biostudies-literatureYue TJSPS KAKENHIAMEDJST SPRINGe1011818https://www.ebi.ac.uk/biostudies/studies/S-EPMC12370196biostudies-literatureUnknown21(8)High-fat diet (HFD) is considered a risk factor for age-related memory impairments such as Alzheimer's disease. However, how HFD affects memory formation remains unclear. In this study, we established a model of memory defects caused by HFD in Drosophila. Our results revealed that the HFD impaired intermediate-term memory (ITM), but not short-term memory (STM), produced by classical aversive olfactory conditioning, and decreased autophagic activity in the heads of the HFD-fed flies. Transient reduction in autophagic activity also impaired ITM, but not STM. Genetic enhancement of autophagic activity in neurons effectively restored ITM performance in the HFD-fed flies. Mechanistically, HFD impairs lysosomal function by downregulating the expression of lysosome-related genes, leading to impaired fusion of autophagosomes with lysosomes. These findings suggest that HFD impairs ITM by reducing autophagic activity and lysosomal dysfunction in the neurons.PLoS geneticsHigh-fat diet impairs intermediate-term memory by autophagic-lysosomal dysfunction in Drosophila.PMC12370196JP24K22013JP21H02621JP22H05485JP22gm6710006h0001JP22gm6110024h0004JPMJSP2109JP22H02715Yue TTonoki AItoh MOnuki KJiang MfalseHigh-fat diet impairs intermediate-term memory by autophagic-lysosomal dysfunction in Drosophila.High-fat diet (HFD) is considered a risk factor for age-related memory impairments such as Alzheimer's disease. However, how HFD affects memory formation remains unclear. In this study, we established a model of memory defects caused by HFD in Drosophila. Our results revealed that the HFD impaired intermediate-term memory (ITM), but not short-term memory (STM), produced by classical aversive olfactory conditioning, and decreased autophagic activity in the heads of the HFD-fed flies. Transient reduction in autophagic activity also impaired ITM, but not STM. Genetic enhancement of autophagic activity in neurons effectively restored ITM performance in the HFD-fed flies. Mechanistically, HFD impairs lysosomal function by downregulating the expression of lysosome-related genes, leading to impaired fusion of autophagosomes with lysosomes. These findings suggest that HFD impairs ITM by reducing autophagic activity and lysosomal dysfunction in the neurons.2025-01-01T00:00:00Z2025 Aug2026-04-08T05:32:43.471Z2026-04-07T22:33:23.202ZS-EPMC123701964082505110.1371/journal.pgen.1011818