Anti-inflammatory Molecules Decline in the Aging Brain

Calendar November 1, 2022 | Posted by admin

Aging involves complicated plot twists and a large cast of characters: inflammation, stress, metabolism changes, and many others.

Now, a team of Salk Institute and UC San Diego scientists reveal another factor implicated in the aging process—a class of lipids called SGDGs (3-sulfogalactosyl diacylglycerols) that decline in the brain with age and may have anti-inflammatory effects.

 

The research, published in Nature Chemical Biology, helps unravel the molecular basis of brain aging, reveals new mechanisms underlying age-related neurological diseases, and offers future opportunities for therapeutic intervention.

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Toxic Fatty Acids Play a Critical Role in Brain Cell Death

Calendar October 8, 2021 | Posted by admin

Rodent studies led by researchers at NYU Grossman School of Medicine have found that cells called astrocytes, which normally nourish neurons, also release toxic fatty acids after neurons are damaged. The team suggests that this phenomenon is likely the driving factor behind most, if not all, diseases that affect brain function, as well as the natural breakdown of brain cells seen in aging.

“Our findings show that the toxic fatty acids produced by astrocytes play a critical role in brain cell death and provide a promising new target for treating, and perhaps even preventing, many neurodegenerative diseases,” said Shane Liddelow, PhD, who is co-senior and corresponding author of the researchers’ published paper in Nature. In their report, which is titled, “Neurotoxic reactive astrocytes induce cell death via saturated lipids,” the team concluded. “The findings highlight the important role of the astrocyte reactivity response in CNS injury and neurodegenerative disease and the relatively unexplored role of lipids in CNS signaling.”

 

Astrocytes—star-shaped glial cells of the central nervous system (CNS)—undergo functional changes in response to CNS disease and injury, but the mechanisms that underlie these changes and their therapeutic relevance remain unclear, the authors noted. Interestingly, previous research has pointed to astrocytes as the culprits behind cell death seen in Parkinson’s disease and dementia, among other neurodegenerative diseases. “Astrocytes regulate the response of the central nervous system to disease and injury, and have been hypothesized to actively kill neurons in neurodegenerative disease,” the researchers stated. But while many experts believed that these cells release a neuron-killing molecule to clear away damaged brain cells, the identity of the toxin has remained a mystery.

The studies by Liddelow and colleagues now provide what they say is the first evidence that tissue damage prompts astrocytes to produce two kinds of fats, long-chain saturated free fatty acids and phosphatidylcholines. These fats then trigger cell death in damaged neurons. For their investigation, researchers analyzed the molecules released by astrocytes collected from rodents. “Previous evidence suggested that the toxic activity of reactive astrocytes is mediated by a secreted protein, so we first sought to identify the toxic agent by protein mass spectrometry of reactive versus control astrocyte conditioned medium (ACM),” they wrote.

Source: https://www.genengnews.com/

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CRISPR Treatment Cuts Cholesterol by Up to 57% in a Single Shot

Calendar March 8, 2021 | Posted by admin

Scientists have improved upon a form of gene-editing therapy, creating an experimental treatment that looks to hold great promise for treating high cholesterol – a diagnosis affecting tens of millions of Americans, and linked to a number serious health complications. In new research conducted with mice, researchers used an injection of a newly-formulated lipid nanoparticle to deliver CRISPR-Cas9 genome editing components to living animals, with a single shot of the treatment reducing levels of low-density lipoprotein (LDL) cholesterol by up to 56.8 percent. In contrast, an existing FDA-approved lipid nanoparticle (or LNP; a tiny, biodegradable fat capsule) delivery system could only manage to reduce LDLs by 15.7 percent in testing. Of course, these results have so far only been demonstrated in mice, so the new therapy will take a lot of further testing before we know it’s both safe and equally effective in humans. But based on these results so far, signs are promising.

The way the treatment works relates to a gene in humans called Angiopoietin-like 3 (Angptl3), which produces proteins that inhibit the breakdown of certain fats in the bloodstream. People with a mutation in this gene tend to have lower amounts of fatty triglycerides and cholesterol in their blood – without showing other kinds of health complications – and for years scientists have been trying to recreate the process, with treatments that effectively mimic the effects of the mutation.

“If we can replicate that condition by knocking out the Angptl3 gene in others, we have a good chance of having a safe and long term solution to high cholesterol,” says biomedical engineer Qiaobing Xu from Tufts University. “We just have to make sure we deliver the gene editing package specifically to the liver so as not to create unwanted side effects.”

In the new research, Xu’s team developed a new formulation of LNPs called 306-O12B to target the gene, producing therapeutic effects in wild-type C57BL/6 mice that lasted at stable levels for 100 days after just a single injection of the treatment.

In addition to the cholesterol reduction, the experiment produced a 29.4 percent decrease in triglycerides in the animals’ blood, whereas the FDA-approved delivery method showed only a 16.3 percent reduction.

The findings are reported in PNAS.

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