Disrupted Lipid Metabolism in Alzheimer's Disease
The brain is a relatively fatty organ, and has its own complex lipid metabolism. A range of evidence suggests that detrimental shifts in this lipid metabolism accompany aging and neurodegenerative conditions. Some inroads have been made into linking specific lipid mechanisms to specific aspects of neurodegeneration, such as increased inflammatory activity on the part of microglia. Here, researchers review what is known of the role of lipids in the pathologies exhibited by patients with Alzheimer's disease. As noted, there is much left to understand, and what is known today is just a small step into a large dark room.
Lipid homeostasis is crucial for the physiological function of organisms. In the central nervous system (CNS), altered lipid homeostasis and disrupted lipid metabolism signaling pathways are often seen in aging and neurodegeneration. A plethora of genome-wide association studies (GWAS) have identified variants in genes involved in lipid-modifying processes such as transportation, synthesis, and conversion, suggesting altered lipid metabolism may serve as key drivers of late onset Alzhemer's disease (LOAD). However, the chemical diversity and functional heterogeneity of lipids have long posed challenges in characterizing lipid alterations and understanding their biological implications in Alzheimer's disease (AD).
In this review, we provided an overview of recent advancements in lipidomics techniques and their applications in AD research. Current findings strongly support the involvement of specific lipid classes, including sphingolipids, cholesterol, and phospholipids, in AD pathology. This is further underscored by numerous studies elucidating the molecular mechanisms by which lipids influence multiple pathological aspects of AD. These insights lay a solid foundation for the identification of diagnostic lipid biomarkers and the development of lipid-related therapies.
The crosstalk of lipids and AD pathologies such as amyloid-β, tau, and neuroinflammation plays a significant role in modulating neurodegeneration. As essential intracellular bioactive molecules and key components of cell membranes, lipids also influence cellular functions by participating in oxidative stress responses and mediating synaptic activities among other mechanisms. Further understanding of these connections will provide guidance for leveraging lipidomics information during targeted therapy of these disease mechanisms. Moreover, integrating lipidomics into the evaluation of the diagnostic and treatment efficacy will broaden our options for developing personalized treatment strategies and identifying new biomarkers for AD. Ongoing research aimed at uncovering novel mechanisms of lipid involvement in AD is poised to provide valuable insights that will guide future data-driven clinical investigations.