INTERMITTENT FASTING COUNTERACTS HIGH SUCROSE DIET–DRIVEN TRANSCRIPTOMIC ALTERATION INVOLVED IN AΒ CLEARANCE AND INFLAMMATION IN APP/PS1 TRANSGENIC MICE REVEALED BY SPATIAL TRANSCRIPTOMIC

In addition to central nervous system pathology , Alzheimer’s disease (AD) is characterized by non-cognitive manifestations, including emotional and metabolic disturbances. Our work has shown that high-sucrose diet (HSD) exacerbates metabolic stresses and AD pathology. Since intermittent fasting (IF) enhances autophagy, improved mitochondrial function, and metabolic regulation, whether IF alleviates HSD-exacerbated symptoms is investigated.
Our results show that IF reduced plaque burden and improved spatial working memory in both normal chow diet (NCD)- and HSD-fed APP/PS1 transgenic (AD) mice in the hippocampus, but not cortex. 10x Visium spatial transcriptomics was applied to investigate the spatial transcriptional mechanisms underlying the beneficial effect of IF on HSD AD mice. Based on IF improves plaque burden and spatial working memory, hippocampus might major improvement nuclei. Clustering analysis shows different cluster in HSD group from NCD and IF groups in the stratum radiatum, lacunosum and molecular layers of hippocampus. We focus on plaque-excluded tissue domains to minimize plaque-dominated transcriptional effects. HSD altered gene enrichment in pathways related to neurotransmitter signaling, synaptogenesis, mitochondrial metabolism, cerebral blood flow, and blood–brain barrier integrity, whereas 8-week IF reversed these gene enrichment.
Differentially expressed gene analysis of HSD vs NCD AD mice, we identified 12 HSD-altered genes which are involved in synaptic function, mitochondrial metabolism, vascular regulation, and cellular homeostasis. Importantly, IF reversed HSD altered patterns. Collectively, these findings indicate that IF not only improves cognitive function and reduces Aβ deposition in APP/PS1 transgenic mice but also improves HSD-exacerbated AD progression.