Researchers have discovered evidence that fat deposition in brain cells may be the underlying cause of Alzheimer’s. Fat droplets seem to accumulate in brain immune cells as the major genetic risk factor for Alzheimer’s, suggesting an as-yet-unrecognized potential cause of the condition.
Alzheimer’s, which is characterized by neurodegeneration and progressive loss of mental skills, remains shrouded in mystery. The precise mechanisms of the disease remain unknown despite years of investigation. However, a recent study adds a new piece to the puzzle.
The accumulation of proteins in neurons has been the primary focus of research for the past few decades as the cause of Alzheimer’s. The formation of “plaques” and “tangles” in neurons is associated with the death of brain cells. Although scientists have recently developed drugs to remove these proteins, they are not the miracle cure that many people anticipated [1].
The function of lipid droplets in brain cells has drawn more attention lately. A team of neurologists, stem cell specialists, and molecular biologists from various American universities, under the direction of the Stanford University School of Medicine, have discovered evidence that suggests brain cell fat accumulation to be the underlying cause of Alzheimer’s. The journal Nature published the study [2].
The Link Between Alzheimer’s Risk Genes and Fat Droplets in the Brain
A recent study investigated the relationship between lipid droplets in microglia, the brain’s immune cells, and Alzheimer’s risk genes. The APOE gene has the strongest correlation with risk.
APOE plays a role in lipid processing, and in Alzheimer’s patients, the gene’s activity in microglia increases [3]. The cells accumulate lipid droplets as a result of APOE’s enhanced activity. However, whether this buildup is beneficial, benign, or hazardous has not been established.
The APOE gene exists in four variants, numbered 1–4, and one of them, APOE4, transports the most fat into brain cells, while APOE2 transports the least.
About the New Study
The researchers examined brain tissue from Alzheimer’s patients who passed away and from a control group that did not have the disease to conduct the study. They determined which genes are “turned on” by measuring gene expression within single cells.
The researchers wondered if the APOE variations had varying risks of acquiring Alzheimer’s disease. They carried out a few experiments to find out.
In the first experiment, scientists employed single-cell RNA sequencing to detect proteins within a test nerve cell. They applied their findings to tissue samples taken from patients who died from Alzheimer’s, who had two copies of either APOE4 or APOE3.
They discovered that the APOE4 gene was associated with an increased number of immune cells with a particular kind of enzyme that promoted the uptake of fat droplets into brain cells.
In another experiment, the team used cells from living individuals with either the APOE4 or APOE3 genotype to grow microglia in a dish. They discovered that adding amyloid to the brain cells of individuals, particularly with the APOE4 variant, caused the cells to accumulate fat more readily.
According to the researchers, the findings show that amyloid accumulation in the brain promotes the push of fat into brain cells, resulting in Alzheimer’s.
Potential for New Alzheimer’s Research
When considered collectively, the research raises the prospect of a novel theory about the pathophysiology of lipid droplets in Alzheimer’s disease.
According to Michael Haney, PhD, an assistant professor in the pathology department at the Perelman School of Medicine at the University of Pennsylvania and one of the study’s authors, the team believes that the protein accumulation typical to Alzheimer’s triggers the microglia to go into a pro-inflammatory state, which then causes the synthesis of lipid synthesis enzymes to be upregulated and lipid to accumulate in structures called lipid droplets [4].
Although lipid buildup in microglia is a novel discovery, researchers have observed this phenomenon before. According to Haney, it also happens outside of the brain when immune cells encounter microorganisms.
He added that they believe plaques cause a similar reaction in these brain immune cells, which causes lipid buildup and a pro-inflammatory, hazardous condition for these cells.
Can it be A New Step Towards Novel Alzheimer’s Treatment?
The authors of the current study believe that focusing on the role of fat accumulation will lead to novel approaches to treating Alzheimer’s in the future. Nevertheless, challenges prevail.
According to Haney, lipids and lipid-related proteins have significant functions outside the brain in processes you don’t want to interfere with, which makes it challenging to formulate drugs to target these lipids or the Alzheimer’s risk genes that transport lipids.
Put another way, he explained, they must figure out how to specifically target lipid buildup rather than lipids in general since doing so would lead to several additional issues.
However, Haney is optimistic as he believes this could be achievable with a deeper comprehension of how this accumulation particularly happens in microglia and what toxic substances they might be secreting.
Haney intends to carry on this line of work. He plans to conduct additional research to characterize the variety of illnesses in which microglia develop lipid droplets, how they build up these lipids, and how they may potentially damage neighboring neurons.
References
- Manly, J.J. and Deters, K.D., 2023. Donanemab for Alzheimer disease—who benefits and who is harmed?. JAMA.
- Haney, M.S., Pálovics, R., Munson, C.N., Long, C., Johansson, P.K., Yip, O., Dong, W., Rawat, E., West, E., Schlachetzki, J.C. and Tsai, A., 2024. APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia. Nature, pp.1-8.
- Victor, M.B., Leary, N., Luna, X., Meharena, H.S., Scannail, A.N., Bozzelli, P.L., Samaan, G., Murdock, M.H., von Maydell, D., Effenberger, A.H. and Cerit, O., 2022. Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity. Cell Stem Cell, 29(8), pp.1197-1212.
- Newman, T. Alzheimer’s may be caused by a build-up of fat in brain cells. Medical News Today. https://www.medicalnewstoday.com/articles/alzheimers-may-be-caused-by-a-build-up-of-fat-in-brain-cells. Published Online: 21st March, 2024. Accessed: 4th April, 2024.
- Wilson, C. Alzheimer’s may be caused by a build-up of fat in brain cells. New Scientist. https://www.newscientist.com/article/2422090-alzheimers-may-be-caused-by-a-build-up-of-fat-in-brain-cells/. Published Online: 13th March, 2024. Accessed: 4th April, 2024.
- Yirka, B. Root cause of Alzheimer’s may be fat buildup in brain cells, research suggests. Medical Xpress. https://medicalxpress.com/news/2024-03-root-alzheimer-fat-buildup-brain.html. Published Online: 19th March, 2024. Accessed: 4th April, 2024.
