Unsheathing the role of myelin lipids in Alzheimer’s disease

Alzheimer’s disease, or AD, is a devastating neurodegenerative disease that leads to irreversible cognitive decline in older adults. In the early 2000s, Xianlin Han and his colleagues found that patients with early AD had dramatically reduced levels of sulfatides, a class of lipids that forms myelin sheaths in the nervous system. Myelin sheaths insulate nerve fibers, like how rubber insulates electrical cables, and facilitate the quick and efficient signal transduction between nerve cells. Thus, disruption of myelin sheaths can significantly impair information travel along the nervous system. Han and colleagues’ findings highlighted the importance of lipids in AD and suggested a possible role for sulfatides in AD pathogenesis.

Han was this month’s speaker on ASBMB Breakthroughs, a webinar series highlighting research from ASBMB journals. He is the chaired professor of medicine at the Barshop Institute at the University of Texas Health San Antonio and an associate editor of the Journal of Lipid Research. During his talk, sponsored by JLR, Han shared his pioneering work in the field of lipidomics, specifically in the context of AD.

About two decades ago, scientists started to wonder if they could use mass spectrometry, or MS, analysis, to study complex lipid molecules.

“These questions of how lipids function, change and interact with each other, along with the advances in MS technology, led to the emergence of this new discipline called lipidomics,” Han said.

To cement the new field, Han and his colleague, Richard W. Gross, coined the term “lipidomics” in a 2003 paper in JLR. Lipidomics analyzes the structure and quantity of lipids in cells and tissues using MS analysis. It is a subdiscipline of metabolomics, the study of metabolic pathways and their components. Han explained that the unique physical, chemical and biological properties of lipids warranted the establishment of this new field. For example, unlike other metabolites, lipids form aggregates in solutions, so researchers need specific techniques to analyze cellular lipids.

“Lipids are very important, but also very complicated,” Han said.

Han’s team developed multidimensional MS-based shotgun lipidomics, or MDMS–SL, a platform comprised of multiple steps, such as a multiplexed sample preparation, that optimize a sample for accurate identification of and distinction between lipid classes. Using MDMS–SL, Han and others can analyze over 95% of the lipid content in samples, and screen thousands of lipid molecular species with a minimal amount of starting material with over 90% precision. Prior to this technique, the field considered 60% precision acceptable.

Han’s group has applied these techniques to study how lipids change in the context of diseases, such as AD, with the goal of uncovering new drug targets. Since establishing the link between sulfatide loss and AD in the early 2000s, Han and his colleagues have continued to investigate the biological consequences of lipid loss.
“This dramatic loss of sulfatide really stood out to us, so we were very interested in learning whether it’s truly connected to the onset of AD,” Han said.

Sulfatides are synthesized by the enzyme cerebroside sulfotransferase, or CST, so Han’s team genetically manipulated mice to disrupt this enzyme. They observed that mice lacking CST displayed key hallmarks of AD, such as significant cognitive decline as well as microglial and astrocyte activation, which drives neuroinflammation. The researchers also found additional effects of CST loss, including those affecting organs other than the brain.

“A surprising finding was that mice (without) CST had enlarged bladders,” Han said, “which we thought could explain the loss of bladder control in AD patients.”

Scientists know that sulfatide levels increase with age early in life, reach a plateau around middle age and then start to decline around the age of 65, the age at which individuals typically start to show signs of AD. However, Han and his colleagues found that known AD risk factors, such as the APOE4 gene and Type 2 diabetes, promote an even more dramatic loss of sulfatide.

“We believe that this additional loss of sulfatide ultimately causes AD,” Han said. “And we think that the replenishment of sulfatide can be a viable approach for treating AD.”