In a healthy brain, immune cells called microglia patrol the area looking for damage, clearing away debris and harmful proteins. But in the presence of the APOE4 protein – the main genetic risk factor for Alzheimer’s disease – the same cells cause damaging inflammation and clumps of misfolded proteins, according to a new study by scientists at Gladstone Institutes.
The team created a new research model for studying Alzheimer’s disease, transplanting human neurons that produce the APOE4 protein into the brains of mice.
When they removed microglia from the brain, they found that the APOE4 protein no longer caused as many deposits of amyloid or tau; two types of misfolded proteins that are characteristic of Alzheimer’s disease.
“The study underlines the importance of microglia, in combination with APOE4 produced by human neurons, in Alzheimer’s disease,” said Gladstone Senior Investigator Yadong Huang, MD, PhD, who oversaw the new study published in Cell Stem cell. “Our findings suggest that drugs that reduce microglia may ultimately be useful in treating the disease.”
A humanoid model
There are three major forms of APOE protein in humans. Compared to the most common version of the protein APOE3, the APOE4 protein increases the risk and APOE2 decreases the risk of Alzheimer’s disease.
About one in four Americans has at least one copy of the APOE4 gene, and about 3 percent have two copies, making these individuals particularly susceptible to the disease.
“People with two copies of the APOE4 gene have a 12 times greater risk of developing Alzheimer’s disease than people with APOE3,” said Huang, who is also director of the Center for Translational Advancement at Gladstone and professor in the departments of Neurology and Neurology. Pathology at UC San Francisco.
To study the complex interplay between APOE variants and brain cells, Huang and his team have long relied on mouse models, just as many other research groups do. However, imitating the human brain in a mouse is difficult; adding human genes for APOE4 to mice, as is often done, does not fully reflect how human brain cells behave in Alzheimer’s disease.
In the new study, Huang’s team developed a ‘chimeric’ mouse model that not only carries human APOE genes, but also contains human neurons that are transplanted into the brain. Importantly, the neurons are transplanted after the brain matures, allowing the researchers to mimic Alzheimer’s disease later in life.
Previous attempts to establish a mouse model expressing the hallmarks of late-onset Alzheimer’s disease have been unsuccessful when they used the APOE4 protein alone, without transplanted human neurons.
“Creating this mouse model gave us a much more realistic way to study how human neurons carrying the APOE4 gene contribute to Alzheimer’s disease in the living brains of older adults,” said Antara Rao, a graduate student in the lab van Huang who led the experiments for the new study.
Huang and his colleagues already knew that APOE4 leads to higher-than-usual levels of amyloid plaques and tau tangles in human brains. In the new chimeric mouse model, the researchers confirmed that the presence of human APOE4 neurons leads to high levels of both amyloid and tau deposits as the mice aged.
They also showed that human APOE3 neurons lead to moderate levels of the aggregates, and human neurons lacking the APOE gene resulted in fewer tau aggregates and scattered amyloid deposits rather than dense, damaging aggregates.
It turns out that more accurately modeling Alzheimer’s disease requires human neurons, rather than mouse neurons, that produce APOE4 in mouse brains.”
Yadong Huang, MD, PhD, Gladstone senior investigator
Protective effect by reducing microglia
Huang’s group previously discovered that mouse neurons that produce human APOE4 release molecular signals that activate microglia. This time they used the new mouse model to investigate in more detail the connection between microglia and human neurons that produce APOE4.
The researchers used a drug to selectively remove microglia from the brains of the chimeric mice. In mice with human APOE4 neurons, they found that levels of amyloid and tau aggregates were significantly reduced, suggesting that APOE4 and microglia work together to drive key features of Alzheimer’s disease.
The team then turned to single-cell RNA sequencing – a powerful technique for studying gene activity in individual cells – to determine which genes were activated in the microglia of each mouse model.
They found that in the presence of human neurons containing APOE4 and APOE3, the levels of inflammatory molecules in microglia increased. Microglia with the most inflammatory molecular signatures made up 30 percent of all microglia in mice with human APOE4 neurons, 20 percent of all microglia in mice with human APOE3 neurons, and only 8 percent of all microglia in mice with human neurons lacking the APOE gene. .
“Together, these results suggest that microglia are activated by APOE4 produced by human neurons and in turn may help form the misfolded protein aggregates seen in Alzheimer’s disease,” says Rao.
A path to new treatments
The findings give researchers new avenues to understand how microglia go awry in Alzheimer’s disease, switching from their normally protective state to a damaging state in the presence of APOE4 produced by human neurons.
The study also suggests that drugs that can reduce the levels of APOE4 in neurons or target microglia – either by reducing the number of microglia or their level of inflammatory activity – could be a promising strategy for slowing or preventing the progression of Alzheimer’s disease in people with Alzheimer’s disease. APOE4 gene.
Still, more work is needed to demonstrate whether these potential strategies would be effective in humans, what the side effects of targeting neuronal APOE4 or microglia would be, and how the timing of such treatment would work.
The researchers also hope to use their new chimeric mouse to study the role of other cell types in Alzheimer’s disease.
“Our new mouse model, together with these initial results, provides a path forward toward a better understanding of Alzheimer’s disease, especially in the context of APOE4, and toward the development of new drugs that can treat the disease,” says Huang.
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Magazine reference:
Rao, A., et al. (2024). Depletion of microglia reduces human neuronal APOE4-related pathologies in a chimeric Alzheimer’s disease model. Cell Stem cell. doi.org/10.1016/j.stem.2024.10.005.