Fig. 4

Abnormalities of fatty acid metabolism dominated by astrocytes in Alzheimer’s disease (AD) AD astrocytes are activated by oxidative stress and have abnormal uptake, catabolism and synthesis of fatty acids, resulting in neuronal lipotoxicity. In astrocytes, ApoE4 protein inhibits fatty acid catabolism by inducing the expression of Drp1 (which promotes mitochondrial division) and inhibiting carnitine palmitoyltransferase (CPT), resulting in an increase in intracellular fatty acids and an increase in the formation of fatty acid lipid peroxyl radicals and hydroperoxides. The formation of oxygen radicals and hydroperoxides is increased, including epoxyeicosatrienoic acid (EET), epoxydipentaenoic acid (EDP) and pro-oxidant mediators (SPMs), which inhibit pro-inflammatory signalling, and subsequently increase the inflammatory response of astrocytes. Excess fatty acid excretion from astrocytes induces apoptosis in oligodendrocytes, resulting in myelin debris. Myelin debris activates microglia into a pro-inflammatory phenotype and induces antigen presentation, and also acts as a co-fuel source to increase fatty acid β-oxidation and ketogenesis in astrocytes