Role of fat droplet protein in Alzheimer’s disease

Researchers from UNC School of Medicine, Sarah Cohen, PhD, and former PhD student Ian Windham, made a development about apolipoprotein E (APOE), a major genetic risk factor for late-onset Alzheimer’s disease. 

Inheriting the APOE4 genetic variant from parents increases the risk of Alzheimer’s two to three times. Understanding how APOE4 affects brain cells could lead to better treatments targeting the underlying mechanisms of the disease.

Cohen and Windham executed a detailed five-year study for better understanding and visualization between APOE4, Alzheimer’s Disease, and fat molecules called lipids in the brain.

Cohen, assistant professor of cell biology and physiology and senior author of the paper published in the Journal of Cell Biology, said, “We discovered that brain cells known as astrocytes are more vulnerable to damage and may even go dysfunctional when APOE4 surrounds their lipid storage centers. This mechanism could explain why exactly APOE4 increases one’s risk of Alzheimer’s on the cellular level.”

The brain’s 60% lipid composition is vital for energy storage and myelin. Astrocytes remove toxic lipids and prevent their buildup in the brain. If astrocytes suffer damage or dysfunction, they’re unable to fulfill their cleaning role. Consequently, microglia and other brain cells are unable to clear amyloid beta plaques, contributing to Alzheimer’s.

APOE, made by astrocytes, acts as a transport system for lipids in the brain. Windham and Cohen wanted to observe how lipids behave in astrocytes. Using fluorescent tagging, they tracked APOE’s movements inside living cells. 

When they fed astrocytes oleic acid, they saw APOE4 rush to lipid droplets, altering their size and shape. This revealed that APOE4 can stay within astrocytes, affecting their function and possibly hindering microglia’s ability to clear amyloid beta.

Further research is necessary to understand the details. Cohen aims for their findings to highlight the significance of lipid droplets in Alzheimer’s and other neurodegenerative diseases. Cohen highlights that Alois Alzheimer identified three critical features of neurodegenerative diseases: amyloid beta plaques, tau tangles, and lipid accumulations. While the first two receive much focus, the role of lipids is gaining attention, particularly with APOE being a major genetic risk factor.

The findings of this study underscore the importance of further exploring the relationship between protein accumulation on fat droplets and late-onset Alzheimer’s disease. Understanding this association could lead to novel therapeutic strategies for combating LOAD.

Journal reference:

1. Ian A. Windham, Alex E. Powers et al., APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size. Journal of Cell Biology. DOI: 10.1083/jcb.202305003.