Mice enter their twilight years at around two years of age, which is roughly equivalent to 80 years in humans. When scientists introduce specific mutated genes into mice and age them over time, the mice become forgetful and irritable, eventually displaying the same symptoms of Alzheimer's disease that many older adults experience.
Now, a new study shows that as Alzheimer's disease takes hold in mice and humans, the brain's immune cells, microglia, gradually shrink. A key genetic variant associated with Alzheimer's disease, APOE4, may mediate these changes. Relevant research results were published in the journal Immunity, and the paper is titled "An exhausted-like microglial population accumulates in aged and APOE4 genotype Alzheimer's brains."
Professor Sohail Tavazoie, co-corresponding author of the paper, said, "Immune cells in the brains of old mice and those carrying APOE4 gene variants are exhausted. We also found a similar phenomenon in the human data set." The researchers call this new type of exhausted immune cell terminally inflammatory microglia (TIM). TIMs have lost their ability to effectively clear plaque from the brain and therefore may contribute to Alzheimer's disease.
The new study also reveals how the Alzheimer's drug aducanumab interacts with immune cells in the brain. "When mice carrying the APOE4 gene variant were treated with aducanumab, we found that their TIMs restored some function," said Alon Millet, co-first author of the paper and a graduate student researcher in the Tavazoie lab.
Age and Inflammation
Humans carry one of three APOE gene variants: APOE2, APOE3, and APOE4. Previous research from Tavazoie's lab has shown that these variants play a key role in how the body responds to diseases ranging from cancer to COVID-19. But the link between Alzheimer's disease and APOE4 is particularly clear: Carriers of the APOE4 variant make up about 20 percent of the population and are considered one of the strongest genetic risk factors for Alzheimer's disease.
Tavazoie, Millet and Jose Ledo spent four years developing mouse models of Alzheimer's disease that expressed human APOE variants and then aging them to better understand how APOE4 affects their brains as Alzheimer's disease develops. "Systematically breeding these mice is a major undertaking," Tavazoie said. "This is an ongoing project made possible by the special expertise of Ledo and Millet."
The researchers then constructed a single-cell atlas of immune cells in the brains of these mice and identified a population of microglia that was imbued with signs of stress and inflammation that had never been described before.
The brains of mice carrying APOE4 gene variants were overpopulated with TIMs, while those of mice carrying other APOE gene variants had relatively few TIMs. Once they knew what to look for, researchers also began to find TIMs in human brain tissue donated by patients carrying APOE4 gene variants. Their findings suggest that APOE4 may wear down immune cells in the brain, increasing the risk of Alzheimer's disease.
Figure 1. Age and APOE4 enrich for TIM, microglia co-expressing stress and inflammatory markers. (Millet A, et al., 2023.)
The researchers also found that treating mice with the recently approved Alzheimer's drug aducanumab improved their condition and restored damaged TIMs. Interestingly, the drug was more effective in mice carrying a variant of the APOE4 gene. "While these preliminary findings are not immediately applicable to the clinic, this may be the first hint that aducanumab works differently in different genotypes," Millet said.
Help the immune system help itself
Some scientists speculate that a healthy immune system removes plaque before it accumulates in the brain, and that Alzheimer's disease occurs when the immune system fails and plaque builds up. According to this theory, getting exhausted microglia back to work might give the brain the boost it needs to protect itself. If so, TIM would be a promising therapeutic target.
"TIMs sit in this inflammatory environment for years until they can't handle it anymore," Millet said. "If we can get them back to a healthy state, maybe the immune system can keep Alzheimer's disease under control."
In this regard, researchers will now explore the signaling molecules that lead to the formation of TIMs, with a view to developing drugs that interfere with this process, keeping microglia healthy and reducing cognitive decline. In the long term, this could lead to a new type of Alzheimer's disease treatment.
The researchers will also study whether TIM is present in other diseases. Millet speculates that while TIMs may have escaped attention so far, these exhausted immune cells may also be implicated in other brain diseases, from tumors to Parkinson's disease. "Inflammation causes TIM accumulation, so perhaps what we are seeing is not specific to Alzheimer's disease," he said. "If we give them enough time, most microglia may eventually become TIMs."
Reference
Millet A, Ledo J H, Tavazoie S F. An exhausted-like microglial population accumulates in aged and APOE4 genotype Alzheimer's brains. Immunity, 2023.