Category Archives: Research News (General)

A new study has found that a healthy diet, regular physical activity and a normal body mass index can reduce the incidence of protein build-ups that are associated with the onset of Alzheimer’s disease.

In the study, 44 adults ranging in age from 40 to 85 (mean age: 62.6) with mild memory changes but no dementia underwent an experimental type of PET scan to measure the level of plaque and tangles in the brain. Researchers also collected information on participants’ body mass index, levels of physical activity, diet and other lifestyle factors. Plaque, deposits of a toxic protein called beta-amyloid in the spaces between nerve cells in the brain; and tangles, knotted threads of the tau protein found within brain cells, are considered the key indicators of Alzheimer’s.

The study, published in the American Journal of Geriatric Psychiatry, found that each one of several lifestyle factors — a healthy body mass index, physical activity and a Mediterranean diet — were linked to lower levels of plaques and tangles on the brain scans. (The Mediterranean diet is rich in fruits, vegetables, legumes, cereals and fish and low in meat and dairy, and characterized by a high ratio of monounsaturated to saturated fats, and mild to moderate alcohol consumption.)

Earlier studies have linked a healthy lifestyle to delays in the onset of Alzheimer’s. However, the new study is the first to demonstrate how lifestyle factors directly influence abnormal proteins in people with subtle memory loss who have not yet been diagnosed with dementia. Healthy lifestyle factors also have been shown to be related to reduced shrinking of the brain and lower rates of atrophy in people with Alzheimer’s.

The next step in the research will be to combine imaging with intervention studies of diet, exercise and other modifiable lifestyle factors, such as stress and cognitive health.

Reprinted from materials provided by UCLA.

For decades, scientists have known that people with two copies of a gene called apolipoprotein E4 (ApoE4) are much more likely to have Alzheimer’s disease at age 65 than the rest of the population. Now, researchers have identified a connection between ApoE4 and protein build-up associated with Alzheimer’s that provides a possible biochemical explanation for how extra ApoE4 causes the disease.

Their findings, which appear in the Journal of the American Chemical Society, underscore the importance of looking at genes and proteins not classically associated with Alzheimer’s to make progress in understanding the disease.

Late-onset Alzheimer’s disease — the subset of the disorder occurring in people age 65 and over — affects more than 5 million Americans, and is characterized by progressive memory loss and dementia. Scientists have put forth a variety of hypotheses on its causes, including the accumulation of protein clusters called beta-amyloid plaques and tau tangles in the brain.

Apolipoprotein E comes in three versions, or variants, called ApoE2, ApoE3 and ApoE4. All the ApoE proteins have the same normal function: carrying fats, cholesterols and vitamins throughout the body, including into the brain. While ApoE2 is protective and ApoE3 appears to have no effect, a mutation in ApoE4 is a well-established genetic risk factor for late-onset Alzheimer’s disease. Previous reports have suggested that ApoE4 may affect how the brain clears out beta-amyloid, but what was happening at the molecular level wasn’t clear.

Scientists had previously uncovered hints that ApoE4 might degrade differently than the other variants, but the protein that carried out this breakdown of ApoE4 was unknown.

To find the protein responsible for degrading ApoE4, the researchers screened tissues for potential suspects and homed in on one enzyme called high-temperature requirement serine peptidase A1 (HtrA1).

When they compared how HtrA1 degraded ApoE4 with ApoE3, they found that the enzyme processed more ApoE4 than ApoE3, chewing ApoE4 into smaller, less stable fragments. The researchers confirmed the observation in both isolated proteins and human cells. The finding suggests that people with ApoE4 could have less ApoE overall in their brain cells — and more of the breakdown products of the protein.

But it’s not just a lack of full-length ApoE or an increase in its fragments that may be causing Alzheimer’s in people with ApoE4. The researchers also found that ApoE4 — because it binds so well to HtrA1 — keeps the enzyme from breaking down the tau protein, responsible for tau tangles associated with Alzheimer’s.

The results need be tested and confirmed in animal studies before researchers can be sure that HtrA1 is the link between ApoE4 and Alzheimer’s in humans. But if they hold true, they could point toward a better understanding of the disease and potential new treatment strategies.

Paper: “HtrA1 Proteolysis of ApoE In Vitro Is Allele Selective”
Reprinted from materials provided by the Salk Institute.

Synucleinopathies, a group of neurodegenerative diseases including Parkinson’s disease, are characterized by the pathological deposition of aggregates of the misfolded α-synuclein protein into inclusions throughout the central and peripheral nervous system. Intercellular propagation (from one neuron to the next) of α-synuclein aggregates contributes to the progression of the neuropathology, but little was known about the mechanism by which spread occurs.

In this study, scientists used fluorescence microscopy to demonstrate that pathogenic α-synuclein fibrils travel between neurons in culture, inside lysosomal vesicles through tunneling nanotubes (TNTs), a new mechanism of intercellular communication.

After being transferred via TNTs, α-synuclein fibrils are able to recruit and induce aggregation of the soluble α-synuclein protein in the cytosol of cells receiving the fibrils, thus explaining the propagation of the disease. The scientists propose that cells overloaded with α-synuclein aggregates in lysosomes dispose of this material by hijacking TNT-mediated intercellular trafficking. However, this results in the disease being spread to naive neurons.

This study demonstrates that TNTs play a significant part in the intercellular transfer of α-synuclein fibrils and reveals the specific role of lysosomes in this process. This represents a major breakthrough in understanding the mechanisms underlying the progression of synucleinopathies.

These compelling findings, together with previous reports from the same team, point to the general role of TNTs in the propagation of prion-like proteins in neurodegenerative diseases and identify TNTs as a new therapeutic target to combat the progression of these incurable diseases.

Paper: “Tunneling nanotubes spread fibrillar α‐synuclein by intercellular trafficking of lysosomes”

Reprinted from materials provided by Institut Pasteur.

A new and versatile imaging technique enables researchers to trace the trajectories of whole nerve cells and provides extensive insights into the structure of neuronal networks.

Lesions caused by traumatic brain damage, stroke and functional decline due to aging processes can disrupt the complex cellular network that constitutes the central nervous system, and lead to chronic pathologies, such as dementia, epilepsy and deleterious metabolic perturbations. But exactly how this happens is unknown. Researchers have now refined a novel imaging technique that allows them to visualize and monitor these structural alterations in neuronal networks. The new findings appear in the journal Nature Methods.

Nerve cells transmit electrical impulses over long distances along fibrous connections called axons, which extend from the cell body where the nucleus resides. Indeed, many neurons in the brainstem possess axons that project as far as the base of the spinal column. Thus damage to these axons can affect the function of parts of the central nervous system that are remote from the actual site of injury. The new imaging method is based on a clearing-and-shrinkage procedure that can render whole organs and organisms transparent, making – for instance – the full length of the rodent spinal cord accessible to optical imaging. Moreover, the technique is applicable down to the level of individual cells, which are labeled with fluorescent protein tags and can be visualized under the microscope by irradiating them with visible light. This enables researchers to map complex neuronal networks in rodents in 3D, a significant step in revealing the enigma behind the human brain.

Because essentially all cell types – including immune cells and tumor cells – can be specifically labeled with the aid of appropriate fluorescent markers or antibodies, the new method can be employed in a broad range of biomedical settings. Furthermore, the images obtained can be archived in a database and made available to other researchers, which should help reduce unnecessary duplication of studies.

Paper: “Shrinkage-mediated imaging of entire organs and organisms using uDISCO”

Reprinted from materials provided by LMU Medical Center.

A new multimillion pound study to detect Alzheimer’s disease has been announced. The Deep and Frequent Phenotyping study is funded by the National Institute of Health Research and the MRC and hopes to dramatically improve the success rate of clinical trials for treatments in Alzheimer’s disease.

This landmark £6.9million research project has been designed to identify measurable characteristics, known as biomarkers, which can detect the occurrence of Alzheimer’s disease very early on in the progression of the disease – when a person may have no obvious symptoms.

Between 2002 and 2012, 99% of clinical trials into treatments for Alzheimer’s disease failed. A probable reason for the high failure rate is that treatments are being tested on those who already have irreparable damage to the brain. It is likely that treatments will be more effective in slowing or stopping further at onset of dementia at earlier stages of the disease. Also, by targeting people in the earlier stages, it should be possible to design better clinical trials for treatments that make a real difference and improve people’s lives.

The multisite team, led by the University of Oxford, will work with colleagues at eight UK universities and the Alzheimer’s Society, with the project also receiving support from a coalition of biopharma companies.

The Deep and Frequent Phenotyping study will recruit 250 volunteers from existing study cohorts led by the Dementias Platform UK, and tests will be carried out over the course of 12 months.

Together, the researchers will perform up to 50 tests on 250 volunteers from Dementias Platform UK cohorts, including new tests that have never been used before to detect dementia. The tests will include wearable devices that will give researchers detailed information on people’s movement and gait, and sophisticated retinal imaging that will look at subtle changes affecting a person’s central and peripheral vision.

These potential new biomarkers will be used alone and alongside tests such as brain imaging and assessment of memory and other cognitive functions. They will allow the researchers to recognise the early stages of the disease and those who may be suitable for trials of possible treatments.

“This is the first major clinical study based on Dementias Platform UK and the results could be game changing for dementia research,” said Dr Rob Buckle, director of science programmes at the MRC and JPND Executive Board member. “Our goal is to find treatments that can slow down or even stop the progression of Alzheimer’s disease. Finding biomarkers for clinical trials is crucial for fast-tracking decisions as to whether a trial should stop or continue, and the faster we can find out which drugs work and which ones don’t, the faster we can benefit patients. An ability to deliver more cost-effective clinical trials would also encourage investment and increase the number of such studies in the future.”

Reprinted from materials provided by the University of Oxford.

Researchers have identified — and shown that it may be possible to control — the mechanism that leads to the rapid build-up of the disease-causing ‘plaques’ that are characteristic of Alzheimer’s disease.

The ability of biological molecules, such as our DNA, to replicate themselves is the foundation of life. It is a process that usually involves complex cellular machinery. However, certain protein structures manage to replicate without any additional assistance, such as the small, disease-causing protein fibres — fibrils — that are involved in neurodegenerative disorders, including Alzheimer’s and Parkinson’s.

These fibrils, known as amyloids, become intertwined and entangled with each other, causing the so-called ‘plaques’ that are found in the brains of Alzheimer’s patients. Spontaneous formation of the first amyloid fibrils is very slow, and typically takes several decades, which could explain why Alzheimer’s is usually a disease that affects people in their old age. However, once the first fibrils are formed, they begin to replicate and spread much more rapidly by themselves, making the disease extremely challenging to control.

Despite its importance, the fundamental mechanism of how protein fibrils can self-replicate without any additional machinery is not well understood. In a study published in Nature Physics, a team led by researchers from the Department of Chemistry at the University of Cambridge used a powerful combination of computer simulations and laboratory experiments to identify the necessary requirements for the self-replication of protein fibrils.

The researchers found that the seemingly complicated process of fibril self-replication is actually governed by a simple physical mechanism: the build-up of healthy proteins on the surface of existing fibrils.

The researchers used a molecule known as amyloid-beta, which forms the main component of the amyloid plaques found in the brains of Alzheimer’s patients. They found a relationship between the amount of healthy proteins that are deposited onto the existing fibrils, and the rate of the fibril self-replication. In other words, the greater the build-up of proteins on the fibril, the faster it self-replicates.

They also showed, as a proof of principle, that by changing how the healthy proteins interact with the surface of fibrils, it is possible to control the fibril self-replication.

Paper: “Physical determinants of the self-replication of protein fibrils”
Reprinted from materials provided by the University of Cambridge

The AgedBrainSYSBIO consortium, a four-year project on brain ageing funded by the European Commission under the Health Cooperation Programme of the 7th Framework Programme, is hosting a public workshop, Normal and pathological brain ageing: from systems biology to the clinic.

The workshop, to be held on October 19, 2016, at the Imagine Institute in Paris, will bring together clinicians, biologists, bioinformaticians and statisticians to present the latest advances in the field.

To view the preliminary programme and register for the workshop, visit the AgedBrainSYSBIO website.

A gene associated with Alzheimer’s disease and recovery after brain injury may show its effects on the brain and thinking skills as early as childhood, according to a study published in Neurology.

Prior studies showed that people with the epsilon(ε)4 variant of the apolipoprotein-E gene are more likely to develop Alzheimer’s disease than people with the other two variants of the gene, ε2 and ε3.

For the study, 1,187 children ages three to 20 years had genetic tests and brain scans and took tests of thinking and memory skills. The children had no brain disorders or other problems that would affect their brain development, such as prenatal drug exposure.

Each person receives one copy of the gene (ε2, ε3 or ε4) from each parent, so there are six possible gene variants: ε2ε2, ε3ε3, ε4ε4, ε2ε3, ε2ε4 and ε3ε4.

The study found that children with any form of the ε4 gene had differences in their brain development compared to children with ε2 and ε3 forms of the gene. The differences were seen in areas of the brain that are often affected by Alzheimer’s disease. In children with the ε2ε4 genotype, the size of the hippocampus, a brain region that plays a role in memory, was approximately 5 percent smaller than the hippocampi in the children with the most common genotype (ε3ε3). Children younger than 8 and with the ε4ε4 genotype typically had lower measures on a brain scan that shows the structural integrity of the hippocampus.

“These findings mirror the smaller volumes and steeper decline of the hippocampus volume in the elderly who have the ε4 gene,” said study author Linda Chang, MD, of the University of Hawaii in Honolulu.

In addition, some of the children with ε4ε4 or ε4ε2 genotype also had lower scores on some of the tests of memory and thinking skills. Specifically, the youngest ε4ε4 children had up to 50 percent lower scores on tests of executive function and working memory, while some of the youngest ε2ε4 children had up to 50 percent lower scores on tests of attention. However, children older than 8 with these two genotypes had similar and normal test scores compared to the other children.

Limitations of the study include that it was cross-sectional, meaning that the information is from one point in time for each child, and that some of the rarer gene variants, such as ε4ε4 and ε2ε4, and age groups did not include many children.

Paper: “Gray matter maturation and cognition in children with differentAPOEε genotypes”
Reprinted from materials provided by the American Academy of Neurology.

While strokes are known to increase risk for dementia, much less is known about diseases of large and small blood vessels in the brain, separate from stroke, and how they relate to dementia. Diseased blood vessels in the brain itself, which commonly is found in elderly people, may contribute more significantly to Alzheimer’s disease dementia than was previously believed, according to new study results published in The Lancet Neurology.

“Cerebral vessel pathology might be an under-recognized risk factor for Alzheimer’s disease dementia,” the researchers wrote.

The study analyzed medical and pathologic data on 1,143 older individuals who had donated their brains for research upon their deaths, including 478 (42 percent) with Alzheimer’s disease dementia. Analyses of the brains showed that 445 (39 percent) of study participants had moderate to severe atherosclerosis — plaques in the larger arteries at the base of the brain obstructing blood flow — and 401 (35 percent) had brain arteriolosclerosis — in which there is stiffening or hardening of the smaller artery walls.

The study found that the worse the brain vessel diseases, the higher the chance of having dementia, which is usually attributed to Alzheimer’s disease. The increase was 20 to 30 percent for each level of worsening severity. The study also found that atherosclerosis and arteriolosclerosis are associated with lower levels of thinking abilities, including in memory and other thinking skills, and these associations were present in persons with and without dementia.

The study examined which cognitive difficulties are caused by vessel diseases and whether vessel disease and Alzheimer’s are more destructive in tandem than they would be alone. An editorial in The Lancet Neurology that accompanied the study findings noted that while other studies have indicated that proactive measures like eating a selective diet and getting regular exercise might protect people against getting Alzheimer’s, those interventions might actually be acting on non-Alzheimer’s disease processes, such as cerebrovascular disease.

The participants in the study published in Lancet Neurology came from two (RADC) cohort studies, the Religious Orders Study and the Rush Memory and Aging Project, which have followed people older than 65, in their communities, for more than two decades. Participants receive annual health assessments and agree to donate their brains for research upon their deaths. The Lancet Neurology study used clinical data gathered from participants from 1994 to 2015, and pathologic data obtained from examination of the brains donated for autopsy, and used regression analyses to determine the odds of Alzheimer’s dementia and levels of cognitive function, for increasing levels of brain vessel diseases.

Paper: “Relation of cerebral vessel disease to Alzheimer’s disease dementia and cognitive function in elderly people: a cross-sectional study”
Source: Reprinted from materials provided by Rush University Medical Center.

A team of researchers has developed the first scalable method to identify different subtypes of neurons in the human brain. The research lays the groundwork for “mapping” the gene activity in the human brain and could help provide a better understanding of brain functions and disorders, including Alzheimer’s, Parkinson’s, schizophrenia and depression.

By isolating and analyzing the nuclei of individual human brain cells, researchers identified 16 neuronal subtypes in the cerebral cortex—the brain’s outer layer of neural tissue responsible for cognitive functions including memory, attention and decision making. The team published their findings in the journal Science.

Researchers can use these different neuronal subtypes to build a “reference map” of the human brain—a foundation to understand the differences between a healthy brain and a diseased brain.

“In the future, patients with brain disorders or abnormalities could be diagnosed and treated based on how they differ from the reference map. This is analogous to what’s being done with the reference human genome map,” said Kun Zhang, bioengineering professor at the University of California, San Diego, and a corresponding author of the study.

The new study reflects a growing understanding that individual brain cells are unique: they express different types of genes and perform different functions. To better understand this diversity, researchers analyzed more than 3,200 single human neurons in six Brodmann areas, which are regions of the cerebral cortex classified by their functions and arrangements of neurons.

Through an interdisciplinary collaborative effort, the team developed a new method to isolate and sequence individual cell nuclei. TSRI researchers obtained the samples from a post mortem brain and focused on isolating the neuronal nuclei. Zhang’s lab worked with Fluidigm, a manufacturer of microfluidic chips for single-cell studies, to develop a protocol to identify and quantify RNA molecules in individual neuronal nuclei. Scientists at San Diego-based Illumina sequenced the resulting RNA libraries. Researchers led by biochemistry professor Wei Wang at UC San Diego developed algorithms to cluster and identify 16 neuronal subtypes from the sequenced datasets.

Researchers deciphered what types of genes were “turned on” within each nucleus and revealed that various combinations of the 16 subtypes tended to cluster in cortical layers and Brodmann areas, helping explain why these regions look and function differently.

Neurons exhibited many differences in their transcriptomic profiles—the patterns of genes that are being actively expressed by these cells—revealing single neurons with shared, as well as unique, characteristics that likely lead to difference in cellular function.

In future studies, researchers aim to analyze neurons in other Brodmann areas of the brain and investigate what subtypes exist in other brain regions. They also plan to study neurons from multiple post mortem human brains (this study only involved one) to investigate neuronal diversity among individuals.

Paper: “Neuronal subtypes and diversity revealed by single-nucleus RNA sequencing of the human brain”
Source: Reprinted from materials provided by the University of California, San Diego