New research identifies key cellular mechanism driving Alzheimer’s disease

NEW YORK, NY, December 23, 2024 — Researchers with the Advanced Science Research Center at the CUNY Graduate 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 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, 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.

“These findings reveal a critical link between cellular stress and the neurotoxic effects of microglia in Alzheimer’s disease,” 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. “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.”

Implications for Alzheimer’s Patients
This research underscores the potential of developing drugs that target 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-lead author Leen Aljayousi, a member of Ayata’s lab and a Ph.D. student with the CUNY Graduate Center’s Biology Program.

The study represents a major leap forward in understanding the cellular underpinnings of Alzheimer’s and emphasizes the importance of microglial health in maintaining overall brain function.

About the Advanced Science Research Center at the CUNY Graduate Center
The Advanced Science Research Center at the CUNY Graduate Center (CUNY ASRC) is a world-leading center of scientific excellence that elevates STEM inquiry and education at CUNY and beyond. The CUNY ASRC’s research initiatives span five distinctive, but broadly interconnected disciplines: nanoscience, photonics, neuroscience, structural biology, and environmental sciences. The center promotes a collaborative, interdisciplinary research culture where renowned and emerging scientists advance their discoveries using state-of-the-art equipment and cutting-edge core facilities.

About the Graduate Center of The City University of New York
The CUNY Graduate Center is a leader in public graduate education devoted to enhancing the public good through pioneering research, serious learning, and reasoned debate. The Graduate Center offers ambitious students nearly 50 doctoral and master’s programs of the highest caliber, taught by top faculty from throughout CUNY — the nation’s largest urban public university. Through its nearly 40 centers, institutes, initiatives, and the Advanced Science Research Center, the Graduate Center influences public policy and discourse and shapes innovation. The Graduate Center’s extensive public programs make it a home for culture and conversation.