell Death and Differentiation, a research team has reported that a gene called ATF4 plays a key role in Parkinson’s disease, acting as a ‘switch’ for genes that control mitochondrial metabolism for neuron health. By discovering the gene networks that orchestrate the process of ATF4 expression, the researchers have singled out new therapeutic targets that could prevent neuron loss.

Some forms of Parkinson’s are caused by mutations in the genes PINK1 and PARKIN, which are instrumental in mitochondrial quality control. Fruit flies with mutations in these genes accumulate defective mitochondria and exhibit Parkinson’s-like changes, including loss of neurons.

The researchers used PINK1 and PARKIN mutant flies to search for other critical Parkinson’s genes — and using a bioinformatics approach discovered that the ATF4 gene plays a key role.

The findings build upon recent research that discovered several genes that protect neurons in Parkinson’s disease, creating possibilities for new treatment options.

Two of the genes — PINK1 and PARKIN — affect how mitochondria break down amino acids to generate nucleotides – the metabolism of these molecules generates the energy that cells need to live.

Dysfunctional mitochondrial metabolism has been linked to Parkinson’s and research has previously showed that boosting this metabolism with nucleotides can protect neurons.

Paper: “dATF4 regulation of mitochondrial folate-mediated one-carbon metabolism is neuroprotective”
Reprinted from materials provided by University of Leicester.

Disabling a part of brain cells that acts as a tap to regulate the flow of proteins has been shown to cause neurodegeneration, a new study has found.

The research, which was carried out in mice, focused on the Golgi apparatus — a compartment inside all cells in the body that controls the processing and transport of proteins. It is fundamental for the growth of the cell membrane and also for the release of many types of proteins such as hormones, neurotransmitters and the proteins that make up our skeletons.

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

Although the function of the Golgi apparatus, named after its Italian discoverer, is well understood, it has not been previously been shown to have a role in neurodegeneration. With these results the scientists think they may have found a new avenue to explore in the search for the causes of some neurodegenerative diseases.

How much the Golgi apparatus contributes to the major neurodegenerative diseases such as Alzheimer’s or Parkinson’s is something that is currently unclear, though other studies have made this link.

Paper: “Loss of the golgin GM130 causes Golgi disruption, Purkinje neuron loss, and ataxia in mice”
Reprinted from materials provided by University of Manchester.

Progressive supranuclear palsy (PSP) is a brain disease that belongs to a group of neurological diseases referred to as tauopathies. PSP impairs eye movements, locomotion, balance control, and speech, and is currently incurable. Now scientists have discovered a molecular mechanism that may help in the search for effective treatments for PSP and potentially other tauopathies. Their study, which focuses on a protein called PERK (protein kinase RNA-like endoplasmic reticulum kinase), was published in EMBO Molecular Medicine.

In tauopathies, a molecule called tau forms clumps rather than stabilizing the cytoskeleton as it normally does. Affected neurons can degenerate or even perish. To prevent such events, pathological molecules are normally repaired or disposed of by the organism. The protein PERK is part of such a maintenance system. However, in PSP, this mechanism appears to be defective. In previous studies, the researchers had found that the risk for PSP is associated with variants of the PERK gene, and that loss of PERK function induces tau pathology in humans. For the current study, they examined the functioning of this protein more closely, to see how its effects could be positively influenced. To this end, they investigated samples of brain tissue from deceased patients, cell cultures and mice with a genetic disposition for PSP.

They found that the disease sequelae decrease when PERK is activated with pharmaceuticals. Their findings, the researchers say, show that PERK is an important part of the disease mechanism.

The scientists see potential for tackling other brain diseases because PERK helps eliminate the abnormal tau molecules that also occur in other diseases such as Alzheimer’s disease.

Paper: “A protein called PERK may be a target for treating progressive supranuclear palsy: Acting upon the maintenance system of neurons alleviates disease sequelae in laboratory experiments”
Reprinted from materials provided by DZNE- German Center for Neurodegenerative Disease.

New research has shown that intestinal bacteria can accelerate the development of Alzheimer’s disease. According to the researchers behind the study, the results open up the door to new opportunities for preventing and treating the disease.

Because our gut bacteria have a major impact on how we feel through the interaction between the immune system, the intestinal mucosa and our diet, the composition of the gut microbiota is of great interest to research on diseases such as Alzheimer’s. Exactly how our gut microbiota composition is composed depends on several factors, including which bacteria we receive at birth, our genes and our diet.

By studying both healthy and diseased mice, the researchers found that mice suffering from Alzheimer’s have a different composition of gut bacteria compared to mice that are healthy. The researchers also studied Alzheimer’s disease in mice that completely lacked bacteria to further test the relationship between intestinal bacteria and the disease. Mice without bacteria had a significantly smaller amount of beta-amyloid plaque in the brain. Beta-amyloid plaques are the lumps that form at the nerve fibres in cases of Alzheimer’s disease.

To clarify the link between intestinal flora and the occurrence of the disease, the researchers transferred intestinal bacteria from diseased mice to germ-free mice, and discovered that the mice developed more beta-amyloid plaques in the brain compared to if they had received bacteria from healthy mice.

The researchers say that their study points to a direct causal link between gut bacteria and Alzheimer’s disease. As a next step, the researchers will test new types of preventive and therapeutic strategies based on the modulation of the gut microbiota through diet and probiotics.

Paper: “Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota”
Reprinted from materials provided by Lund University.

Tiny particles that pollute the air — the type that mainly comes from power plants and automobiles — may greatly increase the chance of dementia, including Alzheimer’s disease, according to new research.

Scientists and engineers have found that older women who live in places with fine particulate matter exceeding the U.S. Environmental Protection Agency’s standard are 81 percent more at risk for global cognitive decline and 92 percent more likely to develop dementia, including Alzheimer’s. If their findings hold up in the general population, air pollution could be responsible for about 21 percent of dementia cases.

The adverse effects were stronger in women who had the APOE4 gene, a genetic variation that increases the risk for Alzheimer’s.

The study, published in Translational Psychiatry, adds to an emerging body of research from around the world that links air pollution to dementia. The offending pollutants — known as PM2.5 — are fine, inhalable particles with diameters 2.5 micrometers or smaller.

The researchers analyzed data of 3,647 65- to 79-year-old women. These women lived across 48 U.S. states and did not have dementia when they enrolled. The researchers adjusted for potential bias associated with geographic region, race or ethnic background, education, socioeconomic status, lifestyle and medical conditions.

The researchers said more research is needed to confirm a causal relationship and to understand how air pollution enters and harms the brain. Accurate pollution monitors are important for this task. In addition, future studies will need to include both sexes to evaluate generalizability to men as well as examine how PM2.5 interacts with cigarettes and other pollutants.

Paper:  “Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota”
Reprinted from materials provided by Lund University.

Biologists have known for decades that enduring a short period of mild stress makes simple organisms and human cells better able to survive additional stress later in life. Now, scientists have found that a cellular process called autophagy is critically involved in providing the benefits of temporary stress. The study, published in Nature Communications, creates new avenues to pursue treatments for neurological disorders such as Huntington’s disease.

Autophagy is a means of recycling cells’ old, broken, or unneeded parts so that their components can be re-used to make new molecules or be burned for energy. The process had previously been linked to longevity. The new results suggest that long life and stress resistance are connected at the cellular level.

The scientists incubated C. elegans — tiny roundworms used to study fundamental biology — at 36 °C, significantly above the temperature they are usually kept at in the laboratory, for one hour. After this short heat exposure—a mild form of stress that improves the organism’s survival—autophagy rates increased throughout the worms’ tissues. When they exposed these heat-primed worms to another, longer heat shock a few days later, worms that were deficient in autophagy failed to benefit from the initial mild heat shock, as observed in heat-primed worms with intact autophagy.

The researchers reasoned that a mild heat stress might also improve the worms’ ability to handle another condition that worsens with age—buildup of aggregated proteins, which is stressful for cells. To test this hypothesis, they used worms that model Huntington’s disease, a fatal inherited disorder caused by neuronal proteins that start to stick together into big clumps as patients age, leading to degeneration throughout the brain. Exposing worms that make similar sticky proteins in different tissues to a mild heat shock reduced the number of protein aggregates, suggesting that a limited amount of heat stress can reduce toxic protein aggregation.

The researchers say that their findings could suggest new paths to slowing a range of neurodegenerative diseases, including Huntington’s disease, Alzheimer’s disease, and Parkinson’s disease.

Paper “Hormetic heat stress and HSF-1 induce autophagy to improve survival and proteostasis in C. elegans”
Reprinted from materials provided by Sanford Burnham Prebys Medical Discovery Institute