NEW YORK, NY, December 23, 2024 — Researchers with the 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.
Electron micrographs show typical microglia in
the prefrontal cortex of a 92-year-old healthy female (left) and dark microglia
a 91-year-old female patient with Alzheimer’s disease (right).
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.
Source: New Research Identifies Key Cellular Mechanism Driving Alzheimer’s Disease – Scents of Science
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