Inhibition of acid sphingomyelinase reduces reactive astrocyte secretion of mitotoxic extracellular vesicles and improves Alzheimer’s disease pathology in the 5xFAD mouse

In Alzheimer’s disease (AD), reactive astrocytes produce extracellular vesicles (EVs) that affect mitochondria in neurons. The study found that Aβ-induced generation of the sphingolipid ceramide by acid sphingomyelinase (A-SMase) triggered proinflammatory cytokine release by microglia, which induced the reactive astrocytes phenotype and secretion of EVs enriched with ceramide. Inhibition of A-SMase with Arc39 and Imipramine reduced the secretion of cytokines from microglia. The study then tested the effect of Imipramine on EV secretion and AD pathology in the 5xFAD mouse model. The research suggests A-SMase inhibitors as potential AD therapy by preventing cyotokine-elicited secretion of mitotoxic EVs from astrocytes.

• 1
  A-SMase is activated in microglia by Aβ oligomers via activation of the TLR4 receptor, leading to the release of proinflammatory factors.
• 2
  Inhibition of A-SMase reduces the release of proinflammatory cytokines from microglia, preventing the activation of astrocytes and subsequent ceramide formation.
• 3
  Imipramine treatment in 5xFAD mice reduced the number of mitotoxic EVs released from astrocytes and decreased Aβ plaque deposition and neurodegeneration.