Researchers at the CUNY Graduate Center's Advanced Science Research Center (CUNY ASRC) have unveiled a critical mechanism that links cellular stress in the brain to the progression of Alzheimer's disease (AD). The study, published in the journal Neuronehighlights microglia, the brain's primary immune cells, as central players in the protective and harmful responses associated with disease.
Microglia, often considered the first responders of the brain, 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 a research goal for Pinar Ayata, principal investigator of the study and a professor in the CUNY ASRC Neuroscience Initiative and the biology and biochemistry programs at the CUNY Graduate Center.
“We sought to determine what microglia are harmful in Alzheimer's disease and how can we target them therapeutically,” Ayata said. “We identified a new neurodegenerative phenotype of microglia 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), triggers microglia to produce and release toxic lipids. These lipids damage neurons and oligodendrocyte progenitor cells, two types of cells essential to brain function and most affected in Alzheimer's disease. Blocking this stress response or lipid synthesis pathway reversed Alzheimer's disease symptoms in preclinical models.
Main findings
- Dark microglia and Alzheimer'sThe disease of: Using electron microscopy, researchers identified an accumulation of “dark microglia,” a subset of microglia associated with cellular stress and neurodegeneration, in postmortem brain tissue from patients with Alzheimer's disease. These cells were present at levels twice those seen in healthy individuals.
- Toxic lipid secretion: The ISR pathway in microglia has been 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, providing a promising avenue for therapeutic intervention.
“These results 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 with the biology program at the CUNY Graduate Center. “Targeting this pathway could open new treatment avenues 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 for drug development 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 the Alzheimer's laboratory. 'Ayata and a Ph.D. student with the biology program at the CUNY Graduate Center.
The study represents a major step forward in understanding the cellular underpinnings of Alzheimer's disease and highlights the importance of microglial health in maintaining overall brain function.
