Targeting ceramides in 5XFAD mice reduces amyloid plaque deposition and gliosis

• DOI: 10.1002/alz.082457
• Publication Date: 2023-12-25T15:25:40Z
• Authors: Joseph L Wilkerson; Amandine Chaix; Scott A Summers; William L Holland
• Keywords: Sphingolipid

Abstract Background Alzheimer’s Disease and other neurodegenerative disorders have been linked to metabolic associated with aberrant lipid deposition. Sphingolipids, such as ceramides, are among the most deleterious lipids that accumulate in AD brain. Increased ceramides measured post‐mortem brain samples abundant Aβ‐plaques. As biomarkers, plasma cerebrospinal fluid correlate risk. The potential of ceramide‐lowering strategies treat or prevent has underexplored. We hypothesize causal contributors pathologies amenable therapeutic targeting improve outcomes. Method To address AD, we targeted serine palmitoyl‐transferase (SPT), first enzyme rate‐limiting step ceramide de novo synthesis, drug myriocin 5XFAD mice on a regular chow diet an obesogenic high‐fat diet. also generated inducible genetic models study loss‐of‐ceramides (overexpression ceramide‐degrading Asah1) gain‐of‐ceramides SPT complex), specifically neurons model. used immunocytochemistry assess Aβ plaque numbers size both astrocyte microglial activation numbers. Cognitive behavior was using Barnes maze. Result treated for 17 weeks had reduction hippocampal ceramides. expected, control vehicle‐treated showed significant memory deficit during behavioral testing. Myriocin‐treated significantly improved Treated fewer smaller plaques arborization cortex hippocampus. Microglia were reduced hippocampus mice. In neuron‐specific Asah1 overexpression, number remained unchanged compared control. However, Gfap+ astrocytes Iba1+ microglia/monocyte migration eliminated, resulting no glia glial morphology like non‐5XFAD Conclusion Decreasing production by treatment gliosis Reducing results abrogation throughout mouse.