A team of researchers from the Advanced Science Research Center at the CUNY Graduate Center has made notable progress in unraveling the connection between cellular stress in the brain and the progression of Alzheimer’s disease (AD).
Their recent work, featured in the journal Neuron, underscores the complex role of microglia—those indispensable immune cells of the brain—acting as both defenders and, paradoxically, as contributors to the disease’s advancement.
Microglial Functions in Alzheimer’s Pathology
Microglia have long been recognized as the brain’s first line of defense, but more recent insights reveal their double-edged nature in Alzheimer’s pathology.
While certain microglial cells support brain health, others can actually worsen neurodegeneration.
Leading the charge in this investigation is Professor Pinar Ayata, whose research focuses on the contrasting functions of different microglial populations within the CUNY ASRC Neuroscience Initiative.
Ayata and her team set out to pinpoint the specific microglia that play a harmful role in Alzheimer’s while also exploring therapeutic options to combat their detrimental effects.
In the course of their studies, they identified a previously unknown microglial subtype closely associated with Alzheimer’s, characterized by the activation of a stress-related signaling pathway.
Research Findings
A key finding of their research highlighted the integrated stress response (ISR), a pathway that triggers microglia to produce and release harmful lipids.
These lipids can inflict damage on neurons and oligodendrocyte progenitor cells—both of which are crucial for healthy brain function and significantly compromised in Alzheimer’s disease.
In a promising turn of events, the researchers discovered that inhibiting this stress response or lipid production in preclinical models led to a noticeable reversal of Alzheimer’s symptoms.
- Rise of Dark Microglia: Utilizing electron microscopy, the research team found a striking increase in “dark microglia,” a cell type linked with cellular stress and neurodegeneration.
Notably, these were present at levels twice as high in the brains of Alzheimer’s patients compared to those of healthy elderly individuals.
- Release of Toxic Lipids: The study revealed that activation of the ISR pathway prompts microglia to synthesize and release toxic lipids, resulting in synapse loss, a hallmark of Alzheimer’s disease.
- Potential for Therapeutics: Experiments conducted on mouse models demonstrated that blocking ISR activation or lipid synthesis could prevent synapse loss and the accumulation of neurodegenerative tau proteins, opening up potential new avenues for treatment.
Implications for Alzheimer’s Care
These findings pave the way for developing treatments that could specifically target certain microglial populations or their stress-induced functions.
Co-lead author Leen Aljayousi pointed out that such tailored interventions might significantly slow down or even reverse the trajectory of Alzheimer’s disease, offering new hope to countless patients and their families.
Ultimately, this research represents a significant leap forward in understanding the cellular mechanisms at play in Alzheimer’s, illuminating the vital importance of keeping microglial health in check to support optimal brain function.
Source: ScienceDaily