55 million people are reported to be affected by dementia and by 2050 researchers think the figure will reach up to 139 million. Earlier studies have said that protein buildup within the brain might be the main cause of Alzheimer’s since plaques and tangles coalesce in neurons and are linked to brain cell death.
But some research says that the focus has shifted to the role of lipid droplets within the brain cells. In a recent study published in Nature, says that there might be a link between lipid droplets and Alzeimer’s risk genes in microglia which are immune cells in the brain. The gene most strongly correlated with the risk is the APOE gene.
APOE is usually associated with lipid processing and in people with Alzheimer’s where the gene’s activity is ramped up. This increased activity causes lipid droplets to build up within cells. They measured gene expression within single cells to understand which genres were’ turned on’. It was seen that ACSL 1, a key regulator of lipid droplet formation is one of the most upregulated genes in microglia.
The researchers also used a staining method to see where in the brain these lipid droplet cells were situated. It was found that these lipid-containing cells are clustered around protein plaques. This means that plaques do play an important role in lipid accumulation. To ensure the theory was correct scientists treated microglia with amyloid fibrils, a component of protein plaques linked with Alzheimer’s. It was analyzed that there was a strong increase in lipid droplet accumulation which is particularly pronounced in the presence of APOE 4.
While lipid formation in microglia is a good finding, it’s not a new finding for scientists. The same reaction occurs outside the brain when immune cells encounter bacteria. They think that a similar state is being triggered in these immune cells of the brain in response to plaques which lead to lipid accumulation and pro-inflammatory damaging state of the cells.
It can be said that lipid metabolism is important in Alzheimer’s pathology. Since 50% of the brain is composed of lipids and over 20 years of analysis, there have been substantial changes within lipid pathways, the finding is not surprising. Some conclude that damaging reactive oxygen species initially build because of mitochondrial issues in neurons. These trigger the production of lipids.
Then the toxic pre-oxidized lipids are transported via APOE in the form of lipid droplets in glial cells. The same lipid droplets then promote a breakdown of pre-oxidized lipids which protects neurons from damage. Scientists say that one of the main challenges in designing drugs to target lipid or Alzheimer’s risk genes is that the lipid-related proteins have important roles outside the brain in processes that should not be disturbed. In other words, another way to target lipid accumulation needs to be found because that will cause another range of difficulties. The important aspect of this study is that the finding might open doors to personalized treatment based on genetics, dietary and other lifestyle factors when designing drugs.
Journal reference – Haney, M. S., Pálovics, R., Munson, C. N., Long, C., Johansson, P. K., Yip, O., … Wyss-Coray, T. (2024). APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia.
Retrieved from https://www.nature.com/articles/s41586-024-07185-7
