Toxic Fatty Acids Could Represent New Target for Treating Neurodegenerative Disorders

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, “These 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.

This line of investigation failed to identify proteins that might clearly mediate astrocyte toxicity, so the team then further purified the reactive ACM in their search for toxic activity. Using various techniques they identified an enrichment of lipoparticle proteins, such as APOE and APOJ, in the reactive ACM “… suggesting a possible change in astrocyte lipid efflux and highlighting astrocyte-secreted lipoparticles as potential bearers of toxicity,” they wrote. Further experimentation then demonstrated that neurotoxic reactive astrocytes drive the death of neurons by delivering free fatty acids (FFAs) and very-long-chain fatty acid acyl chains (VLCPCs). “Notably, there was a substantial upregulation of phosphatidylcholines with VLCPCs in reactive astrocyte cell membranes, and long-chain saturated FFAs in reactive ACM,” they wrote. “These lipids are normally of relatively low abundance in quiescent astrocyte membranes and APOE and APOJ-containing lipoparticles.”

They also genetically engineered some groups of mice to prevent the normal production of the toxic fats and looked to see whether neuron death occurred after an acute injury. They found that when fatty acid formation in mice was blocked, 75% of neurons survived, compared with 10% neuronal survival when the fatty acids were allowed to form. The researchers’ earlier work had shown that brain cells continued to function when shielded from astrocyte attacks.

Liddelow, an assistant professor in the department of neuroscience and physiology at NYU Langone Health, suggested that targeting these fats instead of the cells that produce them may be a safer approach to treating neurodegenerative diseases, because astrocytes also have important functions feeding nerve cells and clear away their waste. Stopping them from working altogether could interfere with healthy brain function. And as the team reported, “Given that lipid trafficking is the primary CNS function of lipoproteins, further study of glial lipid metabolism will yield a better understanding of how these proteins may participate in neurodegeneration and whether they could serve as disease biomarkers.”

Although it remains unclear why astrocytes produce these toxins, it is possible they evolved to destroy damaged cells before they can harm their neighbors, said Liddelow. He noted that while healthy cells are not harmed by the toxins, neurons become susceptible to the damaging effects when they are injured, mutated, or infected by prions, the contagious, misfolded proteins that play a major role in mad cow disease and similar illnesses. Perhaps in chronic diseases like dementia, this otherwise helpful process goes off track and becomes a problem, the study authors said. They concluded, “More work will hopefully outline the many signaling pathways that are mediated by lipids in the brain, and investigate the therapeutic potential of inhibiting toxic lipid secretion and lipoapoptosis in disease and injury.”

“Our results provide what is likely the most detailed molecular map to date of how tissue damage leads to brain cell death, enabling researchers to better understand why neurons die in all kinds of diseases,” said Liddelow, who is also an assistant professor in the department of ophthalmology at NYU Langone.

He cautioned that while the findings are promising, the genetic techniques used to block the enzyme that produces toxic fatty acids in mice are not ready for use in humans. The researchers’ next plan is to explore safe and effective ways to interfere with the release of the toxins in human patients. Liddelow and his colleagues had previously shown these neurotoxic astrocytes in the brains of patients with Parkinson’s disease, Huntington’s disease, and multiple sclerosis, among other diseases.