Your immune system could be the cause of memory loss
Research shows that the brain reacts to Alzheimer’s disease as if it were an infection, opening a new avenue for preventing cognitive decline
Your immune system is your body’s guard against illness. So, when it’s activated, you’re being shielded from disease, right? Well, not always.
Recent findings from the Gan Lab at Cornell University reveal that tau, a hallmark of Alzheimer’s disease, triggers a response in microglia, the brain’s immune cells. But instead of protecting the brain, this immune response appears to reduce cognitive resilience — the ability to maintain cognitive health and functioning.
The study used mice to show that tau causes the release of mitochondrial DNA in the brain. An enzyme called cGAS[1] detects this stray DNA as a sign of damage and slams the emergency button, triggering a response similar to an antiviral reaction. This leads to a decrease in MEF2C[2], a protein crucial for neurons to maintain healthy communication and form new connections. In other words, the immune response damages our ability to learn and remember things, even before symptoms of Alzheimer’s disease become apparent.
A previous study by MIT Professor Li-Huei Tsai’s lab identified MEF2C as a key player in cognitive resilience. It was also known that microglia were involved in the development of Alzheimer’s disease. However, according to YiGe Huang, graduate student and co-first author of the recent paper, this study connected the two and established a “crosstalk between microglia and neurons”.
This is a surprising find, as cGAS was typically considered a defense pathway and not thought to contribute to brain pathology. Cynthia Leifer, an immunology professor at Cornell University, who was not involved in the study, commented that it reveals “an exciting and potential important new role” for the cGAS pathway.
The research team believes that the findings point to a novel therapeutic target: the DNA sensor cGAS. When cGAS was inhibited or “knocked out” to completely block its function, the mice performed better on their learning and memory tests, coinciding with normal levels of MEF2C and other factors that affect cognitive ability. What’s unique and powerful about this approach is that it does not depend on the amount of tau protein in the brain, which is the focus of many pharmaceutical research endeavors. Rather than attempting to decrease the amount of tau protein in the brain, Huang states that inhibiting cGAS “circumvents that pathway” and directly addresses the key concern: preserving neuronal function and memory.
Inhibiting cGAS, however, raises a concern that circles back to its primary function: to activate an immune response. Huang notes that there is a possibility that if cGAS is prevented from detecting stray DNA, thebrain might be more susceptible to infection. While a valid consideration, Huang notes that mice lacking this defense mechanism were healthy, which Leifer argues may be due to backup mechanisms that kick in to protect the host.
Even so, further investigation is necessary to confirm the findings of the study and translate it to human Alzheimer’s disease. For Leifer, it will take a set of “detailed and robust mechanistic studies” to clearly connect that MEF2C is the primary cause of this immune-related cognitive decline.
1 cyclic cGMP-AMP synthase
2 myocyte-specific enhancer factor 2C