Study Links Key Cellular Mechanism to Progression of Alzheimer's Disease - Video

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.

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.

This research underscores the potential of developing drugs that target specific microglial populations or their stress-induced mechanisms.

Reference: https://asrc.gc.cuny.edu/headlines/2024/12/new-research-identifies-key-cellular-mechanism-driving-alzheimers-disease/