Approximately 25% of individuals carry the APOE4 gene variant, which significantly raises their risk of developing Alzheimer’s disease.
While scientists have long known that APOE4 contributes to brain changes associated with dementia, the precise mechanism behind this effect has remained unclear.
However, researchers at Gladstone Institutes have made a groundbreaking discovery: neurons producing APOE4 release a signaling molecule called HMGB1 at significantly higher rates than neurons with other APOE variants.
When HMGB1 is released, it activates immune cells in the brain called microglia, setting off a chain reaction of inflammation and neuron degeneration.
The Study and Its Findings
In their study, published in Cell Reports, the researchers examined the relationship between APOE4 and neurodegeneration. They used mouse models carrying APOE4 and other factors linked to dementia.
By blocking the release of HMGB1 using a combination of experimental drugs, the researchers observed that microglial activation and neurodegeneration in these mice significantly decreased.
Lead author Dr. Yadong Huang, who is also a professor of neurology and pathology at the University of California, San Francisco, expressed excitement about the findings, stating that “targeting this pathway leads to such strong protection against APOE4-driven neurodegeneration.”
This discovery not only sheds light on the role of APOE4-induced neuroinflammation in Alzheimer’s disease but also opens up new avenues for treatment.
Addressing the “Chicken or Egg” Question
The study sought to answer a long-standing question in Alzheimer’s research: does neurodegeneration precede inflammation or vice versa? By focusing on APOE4 and its impact, the researchers provided insight into this question.
APOE4 is one of three versions of the APOE gene, and individuals with this variant are significantly more likely to develop Alzheimer’s disease.
The researchers honed in on neurons with the APOE4 variant to investigate whether they produced signaling molecules capable of activating microglia.
They identified HMGB1, an immune molecule known for triggering strong inflammatory responses.
Key Findings
Neurons with APOE4 produced higher levels of HMGB1 when exposed to stress compared to neurons with other APOE variants.
Removing APOE4 from neurons prevented the release of HMGB1, confirming the link between APOE4 and HMGB1 release.
Blocking the release of HMGB1 using experimental drugs reduced microglial activation and neurodegeneration in mouse models with APOE4.
Implications and Future Research
This discovery points to a potential new drug target for Alzheimer’s disease.
Experimental drugs that block HMGB1 release, which have already undergone clinical trials for other conditions, could be explored for their efficacy in preventing or treating APOE4-related Alzheimer’s disease.
Dr. Huang and his team are continuing their research to explore additional ways to target HMGB1, its release from neurons, and its impact on microglia.
As research advances in this field, there is hope that innovative treatments for Alzheimer’s disease may emerge, providing hope for individuals at increased risk due to the APOE4 gene variant.
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The research findings can be found in Cell Reports.
