i3S discovers new therapeutic target to combat Alzheimer's disease

Restoring the transport and concentration of vitamin C, which is deficient in the brain cells of Alzheimer's patients, may be important for delaying the onset and progression of the disease. A research team from the Institute for Research and Innovation in Health at the University of Porto (i3S) has discovered that transporting and normalising vitamin C concentration within microglia cells—the “immune system of the brain”—in preclinical models of Alzheimer's disease restores the normal functioning of these cells and delays the onset and progression of the disease. The study was published in the prestigious journal Redox Biology.

Vitamin C is essential for normal brain function, acting as a powerful antioxidant that protects neurons and glial cells, including microglia. Vitamin C is taken up in the form of ascorbate through a specific transporter (SVCT2) into microglia cells, which function as the brain's immune system and are important for its development, maintenance, and response to trauma or disease. Microglial dysfunction may play a central role in triggering and/or progressing many neurological diseases, including Alzheimer's and Parkinson's disease.

During ageing, and in conditions such as Alzheimer's disease (AD), vitamin C levels in the brain decrease and cannot be adequately replenished by either oral or intravenous supplementation. This suggests a loss of efficiency in the ability to transport vitamin C into microglia cells, which is precisely what the i3S team demonstrated in this study: “We found that in animal models with Alzheimer's disease, the specific vitamin C transporter is greatly reduced.” 

But this is not only true in preclinical models, emphasizes João Relvas, who led the research: “More recent results from our laboratory in collaboration with the Portuguese Brain Bank, which have not yet been published, show that transporter levels are also reduced in microglia in human brains with Alzheimer's disease, which may give greater translational relevance to the study now published.”

Camila Portugal, the study's lead author, explains that the team was also able to prove that "by increasing the expression of this transporter and, consequently, restoring vitamin C levels in microglia, we were able to restore the normal functioning of these cells in the brain with Alzheimer's disease. More importantly, the data indicate that this seems to be sufficient not only to delay the onset of the disease, but also to delay its progression once it has already begun to manifest itself."

“The results are clear: this transporter can be considered a therapeutic target,” emphasises Renato Socodato, a member of the i3S Glial Cell Biology group. "In this research, we used genetic engineering to increase the expression of the transporter and, consequently, the uptake of vitamin C by microglia, but in the future, we want to use pharmacological agents. Ideally, the patient would take a drug that would increase the level of the transporter and the uptake of vitamin C by microglia, which would provide some protection against Alzheimer's disease," he explains. 

In this context, the team is already working on the next step: evaluating thousands of pharmacological compounds to find a molecule that can maintain adequate levels of the transporter and, consequently, vitamin C within cells.

For João Relvas, leader of the group that developed this research at i3S and professor at the Faculty of Medicine of Porto (FMUP), "this work is also very relevant because it demonstrates that it is the uptake and not the supplementation of vitamin C that is critical. In other words, no matter how much vitamin C we ingest, if we don't have the transport machinery working, it doesn't enter the microglia cells and its effect is nil." 

The researcher adds that he has data indicating that decreased vitamin C transport is associated with neuroinflammation in other neurodegenerative diseases, such as Parkinson's disease, so he assures us that “this approach could eventually be transposed to other diseases, and we already have some experimental data that supports this strategy.”