In a mouse model of Alzheimer’s disease, blocking one pathway for producing ceramides, a class of cellular lipids, improved learning, while blocking another increased amyloid burden

In a mouse model of Alzheimer’s disease, blocking one pathway for producing ceramides, a class of cellular lipids, improved learning, while blocking another increased amyloid burden

In a bioRxiv preprint posted on September 11, the authors compared two ways to reduce ceramide levels. Eight-month-old female PDAPP-J20 mice, which develop amyloid plaques in the brain and memory impairments, received GW4869 or myriocin for three weeks. GW4869 blocks neutral sphingomyelinase (nSMase), which releases ceramides from sphingomyelin; myriocin blocks serine palmitoyltransferase (SPT), which is involved in making them from scratch.

Cells produce ceramides through two pathways. The authors tested what would change when each of the two enzymes was inhibited. Their rationale was a proposed inflammatory feedback loop: the signaling protein TNF-α activates nSMase, which in turn increases TNF-α production through NFκB, a protein that switches on inflammatory genes.

After treatment with GW4869, mice learned to navigate the Barnes maze as well as healthy controls. In one region of the hippocampus, a brain structure involved in memory, amyloid plaques occupied less area, and microglia, the brain’s immune cells, showed fewer signs of activation around plaques. Mice given myriocin remained impaired in learning, and plaques occupied a larger area in this region than in untreated transgenic mice.

The cell culture experiments examined a possible mechanism for this difference. In cultured microglia, amyloid caused NFκB to move into the cell nucleus; GW4869 suppressed this movement and reduced the amount of fluorescently labeled amyloid inside the cells. A second, chemically distinct nSMase inhibitor, cambinol, reduced TNF-α production but did not reduce intracellular amyloid in this measurement.

In this model, the outcome depended on the ceramide production pathway: the nSMase blocker GW4869 improved learning and reduced amyloid burden, while the SPT blocker myriocin worsened some measures.