New research uncovers a key cellular mechanism driving Alzheimer’s disease, offering potential insights for future treatments and a deeper understanding of the condition.
Researchers have revealed a crucial mechanism connecting cellular stress in the brain to Alzheimer’s disease (AD) progression. Published in Neuron, the study emphasizes microglia, the brain’s primary immune cells, as key players in both the protective and harmful responses linked to the disease. ()
Microglia: Brain’s Double-Edged Sword in Alzheimer’s
Microglia, often dubbed the brain’s first responders, are now recognized as a significant 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 focus for Pinar Ayata, the study’s principal investigator and a professor with the CUNY ASRC Neuroscience Initiative and the CUNY Graduate Center’s Biology and Biochemistry programs.
“We set out to answer what are the harmful microglia in Alzheimer’s disease and how can we therapeutically target them,” said Ayata. “We pinpointed 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), prompts microglia to produce and release toxic lipids. These lipids damage neurons and oligodendrocyte progenitor cells—two cell types essential for brain function and most impacted in Alzheimer’s disease. Blocking this stress response or the lipid synthesis pathway reversed symptoms of Alzheimer’s disease in preclinical models.
Key Findings
- Dark Microglia and Alzheimer’s Disease: 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 from Alzheimer’s patients. These cells were present at twice the levels seen in healthy-aged individuals.
- Toxic Lipid Secretion: 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, inhibiting ISR activation or lipid synthesis prevented synapse loss and accumulation of neurodegenerative tau proteins, offering a promising pathway for therapeutic intervention.
“Targeting this pathway may open up new avenues for treatment by either halting the toxic lipid production or preventing the activation of harmful microglial phenotypes,” said 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.
Reference:
- A neurodegenerative cellular stress response linked to dark microglia and toxic lipid secretion – (https://www.cell.com/neuron/abstract/S0896-6273(24)00875-4)
Source-Eurekalert
