Inhibition of FAAH Prevents Pathology in ASMD by Rescuing Endocannabinoid Signaling

ABSTRACT: Acid sphingomyelinase deficiency (ASMD) leads to sphingomyelin (SM) accumulation, neurodegeneration and early death. We describe the down regulation of the endocannabinoid (eCB) system in neurons of ASM knockout (ASM-KO) mice and a ASMD patient. High SM reduced eCB receptor CB1 expression in neuronal processes and induced its accumulation in lysosomes. Activation of CB1 receptor signaling, through inhibition of the eCB-degrading enzyme FAAH, reduced SM levels in ASMKO neurons. Oral treatment of ASMKO mice with a FAAH inhibitor prevented SM buildup, alleviated inflammation, neurodegeneration and behaviorial alterations, and extended lifespan. This treatment showed benefits even after a single administration at advanced disease stages. We found CB1 receptor down-regulation in neurons of a mo

SUBMITTER: Dr. Maria Dolores Ledesma 

PROVIDER: S-SCDT-EMM-2019-11776-T | biostudies-other |

REPOSITORIES: biostudies-other