Microglia are the primary immunological cells in the brain. They control injury repair, neural network maintenance, and brain development. In Alzheimer’s dementia (AD), they are also a prominent incidental cell type.
However, the question of how microglia leads to neurodegeneration remains unresolved. A new study by researchers at the Advanced Science Research Center at the CUNY Graduate Center (CUNY ASRC) has unveiled how cellular stress in the brain is associated with the progression of Alzheimer’s disease (AD).
The study found that microglia are responsible for both the protective and harmful responses associated with the disease.
The role of microglia is double-edged: some protect brain health, while others worsen neurodegeneration. Understanding the functional differences between these two is a key focus of this research.
Researchers are keen to determine the harmful microglia in Alzheimer’s disease and how to target them therapeutically. They identified a novel neurodegenerative microglia phenotype in Alzheimer’s disease characterized by a stress-related signaling pathway called the integrated stress response (ISR).
Activation of ISR causes microglia to generate and release toxic lipids. These lipids harm neurons and oligodendrocyte progenitor cells—two cell types essential for brain function and most impacted by Alzheimer’s disease. They also cause synapse loss, a hallmark of Alzheimer’s disease.
In preclinical models, Alzheimer’s disease symptoms were reversed by blocking the lipid production pathway or this stress response.
The team used electron microscopy to identify an accumulation of “dark microglia,” a subset of microglia associated with cellular stress and neurodegeneration, in postmortem brain tissues from Alzheimer’s patients.
In studies with mice, ISR activations or lipid synthesis prevented synapse loss and accumulation of neurodegenerative tau proteins, offering a promising pathway for therapeutic intervention.
The study’s co-lead author, Anna Flury, a member of Ayata’s lab and a Ph.D. student with the CUNY Graduate Center’s Biology Program, said, “These findings reveal a critical link between cellular stress and the neurotoxic effects of microglia in Alzheimer’s disease. Targeting this pathway may open new avenues for treatment by either halting the toxic lipid production or preventing the activation of harmful microglial phenotypes.”
Co-lead author Leen Aljayousi, a member of Ayata’s lab and a Ph.D. student in the CUNY Graduate Center’s Biology Program, said, “This research underscores the potential of developing drugs that target specific microglial populations or their stress-induced mechanisms. Such treatments could significantly slow or even reverse the progression of Alzheimer’s disease, offering hope to millions of patients and their families.”
Journal Reference:
- Anna Flury, Leen Aljayousi, et al. A neurodegenerative cellular stress response linked to dark microglia and toxic lipid secretion. Neuron. DOI: 10.1016/j.neuron.2024.11.018
