Scientists Find Oleic Acid is Key to Activating the Brain's 'fountain of youth'

April 29, 2022

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HOUSTON, TX - Cognitive difficulties and learning disabilities are common in individuals with neurodevelopmental disorders and intellectual disabilities. While searching for new ways to prevent or treat these and other related conditions, a team at Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital identified a missing piece of the puzzle of how specific types of learning and memory are sustained and regulated in the brain.

The study, published in the Proceedings of the National Academy of Sciences, reveals the function of a very common fatty acid, oleic acid, in the brain.  Oleic acid is produced in the brain by neural stem cells, where it triggers the process that enables new learning and memory. This exciting finding has paved the path to discovering potential new therapeutic strategies to counteract cognitive difficulties in patients with neurological and intellectual disability disorders.

“Years ago, scientists thought that the adult mammalian brain was not able to repair and regenerate. But research has shown that some brain regions have the capacity to generate new neurons, a process called neurogenesis,” said the lead author Dr. Mirjana Maletic-Savatic, associate professor of pediatrics-neurology at Baylor and Texas Children’s and an investigator at the Duncan NRI. “The hippocampus region of the adult mammalian brain has the ongoing capacity to form new neurons, to repair and regenerate itself, enabling learning and memory and mood regulation after birth. Ever since neurogenesis was discovered, it has been envisioned as ‘the fountain of youth.’ But, with increasing age, in certain diseases or after exposure to certain drugs or insults, neurogenesis decreases and this has been associated with cognitive decline and depression.”

In this study, the team searched for a way to tap into this fountain of youth, to reignite the process of neurogenesis to prevent its decline or restore it.

“We knew that neurogenesis has a ‘master regulator,’ a protein within neural stem cells called TLX that is a major player in the birth of new neurons. We, however, did not know what stimulated TLX to do that. Nobody knew how to activate TLX,” said co-corresponding author Dr. Damian Young, associate professor of pharmacology and chemical biology and of pathology at Baylor and Texas Children’s and member of Baylor’s Dan L Duncan Comprehensive Cancer Center. Young is also associate director of the Baylor's Center for Drug Discovery located in Duncan NRI.

“We discovered that a common fatty acid called oleic acid binds to TLX and this increases cell proliferation and neurogenesis in the hippocampus of both young and old mice,” said co-first author Dr. Prasanna Kandel, who was a graduate student at Baylor while working on this project. “This oleic acid is produced within the neural stem cells in order to activate TLX.”

While oleic acid is also the major component in olive oil, this would, however, not be an effective source of this fatty acid because it would likely not reach the brain, the researchers explained. It must be produced by the cells themselves.

The finding that oleic acid regulates TLX activation has major therapeutic implications. “TLX has become a ‘druggable’ target, meaning that knowing how it is activated naturally in the brain helps us to develop drugs capable of entering the brain and stimulating neurogenesis,” Young said. “This strategy could potentially be used to treat diseases such as major depressive disorders and Alzheimer’s disease as well as neurodevelopmental disorders associated with learning disabilities. This is incredibly exciting because it provides a new way of treating these debilitating diseases in need of effective treatments.”

“Beside the scientific progress, I am hopeful that the current findings and ongoing related work will have real impact on people who are in need of improved and effective therapies, like my mother who suffers from clinical depression,” Kandel said.

Read a scientific commentary published in the Proceedings of National Academy of Sciences about this work.

This project was supported by the Cancer Prevention and Research Institute of Texas (CPRIT) Core Facility Support Award (CPRIT-RP180672), the National Institutes of Health (CA125123 and RR024574) and Baylor College of Medicine’s Intellectual and Developmental Disabilities Research Center grant (P50HD10355) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The work was partially supported by Baylor College of Medicine start-up funds, the Albert and Margaret Alkek Foundation, the McNair Medical Institute at the Robert and Janice McNair Foundation, the CPRIT grant R1313 (V.K.); the R. P. Doherty, Jr. Welch Chair in Science (Q-0022, D.D.M.), BCM Seed Funding 1P20CA221731-01A1 (D.W.Y.); and NIGMS R01 GM120033. Further support was provided by Cynthia and Antony Petrello Endowment, Mark A. Wallace Endowment, McKnight Foundation, Dana Foundation, and Baylor College of Medicine’s Computational and Integrative Biomedical Research Center seed grant.

Rajalaxmi Natarajan, PhD
[email protected]
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