A football player who suffers repeated concussions, a red meat enthusiast who eats beef from a cow with bovine spongiform encephalopathy, and the child of a parent who died from Huntington’s disease are all at risk for neurodegeneration. No one therapeutic can neutralize the causes of all of the various neurodegenerative diseases that plague people, but researchers like neuroscientist Akiko Nakano-Kobayashi and molecular biologist Masatoshi Hagiwara, both from Kyoto University Graduate School of Medicine, are developing drugs that can counteract neuronal death in a variety of contexts. They focus on compounds that restore and enhance the function of glial cells, which ordinarily support and protect neurons.
Nakano-Kobayashi and Hagiwara initially sought a compound that would promote the proliferation of neurons in people born with Down Syndrome. They identified one that appeared to fit the bill, named it ALGERNON, and showed that it could normalize brain structure in a mouse model (1). But when they tweaked the molecule to improve its absorption and distribution and tested the new-and-improved ALGERNON2, they realized their molecule did something unexpected. “We first thought that ALGERNON works in neuronal stem cells to promote neurogenesis, but actually what we found is that ALGERNON2 has a function to protect neurons,” said Nakano-Kobayashi. She and Hagiwara tested the new version on a mouse model of Parkinson’s disease and found that the molecule prevented neurodegeneration by increasing glial expression of Nrf2, a protein that activates antioxidants in response to stress and damage (2).
Pleased with their results, the researchers decided to test ALGERNON2 on another mouse model of neurodegenerative disease. They chose 5xFAD mice, a model of Alzheimer’s disease. They reported the results of their latest study in PNAS, showing once again that ALGERNON2 increases Nrf2 in glial cells and consequently improves neuronal health (3).
This time around, Nakano-Kobayashi and Hagiwara focused on astrocytes, a specific type of glial cell. Astrocytes complete a variety of tasks to keep the brain healthy, but when the brain experiences injury or infection, astrocytes become reactive to combat the threat (4). Scientists are actively researching the role that reactive astrocytes play in neurodegenerative diseases. Some have argued that particular patterns of gene expression cause reactive astrocytes to become neurotoxic and kill neurons (5). Alexej Verkhratsky, a neuroscientist at the University of Manchester, disagreed. “The brain has an incredibly powerful defensive system, which are all these neuroglial cells,” Verkhratsky said. “These cells lose their capacity to protect, and that’s why neurons die.”
Nakano-Kobayashi and Hagiwara, however, carried out their study under the model that a particular gene expression profile in reactive astrocytes indicates that they have become neurotoxic. The researchers evaluated how alterations in Nrf2 expression altered expression of other genes in astrocytes. They observed that knocking out Nrf2 further increased expression of genes whose upregulation some researchers associate with neurotoxicity, whereas treating astrocytes with Nrf2 stabilizing agents suppressed those genes. The researchers found evidence that Nrf2 achieved these effects by blocking inflammation-inducing cytokines from promoting the expression of the genes in question.
Hagiwara and Nakano-Kobayashi also looked for evidence that treating the 5xFAD mice with ALGERNON2 could improve the animals’ cognitive abilities. They took wildtype mice, 5xFAD mice, and 5xFAD mice treated with ALGERNON2, placed each mouse in a miniature pool with a platform to stand on, and measured how much time it took for the mouse to get out of the water. Then they tested how much the mice improved over the next three days.
Untreated 5xFAD mice were always much slower than their wildtype counterparts, while 5xFAD mice that received ALGERNON2 approached the times of the wildtype mice. That was the most exciting result for Hagiwara. “That’s amazing,” he said. “ALGERNON2 is just a small molecule, and it improves learning.”
Although Hagiwara and Nakano-Kobayashi are optimistic that ALGERNON2 could one day play a role in treating people with Alzheimer’s disease, Verkhratsky is not so sure. “Rodent models of Alzheimer’s disease have been in place for the last 25 years. What did we learn from them? I’m afraid nothing, or almost, at any rate,” Verkhratsky said. He thinks the compound could be broadly useful if its ability to activate Nrf2 translates from mouse models to humans, but he doesn’t see ALGERNON2 as a potential cure for Alzheimer’s disease.
Nakano-Kobayashi and Hagiwara plan to start with a different disease when they begin testing ALGERNON2 in humans anyway. “Alzheimer’s is very competitive,” said Hagiwara. “The cost of the clinical trial is very high, so maybe the first trial should be a genetic disease where the number of patients is very small.” There are a variety of disorders that can initiate neurodegeneration, but therapeutics that restore or enhance the function of the brain’s own protective glial cells could become the common ingredient in many treatment strategies.
- Nakano-Kobayashi, A. et al. Prenatal neurogenesis induction therapy normalizes brain structure and function in Down syndrome mice. PNAS 114, 10268-10273 (2017).
- Nakano-Kobayashi, A. et al. Therapeutics potentiating microglial p21-Nrf2 axis can rescue neurodegeneration caused by neuroinflammation. Science Advances 6, eabc1328 (2020).
- Nakano-Kobayashi, A. et al. Astrocyte-targeting therapy rescues cognitive impairment caused by neuroinflammation via the Nrf2 pathway. PNAS 120, e2303809120 (2023).
- Escartin, C. et al. Reactive astrocyte nomenclature, definitions, and future directions. Nature Neuroscience 24, 312-325 (2021).
- Liddelow, S. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481-487 (2017).