Lipids in the Pathogenesis of Alzheimers Disease

The pathogenesis of Alzheimers Disease remains elusive, representing one of the most pressing challenges in modern neuroscience. Recent, researches have increasingly highlighted lipids in AD pathology, suggesting novel pathways for AD pathogenesis and therapeutics. Apolipoprotein E (APOE) as lipid transporters, are widely recognized as the gene risk factor of AD, with the APOE4 allele conferring earlier onset and more severe phenotypes. Beyond lipid transportation, APOE can also bind to amyloid-beta and other proteins and lipids, thereby modulating pathological processes. In brain tissues from AD patients, microglia frequently accumulate abnormal lipid droplets in association with amyloid- and other aggregates. In astrocytes, lipoparticles enriched in saturated fatty acid have been shown to exert the neurotoxic effect. To detect the type of these abnormally accumulated lipids in glia and neurons, lipidomic analyses were made and they showed the content of glycerophospholipid decreased and the content of sphingolipid and long-chain sphingomyelin increased. Many of the abnormal lipids accumulations above are caused by organelle impairment, mitochondrial dysfunction can lead to the reactive oxygen species (ROS) mediated abnormal lipid metabolism. While lysosomal impairment, especially mutations in the PLD gene family, leads to defective lipid degradation and pathological lipid accumulation. Overall, these findings emphasize the importance of lipid metabolism in AD and provide mechanistic insights into the disease progression.