Fig. 1. Neuronal acid sphingomyelinase (ASM) mediates autophagic dysfunction in the Alzheimer’s disease (AD) brain.

In AD, neuronal ASM is increased by environmental or cellular stressors. Intracellular and secreted ASM undergoes lysosomal uptake via M6PR. Excessively increased lysosomal ASM affects lysosomal disruption, and intracellular ASM decreases lysosomal biogenesis by reducing the expression levels of the transcription factor EB target gene in the cell nucleus. This lysosomal disruption by ASM leads to the inhibition of autophagic protein degradation and subsequent autophagosome accumulation, as indicated by the expression of abnormal proteins such as Aβ and other cytotoxic proteins. Eventually, autolysosome formation decreases, and autolysosome deposition contributes to Aβ deposition in the AD brain.