2025/12/09 by Li Sun, Mei Hu, Jianlu Lyu +5 · 1 voice
Medicine · Biochemistry, Genetics and Molecular Biology · #Cannabis and Cannabinoid Research #Autophagy in Disease and Therapy #Pharmacological Receptor Mechanisms and Effects
paper · doi:10.64898/2025.12.04.692105
openalex publication_date 2025/12/09 · openalex created_date 2025/12/10 · openalex updated_date 2026/07/25
Alzheimer's disease (AD) is the leading cause of dementia in the elderly, yet effective therapies remain lacking. Here, we identify monoacylglycerol lipase (MAGL), the principal enzyme that degrades the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain, specifically in astrocytes as a promising therapeutic target for AD. APP transgenic (TG) mice with astrocyte-specific MAGL deletion (TG-aKO), but not neuron-specific deletion (TG-nKO), exhibit markedly reduced Aβ pathology, neurodegeneration, and neuroinflammation, along with preserved synaptic structure and function and improved cognition. These benefits are recapitulated in TG mice by AAV-mediated silencing of astrocytic MAGL, whereas MAGL overexpression exacerbates neuropathology and accelerates synaptic and cognitive decline. Transcriptomic analyses reveal that dysregulated synapse-, inflammation-, and AD-related gene expression profiles are reversed in TG-aKO mice. MAGL expression is elevated in astrocytes from both AD patients and TG mice. Remarkably, a single intracerebroventricular (ICV) injection of AAV-MAGL-shRNA administered at either presymptomatic or postsymptomatic stages prevents or reverses neuropathology and synaptic and cognitive impairments in TG mice, providing preclinical evidence that astrocytic MAGL silencing represents an effective therapeutic strategy for AD.