Little-known brain protein may be key to treating Alzheimer’s and ageing

Researchers from the National University of Singapore have made a groundbreaking discovery about the role of a little-known protein in the brain, which could revolutionize the treatment of Alzheimer’s disease and other neurological conditions. Their study, published in Cell Research, reveals that the protein Mfsd7c plays a critical role in managing choline levels in the brain, challenging previous assumptions and offering new therapeutic possibilities.

Alzheimer’s disease and other neurological disorders present significant health challenges, particularly as the global population ages. Current treatments are limited, and there is a pressing need for novel therapeutic strategies. Choline, a nutrient essential for brain function, is known to decline with age and in conditions like Alzheimer’s disease.

Understanding how choline is transported and regulated in the brain could provide critical insights into developing new treatments. The protein Mfsd7c, linked to Fowler syndrome, a severe neurological disorder, became the focus of this study to uncover its potential role in brain choline metabolism.

The research team, led by Associate Professor Nguyen Nam Long, utilized a combination of pre-clinical models and advanced metabolomics analyses to explore the function of Mfsd7c. Metabolomics is a technique that allows scientists to measure the unique chemical fingerprints that cellular processes leave behind, specifically the study of metabolites, which are the end products of these processes.

The study involved injecting a compound called lysophosphatidylcholine (LPC) into the pre-clinical models. LPC enters the brain and releases choline, enabling the researchers to trace the source of choline in the brain. The key experiment involved inhibiting the Mfsd7c protein in these models and observing the effects on choline levels.

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The researchers discovered that contrary to the long-held belief that the brain imports free choline directly from the bloodstream, Mfsd7c is essential for exporting excess choline from the brain. This finding was significant because it revealed a new mechanism of choline transport at the blood-brain barrier.

Choline is crucial for brain function, aiding in memory, mood regulation, and muscle control. The study demonstrated that the brain takes up choline bound to circulating lipids rather than in its free form. This lipid-associated choline is transported to the brain by LPC, and Mfsd7c then exports any excess choline out of the brain, maintaining a balance.

Interestingly, targeting Mfsd7c in the study models increased brain levels of choline and acetylcholine, a neurotransmitter essential for learning and memory. This is particularly relevant for Alzheimer’s patients and elderly individuals who often have reduced acetylcholine levels. The increase in acetylcholine through Mfsd7c manipulation suggests potential therapeutic strategies to boost brain function in these populations.

“Our study results have revealed an unexpected finding for choline source in the brain. It not only provides a foundation for future work to reveal the disease mechanisms of Fowler syndrome, but also lays the foundation for treatment of neurological diseases,” said Nguyen.

While the findings are promising, the study has several limitations that need to be addressed in future research. Firstly, the research was conducted on pre-clinical models, and it remains to be seen whether the findings will translate to humans. Clinical trials will be necessary to determine the safety and efficacy of targeting Mfsd7c in human patients.

Another limitation is the understanding of how Mfsd7c precisely regulates choline export. The exact mechanisms by which Mfsd7c facilitates choline transport and how this process is influenced by different physiological and pathological conditions require further investigation.

Additionally, while the study highlights the potential of Mfsd7c as a therapeutic target, it does not provide a clear pathway for drug development. Future research should focus on identifying compounds that can modulate Mfsd7c activity and testing their effects on brain choline levels and cognitive function.

The researchers also noted that while increasing choline levels in the brain could be beneficial for conditions like Alzheimer’s, it is crucial to understand the balance required, as excessive choline might have adverse effects. This balance will need to be carefully studied in future therapeutic developments.

The study, “MFSD7c functions as a transporter of choline at the blood–brain barrier,” was authored by Xuan Thi Anh Nguyen, Thanh Nha Uyen Le, Toan Q. Nguyen, Hoa Thi Thuy Ha, Anna Artati, Nancy C. P. Leong, Dat T. Nguyen, Pei Yen Lim, Adelia Vicanatalita Susanto, Qianhui Huang, Ling Fam, Lo Ngah Leong, Isabelle Bonne, Angela Lee, Jorge L. Granadillo, Catherine Gooch, Dejie Yu, Hua Huang, Tuck Wah Soong, Matthew Wook Chang, Markus R. Wenk, Jerzy Adamski, Amaury Cazenave-Gassiot, and Long N. Nguyen.