Tag Archives: Aging

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

Ten international JPND working groups recommended for funding

The EU Joint Programme – Neurodegenerative Disease Research (JPND) has released the results of a “rapid-action” call to support working groups of leading scientists to bring forward novel approaches that will enhance the use of brain imaging for neurodegenerative disease research.

Ten working groups have been recommended for funding to address the methodological challenges facing different imaging modalities, among them MRI, PET, ultrasound, MEG and EEG, as well as multimodal approaches. The working groups cover a range of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Frontotemporal dementia and Huntington’s disease.

“Brain imaging has made enormous progress in recent years and is currently one of the most promising avenues in neurodegenerative disease research,” said Professor Thomas Gasser, Chair of the JPND Scientific Advisory Board. “If we can solve the challenges in the field, brain imaging could rapidly lead to faster and better diagnoses as well as a deeper understanding of the fundamental aspects and mechanisms of neurodegeneration.”

Although imaging techniques have brought about a dramatic improvement in the understanding of neurodegenerative diseases, there remain a number of significant challenges in the field. These include the execution of multi-centre clinical trials of an unprecedented scale, data transfer across imaging centres and the use of imaging for diagnostics and for measuring clinical outcomes.

To address these questions, on January 8, 2016, JPND launched a call for community-led working groups on harmonisation and alignment in brain imaging methods. The proposals recommended for funding are for top scientists to come together and propose, through ‘best practice’ guidelines and/or methodological frameworks, how to overcome key barriers to the use of imaging in neurodegenerative disease research.

The call attracted proposals with partners from across Europe and beyond, including Asia, Australia, North America and South America. A notable number of groups based in the United States were involved in responses to the call. Funding decisions were based upon scientific evaluation and recommendations to sponsor countries by a JPND peer review panel.

“This call perfectly embodies JPND’s mission and objectives,” said Professor Philippe Amouyel, Chair of the JPND Management Board. “The purpose of JPND is to strengthen coordination and collaboration in neurodegenerative disease research across different countries. We want to ensure that research efforts are not duplicated, to build consensus and to accelerate a path toward a cure that works. This call convenes groups of leading experts to hammer out the hard questions, including the challenges of interoperability and shared and open data, to allow researchers to more rapidly and more fully exploit imaging techniques going forward.”

Each working group is expected to run for a maximum of 9 months. The outputs of the working groups are to be produced by the end of the funding period, and will be published on the JPND website and used for further JPND actions. In addition, a common workshop will be organised to bring together and present the recommendations of each working group, encouraging the further exchange of ideas and wider dissemination to different stakeholder groups.

For more information on the working groups recommended for funding, click here.