Scientists investigating Alzheimer’s disease have made a major breakthrough in identifying a key cellular mechanism that causes the most common cause of dementia.
Research from the City University of New York (CUNY) provides a promising target for drug treatments that could slow and reverse the progression of the disease.
The study, published in the journal Neuron, highlights the important link between microglia, the brain’s primary immune cells, and cellular stress in the brain – both protective and detrimental responses associated with Alzheimer’s disease.
Microglia, often referred to as the brain’s first responders, are now recognized as an important causal cell type in Alzheimer’s pathology. But these cells play a double-edged role. Some protect brain health, while others worsen neurodegeneration.
“We are beginning to find answers to the question of what microglia are harmful in Alzheimer’s disease and how we can target them therapeutically,” said lead researcher of the study and CUNY’s Director of Neuroscience within the Center for Advanced Science Research. said Pinar Ayata, professor in charge of the initiative.
His team identified a “novel neurodegenerative microglial phenotype” in Alzheimer’s disease characterized by stress-related signaling pathways.
Activation of this stress pathway, known as the integrated stress response (ISR), induces microglia to produce and release toxic lipids. These lipids are essential for brain function and damage neurons and oligodendrocyte progenitor cells, the two cell types most responsible for Alzheimer’s disease.
Blocking these stress responses or lipid synthesis pathways reversed symptoms of Alzheimer’s disease in preclinical models.
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Using electron microscopy, the team identified an accumulation of “dark microglia,” a subset of microglia associated with cellular stress and neurodegeneration, in postmortem brain tissue from Alzheimer’s patients.
These cells were present at twice the levels seen in healthy older adults.
“These findings reveal an important link between cellular stress and the neurotoxic effects of microglia in Alzheimer’s disease,” said Anna Flury, co-author of the study.
Professor Ayata’s lab member and Ph.D. “Targeting this pathway may open new avenues for treatment by halting toxic lipid production or preventing activation of deleterious microglial phenotypes.”
The team’s work highlights the potential for developing drugs that target specific microglial populations or their stress-inducing mechanisms.
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“These treatments could significantly slow or reverse the progression of Alzheimer’s disease, giving hope to millions of patients and their families,” concluded lead author and co-author Leen Aljayousi of Professor Ayata’s lab.
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