Researchers at the CUNY Advanced Scientific Research Center (CUNY ASRC) have revealed a critical mechanism linking cellular stress in the brain to the progression of Alzheimer’s disease (AD). The study, published in the journal Neuronhighlights microglia, the brain’s primary immune cells, as central players in both the protective and harmful responses associated with disease.
Microglia, often referred to as the brain’s first responder, are now recognized as an important causal cell type in Alzheimer’s pathology. However, these cells play a double-edged role: some protect brain health, while others worsen neurodegeneration. Understanding the functional differences between these microglial populations has been the research focus of Pinar Ayata, principal investigator of the study and professor of the CUNY ASRC Neuroscience Initiative and the CUNY Graduate Center Biology and Biochemistry programs.
“We set out to answer what the harmful microglia are in Alzheimer’s disease and how we can target them therapeutically,” Ayata said. “We identify a novel neurodegenerative microglia phenotype in Alzheimer’s disease characterized by a stress-related signaling pathway.”
The research team discovered that activation of this stress pathway, known as the integrated stress response (ISR), causes microglia to produce and release toxic lipids. These lipids damage neurons and oligodendrocyte progenitor cells, two types of cells essential for brain function and those most affected in Alzheimer’s disease. Blocking this stress response or lipid synthesis pathway reversed the symptoms of Alzheimer’s disease in preclinical models.
Key findings
- Dark microglia and Alzheimer’sDisease of: Using electron microscopy, the researchers identified an accumulation of “dark microglia,” a subset of microglia associated with cellular stress and neurodegeneration, in postmortem brain tissues of Alzheimer’s patients. These cells were present at levels twice as high as those seen in healthy older people.
- Secretion of toxic lipids: The ISR pathway in microglia was shown to drive the synthesis and release of harmful lipids that contribute to synapse loss, a hallmark of Alzheimer’s disease.
- Therapeutic potential: In mouse models, inhibition of ISR activation or lipid synthesis prevented synapse loss and accumulation of neurodegenerative tau proteins, offering a promising avenue for therapeutic intervention.
“These findings reveal a critical link between cellular stress and the neurotoxic effects of microglia in Alzheimer’s disease,” said study co-senior author Anna Flury, a member of Ayata’s lab and a Ph.D. student in the Biology Program at the CUNY Graduate Center. “Targeting this pathway may open new treatment avenues, either by stopping the production of toxic lipids or preventing the activation of harmful microglial phenotypes.”
Implications for Alzheimer’s patients This research highlights the potential of developing drugs targeting 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,” explained co-senior author Leen Aljayousi, a member of Ayata’s lab and a Ph.D. student in the Biology Program at the CUNY Graduate Center.
The study represents a major advance in understanding the cellular basis of Alzheimer’s and emphasizes the importance of microglial health in maintaining overall brain function.