By Stephen Beech
Scientists investigating Alzheimer’s disease have made a key breakthrough.
They have identified a vital cellular mechanism driving the most common cause of dementia.
American researchers say the breakthrough marks a “promising” target for drug treatments that slow, or possibly even reverse, the disease’s development.
A team from the Advanced Science Research Center at The City University of New York (CUNY ASRC) discovered the critical mechanism that links cellular stress in the brain to the progression of Alzheimer’s.
The study, published in the journal Neuron, highlights microglia – the brain’s primary immune cells – as central players in both the protective and harmful responses associated with the disease.
Microglia – often dubbed the brain’s “first responders” – are now recognized as a significant causal cell type in Alzheimer’s pathology.
However, the 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 Professor Pinar Ayata, the study’s principal investigator.
Ayata said: “We set out to answer what are the harmful microglia in Alzheimer’s disease and how can we therapeutically target them.
“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.
The lipids damage neurons and oligodendrocyte progenitor cells – two cell types essential for brain function and most impacted in Alzheimer’s disease.
Blocking the stress response or the lipid synthesis pathway reversed symptoms of Alzheimer’s in preclinical models.
Using electron microscopy, the research team identified an accumulation of “dark microglia” – a subset of microglia associated with cellular stress and neurodegeneration, in postmortem brain tissues from Alzheimer’s patients.
The cells were present at twice the levels seen in healthy-aged people.
Study co-lead author Anna Flury said: “These findings reveal a critical link between cellular stress and the neurotoxic effects of microglia in Alzheimer’s disease.”
Flury, a member of Ayata’s lab and a Ph.D. student, added: “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.”
The research team says their study highlights the potential of developing drugs that target specific microglial populations or their stress-induced mechanisms.
Co-lead author Leen Aljayousi, a member of Ayata’s lab, added: “Such treatments could significantly slow or even reverse the progression of Alzheimer’s disease, offering hope to millions of patients and their families,”
