Fig. 3. Blood ASM mediates the promotion of various neuropathological features in AD.

Increased blood ASM is recruited to CD4⁺ T-cell membranes and induces ceramide level elevation. The Stat3, JNK, and mTOR signaling phosphorylation induced by ceramide promotes pathogenic Th17 cell differentiation from CD4⁺ T cells. Cytokines secreted from pathogenic Th17 cells lead to BBB disruption through a reduction in tight junction protein expression, and increased BBB permeability facilitates the entry of these cells into the brain parenchyma. Pathogenic Th17 cell infiltration affects microglial activation and leads to defective phagocytic functions, consequently accelerating Aβ accumulation, neuroinflammation, synaptic loss, and memory impairment.