Tag Archives: Alzheimer’s

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.

ReigershoeveAt a recent meeting in Amsterdam, members of the JPND Management Board, which is the decision-making body of JPND, were invited to tour Reigershoeve, a patient-centered residential ‘care farm’ for people living with dementia.

Located in Heemskerk, about a half hour northwest of Amsterdam, Reigershoeve is home to 27 people living with dementia, according to Dieneke Smit, who started the care farm with her father, Henk Smit. The property includes a farm with animals, an art studio, a greenhouse and vast gardens. Residents are grouped into smaller homes, and are encouraged to help cook, clean and maintain the property in a community-living environment.

Reigershoeve

Reigershoeve

Dieneke Smit, who founded Reigershoeve with her father, Henk Smit, and Bart Kooiman, a Programme officer at ZonMw

Dieneke Smit, who founded Reigershoeve with her father, Henk Smit, and Bart Kooiman, a Programme officer at ZonMw.

Reigershoeve

Reigershoeve

Reigershoeve

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Dieneke Smit leading a guided tour of the grounds at Reigershoeve.

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The Reigershoeve farm includes pigs and donkeys.

Reigershoeve

Thank you to Dieneke and the rest of the Reigershoeve community for welcoming the JPND Management Board and showing us around! To learn more about Reigershoeve, visit the website.

A new study provides additional evidence that amyloid-beta protein — which is deposited in the form of beta-amyloid plaques in the brains of patients with Alzheimer’s disease — is a normal part of the innate immune system, the body’s first-line defense against infection. The study, published in Science Translational Medicine, finds that expression of human amyloid-beta (A-beta) was protective against potentially lethal infections in mice, in roundworms and in cultured human brain cells. The findings may lead to potential new therapeutic strategies and suggest limitations to therapies designed to eliminate amyloid plaques from patient’s brains.

“Neurodegeneration in Alzheimer’s disease has been thought to be caused by the abnormal behavior of A-beta molecules, which are known to gather into tough fibril-like structures called amyloid plaques within patients’ brains,” says Robert Moir, MD, of the Genetics and Aging Research Unit in the Massachusetts General Hospital (MGH) Institute for Neurodegenerative Disease (MGH-MIND), co-corresponding author of the paper. “This widely held view has guided therapeutic strategies and drug development for more than 30 years, but our findings suggest that this view is incomplete.”

A 2010 study co-led by Moir and Rudolph Tanzi, PhD, director of the MGH-MIND Genetics and Aging unit and co-corresponding author of the current study, grew out of Moir’s observation that A-beta had many of the qualities of an antimicrobial peptide (AMP), a small innate immune system protein that defends against a wide range of pathogens. That study compared synthetic forms of A-beta with a known AMP called LL-37 and found that A-beta inhibited the growth of several important pathogens, sometimes as well or better than LL-37. A-beta from the brains of Alzheimer’s patients also suppressed the growth of cultured Candida yeast in that study, and subsequently other groups have documented synthetic A-beta’s action against influenza and herpes viruses.

The current study is the first to investigate the antimicrobial action of human A-beta in living models. The investigators first found that transgenic mice that express human A-beta survived significantly longer after the induction of Salmonella infection in their brains than did mice with no genetic alteration. Mice lacking the amyloid precursor protein died even more rapidly. Transgenic A-beta expression also appeared to protect C.elegans roundworms from either Candida or Salmonella infection. Similarly, human A-beta expression protected cultured neuronal cells from Candida. In fact, human A-beta expressed by living cells appears to be 1,000 times more potent against infection than does the synthetic A-beta used in previous studies.

That superiority appears to relate to properties of A-beta that have been considered part of Alzheimer’s disease pathology — the propensity of small molecules to combine into what are called oligomers and then aggregate into beta-amyloid plaques. While AMPs fight infection through several mechanisms, a fundamental process involves forming oligomers that bind to microbial surfaces and then clump together into aggregates that both prevent the pathogens from attaching to host cells and allow the AMPs to kill microbes by disrupting their cellular membranes. The synthetic A-beta preparations used in earlier studies did not include oligomers; but in the current study, oligomeric human A-beta not only showed an even stronger antimicrobial activity, its aggregation into the sorts of fibrils that form beta-amyloid plaques was seen to entrap microbes in both mouse and roundworm models.

Tanzi explains, “AMPs are known to play a role in the pathologies of a broad range of major and minor inflammatory disease; for example, LL-37, which has been our model for A-beta’s antimicrobial activities, has been implicated in several late-life diseases, including rheumatoid arthritis, lupus and atherosclerosis. The sort of dysregulation of AMP activity that can cause sustained inflammation in those conditions could contribute to the neurodegenerative actions of A-beta in Alzheimer’s disease.”

Moir adds, “Our findings raise the intriguing possibility that Alzheimer’s pathology may arise when the brain perceives itself to be under attack from invading pathogens, although further study will be required to determine whether or not a bona fide infection is involved. It does appear likely that the inflammatory pathways of the innate immune system could be potential treatment targets. If validated, our data also warrant the need for caution with therapies aimed at totally removing beta-amyloid plaques. Amyloid-based therapies aimed at dialing down but not wiping out beta-amyloid in the brain might be a better strategy.”

Says Tanzi, “While our data all involve experimental models, the important next step is to search for microbes in the brains of Alzheimer’s patients that may have triggered amyloid deposition as a protective response, later leading to nerve cell death and dementia. If we can identify the culprits — be they bacteria, viruses, or yeast — we may be able to therapeutically target them for primary prevention of the disease.”

Paper: “Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease”
Reprinted from materials provided by Massachusetts General Hospital.

The loss of the Y chromosome in batches of blood cells over time continues to develop as one biological explanation for why men, on average, live shorter lives than women. Researchers reporting in the American Journal of Human Genetics found that men with blood samples showing loss of chromosome Y developed Alzheimer’s as often as people born with genes that put them at the most risk for the disease.

“Most genetic research today is focused on inherited gene variants — mutations that are inherited by the offspring, but what we’re looking at are postzygotic mutations that are acquired during life,” says senior author Lars Forsberg, a researcher in the Department of Immunology, Genetics, and Pathology at Uppsala University in Sweden. “Using new tools to analyze genetic variations that accumulate with age, we can help explain how sporadic diseases like cancer or Alzheimer’s manifest,” says first author Jan Dumanski.

One such postzygotic mutation found in the cells of biological males is the loss of the Y chromosome in a degree of blood cells. Loss of Y occurs in up to 17 percent of men and is more likely to be found in older men and men who smoke. This study expands on the idea that loss of Y, already a known risk factor for cancer, could be a predictive biomarker for a wider range of poor health outcomes, specifically Alzheimer’s. Why loss of Y can be linked to an increased risk for disease remains unclear, but the authors speculate it has to do with reduced immune system performance.

The researchers looked at over 3,000 men to ascertain whether there was any predictive association between loss of Y in blood cells and Alzheimer’s disease. The participants came from three long-term studies that could provide regular blood samples: the European Alzheimer’s Disease Initiative, the Uppsala Longitudinal Study of Adult Men, and the Prospective Investigation of the Vasculature in Uppsala Seniors. Across the datasets, those with the highest fraction of blood cells without a Y chromosome were consistently more likely to be diagnosed with Alzheimer’s.

“Having loss of Y is not 100 percent predictive that you will have either cancer or Alzheimer’s,” Forsberg says, adding that there were men in the study who had the mutation and lived with no symptoms well into their 90s. “But in the future, loss of Y in blood cells can become a new biomarker for disease risk and perhaps evaluation can make a difference in detecting and treating problems early.”

Forsberg, Dumanski, and colleagues will next investigate the effect of loss of Y in larger cohorts and explore in greater detail how it confers risk for specific types of cancers and disease. They also plan to look at the cellular changes caused by loss of Y and how it affects different types of blood cells.

Source: Reprinted from materials provided by Cell Press
Paper: “Mosaic Loss of Chromosome Y in Blood Is Associated with Alzheimer Disease”

Depression symptoms that steadily increase in older adults are more strongly linked to dementia than any other types of depression, and may indicate the early stages of the disease, according to the first ever long-term study to examine the link between dementia and the course of depression, published in The Lancet Psychiatry journal.

Symptoms of depression are common in people with dementia, but previous studies have often looked at single episodes of depression, failing to take into account how depression develops over time. The course of depression varies greatly between individuals — some might experience depressive symptoms only transiently, followed by full remission, others might have remitting and relapsing depression, and some might be chronically depressed. Different courses of depression may reflect different underlying causes, and might be linked to different risks of dementia.

The study included 3325 adults aged 55 and over, who all had symptoms of depression but no symptoms of dementia at the start of the study. The data was gathered from the Rotterdam Study, a population-based cohort study of various diseases in the Netherlands which allowed the authors to track depressive symptoms over 11 years and the risk of dementia for a subsequent 10 years.

Using the Center for Epidemiology Depression Scale (CES-D) and the Hospital Anxiety and Depression Scale-Depression (HADS-D), the authors identified five different trajectories of depressive symptoms — low depression symptoms (2441 participants); initially high symptoms that decreased (369); low starting scores that increased then remitted (170); initially low symptoms that increased (255); and constantly high symptoms (90).

Of the 3325 participants, 434 developed dementia, including 348 cases of Alzheimer’s disease. Among the group with low symptoms of depression, 10% (226/2174) developed dementia. The researchers used this as the benchmark against which to compare other trajectories of depression — the study did not compare the risk of dementia following depression with the risk of dementia for adults in the general population (without depression).

Only the group whose symptoms of depression increased over time was at an increased risk of dementia- 22% of people (55/255) in this group developed dementia. This risk was particularly pronounced after the first 3 years. Individuals with remitting symptoms of depression were not at an increased risk of dementia compared to individuals with low depressive symptoms. The authors say that this suggests that having severe symptoms of depression at one point in time does not necessarily have any lasting influence on the risk of dementia.

The authors say their findings support the hypothesis that increasing symptoms of depression in older age could potentially represent an early stage of dementia. They also say that the findings support previous suggestions that dementia and some forms of depression may be symptoms of a common cause. They say that at the molecular levels, the biological mechanisms of depression and neurodegenerative diseases overlap considerably including the loss of ability to create new neurons, increased cell death and immune system dysregulation.

Source: Materials provided by The Lancet
Paper: “10-year trajectories of depressive symptoms and risk of dementia: a population-based study”