Acid sphingomyelinase as a pathological and therapeutic target in neurological disorders: focus on Alzheimer's disease

Over the past decade, numerous studies have highlighted the importance of acid sphingomyelinase (ASM) in disease treatment in humans. This enzyme functions primarily to generate ceramide, maintain the cellular membrane, and regulate cellular function. However, in the blood and brain of patients with neurological disorders, including major depression, ischemic stroke, amyotrophic lateral sclerosis, multiple sclerosis, and Alzheimer's disease (AD), elevated ASM levels significantly suggest disease onset or progression. In these diseases, increased ASM is profoundly involved in neuronal death, abnormal autophagy, neuroinflammation, blood-brain barrier disruption, hippocampal neurogenesis loss, and immune cell dysfunction. Moreover, genetic and pharmacological inhibition of ASM can prevent or ameliorate various diseases. The therapeutic effects of ASM inhibition have prompted the urgent need to develop ASM inhibitors, and several ASM inhibitors have been identified. In this review, we summarize the current knowledge on the critical roles and mechanisms of ASM in brain cells and blood that are associated with different neuropathological features, especially those observed in AD. Furthermore, we elucidate the potential possibility and limitations of existing ASM-targeting drugs according to experimental studies in neurological disorder mouse models. Understanding how certain cell functions contribute to diseases is vital for creating treatments. This study explores sphingolipid metabolism. However, when this process malfunctions, it can cause various diseases. The enzyme acid sphingomyelinase is key as it produces ceramide, a lipid that, in excess, can cause cell death and contribute to diseases like Alzheimer's and major depression. The study compiles recent findings on how ASM contributes to neurological disorders, particularly Alzheimer's disease. It investigates how ASM impacts brain cells and blood, leading to symptoms like memory loss and inflammation. The review also discusses potential drugs that target ASM, offering hope for treating these disorders. The results show that high ASM levels in the brain and blood are linked to the development and progression of neurological disorders.This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.