Research Roundup: Alzheimer’s, Schizophrenia, Diabetes and More

dropper depositing pink liquid into row of test tubes

There are plenty of great scientific research stories out this week. Here’s a look at just a few of them.

Possible New Approach to Alzheimer’s Treatment

It’s well known that the accumulation of amyloid beta proteins in the brain are significantly involved in the development of Alzheimer’s disease, even if there’s some debate as to exactly what the role is. Monomers of amyloid beta, in other words, the proteins by themselves, have specific jobs they do. But when they accumulate, that’s where the problems start. At least, that’s been the thinking. Now, researchers at the University of Washington have found evidence that smaller aggregates of amyloid beta are the toxic components of the disease. They published their research in the Proceedings of the National Academy of Sciences.

The research group developed synthetic peptides that target and inhibit the small, toxic aggregates. The peptides fold into something called an alpha sheet that can block amyloid beta aggregation at the earliest, most toxic stage when the oligomers form. Their peptides reduced amyloid beta-triggered toxicity in human brain cells in culture and also in two laboratory animal models for Alzheimer’s.

“This is about targeting a specific structure of amyloid beta formed by the toxic oligomers,” stated corresponding author Valerie Daggett, a UW professor of bioengineering and faculty member of the UW Molecular Engineering & Sciences Institute.

Dagget went on to say, “Amyloid beta definitely plays a lead role in Alzheimer’s disease, but while historically attention has been on the plaques, more and more research instead indicates that amyloid beta oligomers are the toxic agents that disrupt neurons.”

They have also developed a laboratory test that uses a synthetic alpha sheet to measure levels of amyloid beta oligomers that might be the basis of a clinical test to detect people at risk of developing Alzheimer’s.

Method to Detect Off-Target Effects of CRISPR

One of the primary concerns in widespread use of CRISPR gene editing is off-target effects. That is to say, while the CRISPR techniques make it easy to identify specific sections of the DNA, which can then be quickly snipped out and replaced, CRISPR, though precise, isn’t completely precise, and may edit other sections of the genome unintentionally. Researchers with the Gladstone Institutes and collaborators at AstraZeneca have developed a way of dealing with that problem. Their work was published in the journal Science.

“When CRISPR makes a cut, the DNA is broken,” stated Beeke Wienert, a postdoctoral scholar in Bruce R. Conklin’s lab at Gladstone. “So, in order to survive, the cell recruits many different DNA repair factors to that particular site in the genome to fix the break and join the cut ends back together. We thought that if we could find the locations of these DNA repair factors, we could identify the sites that have been cut by CRISPR.”

The researchers analyzed a panel of different DNA repair factors. One of them, MRE11, is one of the first responders to the site of the edit. Using MRE11, the group developed a technique called DISCOVER-Seq that identifies the exact genome sites where a cut has been made by CRISPR.

104 High-Risk Genes for Schizophrenia Identified

Researchers at Vanderbilt University Medical Center developed a computational framework to identify 104 high-risk genes for schizophrenia. They published their work in the journal Nature Neuroscience.

“This framework opens the door for several (research) directions,” stated the study’s senior author, Bingshan Li, associate professor of Molecular Physiology and Biophysics and an investigator in the Vanderbilt Genetics Institute. “I think we’ll have a better understanding of how prenatally these genes predispose risk and that will give us a hint of how to potentially develop intervention strategies. It’s an ambitious goal … (but) by understanding the mechanism, drug development could be more targeted.”

Genome-wide association studies (GWAS) have identified more than 100 loci associated with schizophrenia, but the high-risk genes aren’t necessarily located at those loci. Those loci may regulate the activity of genes at a distance. Li and the research team, which included Rui Chen and Quan Wang, developed the Integrative Risk Genes Selector, which collected the top genes from earlier-reported loci based on supporting evidence from multi-dimensional genomics data as well as gene networks. This led to the list of 104 high-risk genes, which code for proteins targeted in other diseases by commercially available drugs. Chen, for example, notes that “schizophrenia and autism have shared genetics.”

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Using microRNAs to Regenerate Heart Muscle

Heart muscle has limited ability to regenerate. After a heart attack, for example, cardiac muscle dies and scar tissue forms, which can lead to heart failure. Researchers at Boston Children’s Hospital developed a way of using microRNAs, tiny regulatory molecules, to regenerate heart muscle. They published their research in the journal Nature Communications.

Da-Zhi Wang, a cardiology researcher at Boston Children’s Hospital, identified a family of microRNAs called miR-17-92 in 2013 that regulates the proliferation of cardiomyocytes. His team, in this new study, found that two microRNAs from that family, miR-19a and miR-19b, are particularly good candidates for treating heart attack. They tested the microRNAs in two different ones. One, they coated them with lipids and delivered them directly into mice. In the other method, they placed the microRNAs into a gene therapy vector that targeted the heart.

miR-19a/b gave immediate and long-term protection in mice after a heart attack. In the first phase, the first 10 days after the heart attack, the microRNAs cut the acute cell death and suppressed inflammatory immune responses. The microRNAs inhibited several genes involved in these processes. Over the long term, the hearts receiving treatment had more healthy tissue, less scarring or dead tissue, and improved contractility.

“The initial purpose is to rescue and protect the heart from long-term damage,” stated Wang. “In the second phase, we believe the microRNAs help with cardiomyocyte proliferation.”

Metformin May Help Weight Loss Maintenance

Metformin is commonly used to treat prediabetes and type 2 diabetes to control high blood sugar. Research that came out of the Diabetes Prevention Program Research Group, which includes researchers from across the country as well as Sweden, indicates that metformin can help in long-term weight loss maintenance. The research was published in the Annals of Internal Medicine.

Weight loss is a major part of preventing or delaying type 2 diabetes. The Diabetes Prevention Program (DPP) was a randomized controlled clinical trial that compared weight loss and diabetes prevention with metformin, intensive lifestyle intervention (ILS), or a placebo in more than 3,000 participates with prediabetes. The DPP’s Outcomes Study (DPPOS) also observed patients after the masked treatment phase ended. These studies are the largest and longest-running trial of metformin for prevention of diabetes.

The research found that after the first year, twice as many patients in the ILS group compared to the metformin group lost at least 5% of their body weight. But those who were in the metformin group had more success at maintaining their weight loss between years 6 and 15. They also found that patients with greater weight loss at one year had long-term weight loss across all groups. The early weight loss also had implications for diabetes diagnoses. In patients who lost at least 5% of their weight in the first year, the cumulative diabetes incidence rates over 15 years were lower.

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