Compiled by Yu Xin
A recent study on Alzheimer's disease suggests that its underlying cause might be linked to the accumulation of lipid droplets in brain cells, offering a novel pathway for treatment.
Michael Haney, the lead author of the study and a researcher at the University of Pennsylvania, suggests that targeting these lipid droplets for treatment might be more effective than current strategies focusing on protein. The study was published in Nature on March 13.
Alzheimer's disease has two commonly proposed causes: one involving the accumulation of amyloid-β protein plaques between nerve cells, and the other implicating tangles formed by tau proteins stored within nerve cells.
The debate over which protein is the main culprit has persisted for decades, with the amyloid-β hypothesis currently prevailing due to moderate success shown by some antibody therapies targeting this protein in slowing memory loss in Alzheimer's patients.
However, Haney points out that this debate overlooks the presence of lipid droplets found in the brains of those who succumb to the disease. In the early 20th century, German doctor Alois Alzheimer first described the disease, noting the presence of amyloid plaques, tau protein tangles, and lipid droplets in the brains of Alzheimer's patients. However, lipids have largely been ignored for decades.
In their latest study, Haney and his team investigated the largest genetic risk factor for Alzheimer's — a gene called APOE, which encodes a protein that aids in the movement of lipids into and out of cells. Different variants of the APOE gene exist in the human body, namely APOE2, APOE3, and APOE4. Among these, APOE2 carries the lowest risk for Alzheimer's, while APOE4 poses the highest risk. However, scientists have been unclear as to why this is the case.
Using single-cell RNA sequencing technology, the team examined which proteins were being produced in individual cells. They analyzed tissue samples from deceased Alzheimer's patients who either had two copies of the APOE4 variant or two copies of the APOE3 variant. The results showed that immune cells in the brains of patients carrying the APOE4 gene variant had higher levels of a certain enzyme, which increased the accumulation of lipid droplets within these cells.
In further experiments, the researchers cultured brain immune cells known as microglia from living cells carrying either the APOE4 or APOE3 mutation. Introducing amyloid-β protein into the cells led to an accumulation of lipids, particularly in cells carrying the APOE4 gene variant.
The research team concluded that the accumulation of amyloid-β protein in brain cells of Alzheimer's patients triggers the accumulation of lipids, which in turn leads to the accumulation of tau protein within neurons, causing cell death and ultimately resulting in symptoms of memory loss and cognitive confusion.
Haney stated that previous studies have identified some genes that increase the risk of Alzheimer's, but their impact is often lower compared to APOE4, and these genes are often related to lipid metabolism or the immune system, further supporting their hypothesis.
Irundika Dias from Aston University in the UK, who was not involved in the study, remarked that previous research suggests that lipid metabolism in other types of brain cells may also play a role. All these findings share a commonality related to lipid metabolism. "This is a very intriguing paper."
Meanwhile, another study indicates that over three-quarters of Alzheimer's cases are associated with harmful APOE gene variants. Dylan Williams and his team from University College London tracked people's health records and recorded the APOE variants they carried. They found that individuals with one or two other variants of the gene, compared to those with two copies of the lowest-risk variant APOE2, were nearly four times more likely to develop Alzheimer's.
Williams suggested that intervening in this molecular pathway could improve the condition of approximately 75% of Alzheimer's patients.
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