An important discovery in Alzheimer’s disease reveals the cellular mechanism linked to stress that causes the illness.

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By discovering a crucial molecular mechanism behind the most prevalent form of dementia, researchers studying Alzheimer’s disease have achieved a significant advancement.

The City University of New York (CUNY) research offers a promising target for pharmacological therapy that may be able to delay or even reverse the progression of the disease.

The study, which was published in the journal Neuron, emphasizes the importance of microglia, the main immune cells in the brain, and their connection to cellular stress in the brain, including both the protective and detrimental reactions linked to Alzheimer’s disease.

Often referred to as the brain’s first responders, microglia are now understood to be a key causative cell type in the pathophysiology of Alzheimer’s. These cells, however, have a dual function; some preserve brain function, while others exacerbate neurodegeneration.

According to Pinar Ayata, the study’s primary investigator and a professor of CUNY’s Advanced Science Research Center’s neuroscience initiative, “We set out to answer what are the harmful microglia in Alzheimer’s disease and how can we therapeutically target them.”

His group identified a stress-related signaling pathway as the hallmark of a “novel neurodegenerative microglia phenotype” in Alzheimer’s disease.

Microglia generate and release toxic lipids when this stress pathway, sometimes referred to as the integrated stress response (ISR), is activated. Neurons and oligodendrocyte progenitor cells, two cell types crucial to brain function and most affected in Alzheimer’s disease, are harmed by these lipids.

In preclinical animals, Alzheimer’s disease symptoms were reversed by blocking the lipid production pathway, or this stress response.

The research team used electron microscopy to find that postmortem brain tissues from Alzheimer’s patients had an abundance of “dark microglia,” a subgroup of microglia linked to cellular stress and neurodegeneration.

The cells were twice as abundant as those found in healthy elderly individuals.

According to study co-lead author Anna Flury, “these findings reveal a critical link between cellular stress and the neurotoxic effects of microglia in Alzheimer’s disease.”

“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,” says Ms. Flury, a Ph.D. student and part of Prof. Ayata’s lab.

The study conducted by the team underscores the possibility of creating medications that target particular microglial populations or the methods by which stress is created in them.

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Co-lead author Leen Aljayousi, a member of Prof. Ayata’s lab, stated, “Such treatments could significantly slow or even reverse the progression of Alzheimer’s disease, offering hope to millions of patients and their families.”