Study: Alzheimer's Risk Gene Triggers Fuels Cell Inflammation In Brain

New Delhi: A recent study by scientists at the Gladstone Institutes in the US has unveiled critical insights into how the APOE4 protein, a significant genetic risk factor for Alzheimer’s disease, impacts immune cells in the brain. The research, published in Cell Stem Cell, demonstrates that the presence of APOE4 protein in the brain can drive healthy microglia immune cells responsible for maintaining brain health into a state that promotes harmful inflammation and the accumulation of misfolded protein clumps. This finding sheds light on a key pathway by which Alzheimer's disease might progress, especially in individuals carrying the APOE4 gene variant.

Microglia typically play a protective role in the brain, patrolling for damage and clearing away debris, including misfolded proteins. However, the study showed that in the presence of APOE4, these cells shift from their normal protective behavior to one that contributes to inflammation and encourages the formation of amyloid plaques and tau tangles. These protein deposits are hallmarks of Alzheimer's and are associated with the disease's cognitive decline.

To investigate this relationship, the scientists developed a novel "chimeric" mouse model. These mice were genetically modified to carry human APOE genes and received transplants of human neurons that produced the APOE4 protein. This approach allowed the team to mimic the conditions found in late-onset Alzheimer's disease more accurately, as the transplanted neurons were introduced after the mice’s brains had matured.

One of the critical experiments involved removing microglia from the brains of the chimeric mice. The researchers observed that without microglia, the presence of APOE4 protein triggered significantly fewer deposits of amyloid and tau. This finding points to a cooperative role between APOE4 and microglia in promoting the pathological features of Alzheimer's disease.

According to the research team, targeting microglia could be a promising strategy for slowing or preventing the progression of Alzheimer’s in people who carry the APOE4 gene. Reducing the number of microglia or modulating their inflammatory activity might disrupt the harmful cycle triggered by APOE4, thereby mitigating amyloid and tau buildup. Yadong Huang, Senior Investigator at Gladstone, suggested that drugs aimed at reducing microglial activity might eventually prove beneficial for treating Alzheimer’s patients.

The study also highlighted the behavior of human neurons lacking the APOE gene entirely. These neurons showed significantly fewer tau deposits and scattered amyloid plaques, suggesting that the absence of APOE can limit the formation of dense and harmful protein aggregates.

The researchers further examined the impact of inflammatory molecules in microglia. They found that levels of these molecules increased in the presence of human neurons containing APOE4 and, to a lesser extent, APOE3. This indicates that APOE variants can influence the inflammatory response of microglia, contributing to Alzheimer’s pathology.

By advancing the understanding of how APOE4 and microglia interact to promote Alzheimer’s disease, the study paves the way for new therapeutic strategies. The research underscores the potential of targeting the APOE4 protein or modulating microglial function to prevent or slow the progression of the disease, offering hope for more effective treatments in the future.