CHARACTERIZATION OF CORTICAL LIPIDOME IN APP<SUP >NL-G-F </SUP>ALZHEIMER’S DISEASE MOUSE MODEL

Alzheimer’s disease (AD), the most prevalent form of dementia in the elderly, is closely linked to disrupted brain lipid metabolism. Nevertheless, its contribution to disease progression remains unclear. APP^NL-G-F AD mouse model recapitulate several AD-associated features, including Aβ deposition, and this study aimed to characterize the changes in lipid metabolism associated with the development of the model. To this end, the cortical tissue lipidome from WT mice and APP^NL-G-F animals at different ages were analyzed using UHPLC-MS. First, tissues from adult and old mice were compared. While WT cortex showed minimal differences between the two age groups, ageing APP animals exhibited elevated levels of cholesterol esters as well as of some phospholipids (mainly phosphatidylethanolamines and lysophosphatidylglycerols) and sphingolipids. Evaluating AD progression on the cortical lipidome revealed that the most pronounced dysregulation could be observed in the older mice. Indeed, older APP mice displayed increased levels of cholesterol esters, phospholipids, sulfatides, and, particularly, ceramides, in comparison to the WT animals. This latter alteration was already present in the adult mice, highlighting ceramide metabolism as key in the development of the model. Overall, these findings support that the APP^NL-G-F model also show lipid homeostasis disturbances, further highlighting the relevance of this metabolism in the development of Alzheimer’s disease.