Role of De Novo Lipogenesis in Neurodegeneration and Neurogenesis Disruption in Alzheimer's Disease and Treatment Perspective.

Progressive neurodegeneration, decline in neurogenesis, and cognitive dysfunction alongside amyloid-β plaque and neurofibrillary tangle formation are prominent pathological features of Alzheimer's Disease (AD). Although the underlying mechanism remains unclear, evidence suggests that surplus intracellular lipids/fatty acids could be the primary mediators. In this regard, increased levels of Saturated Fatty Acids (SFAs), Monounsaturated Fatty Acids (MUFAs), their triglyceride and ceramide derivatives have been reported in the brain of patients with AD. Further, converging evidence from basic and clinical studies suggests that de novo lipogenesis could be the main source of lipid/fatty acid accumulation in the brains of patients with AD. Although elevated cholesterol has long been suggested to induce inflammation and neurodegenera-tion in AD, recent evidence suggests that the effects of SFAs and their lipid derivatives, particularly ceramides, could be more detrimental. Consequently, de novo lipogenesis inhibitors could be the potential therapeutic targets for the early intervention in AD. Intriguingly, several studies have shown that treatment with various natural or synthetic compounds, which inhibit de novo lipogenesis, effectively reduced neurodegeneration, cognitive dysfunction, and inflammation in the model animals of AD. These compounds also increased neurogenesis while reducing lipid/fatty acid accumulation, suggesting that blocking lipid/fatty acid biosynthesis by inhibiting de novo lipogenesis could be an effective strategy in treating AD. Thus, while the study discusses the effects of various FDA-approved AD drugs and selected natural and synthetic inhibitors of de novo lipogenesis on neurodegeneration and neurogenesis in model animals, the doors are open for conducting clinical trials in patients with AD.