Researchers uncover key mechanism linking cellular stress to Alzheimer’s progression
Researchers at New York-based Advanced Science Research Center of the CUNY Graduate Center (CUNY ASRC) have identified a crucial mechanism that connects cellular stress in the brain to the progression of Alzheimer’s disease (AD). The study, published in Neuron, describes microglia—the brain’s primary immune cells—as pivotal players in both protective and harmful responses related to AD.
Microglia, often described as the brain’s first responders, have emerged as key contributors to Alzheimer’s pathology. While some microglial populations support brain health, others intensify neurodegeneration. Understanding these functional differences has been a major focus for the study’s principal investigator, Pinar Ayata, a professor at the CUNY ASRC Neuroscience Initiative and the CUNY Graduate Center’s Biology and Biochemistry programs.
According to Ayata, the research aimed to identify the harmful microglia associated with Alzheimer’s disease and explore therapeutic approaches to target them. The team discovered a previously unknown neurodegenerative microglial phenotype driven by a stress-related signaling pathway known as the integrated stress response (ISR).
This stress pathway triggers microglia to produce and release toxic lipids, which harm neurons and oligodendrocyte progenitor cells—two cell types critical for brain function and particularly vulnerable in Alzheimer’s. The study revealed that blocking either the ISR or the lipid synthesis pathway reversed Alzheimer’s symptoms in preclinical models.
Using electron microscopy, researchers identified an increased accumulation of “dark microglia,” a subset associated with cellular stress and neurodegeneration, in postmortem brain tissues from Alzheimer’s patients. These dark microglia were found at twice the levels observed in healthy-aged individuals. The study further demonstrated that the ISR pathway drives the production of harmful lipids, which contribute to synapse loss—a defining characteristic of Alzheimer’s disease.
In preclinical mouse models, inhibiting the ISR pathway or lipid synthesis prevented synapse loss and reduced the accumulation of neurodegenerative tau proteins. These findings suggest that targeting this pathway could provide a promising avenue for therapeutic intervention.
Lead author Anna Flury, a Ph.D. student in Ayata’s lab, explained that the study reveals a critical link between cellular stress and the neurotoxic effects of microglia in Alzheimer’s disease. Flury noted that targeting this pathway could lead to treatments that either block the production of toxic lipids or prevent the activation of harmful microglial phenotypes.
The implications for Alzheimer’s patients are significant. Developing drugs that specifically target stress-induced mechanisms in microglia could slow or even reverse disease progression. Co-lead author Leen Aljayousi, another Ph.D. student in Ayata’s lab, emphasized that such treatments could offer hope to millions of patients and their families.
Source: CUNY
Category: Education
