AD-Like Neuropsychiatric Dysfunction in a Mice Model Induced by a Combination of High-Fat Diet and Intraperitoneal...

Increasing data suggest a crucial relationship between glycolipid metabolic disorder and neuropsychiatric injury. The aim of this study is to investigate the behavioral performance changes and neuropathological injuries in mice challenged with high-fat diet (HFD) and streptozotocin (STZ). The glucose metabolism indicators and behavioral performance were detected. The mRNA expression of IL-1β, IL-6, TNF-α, ocln, zo-1, and clnds and protein expression of APP, p-Tau, p-IRS1, p-AKT, p-ERK, and TREM1/2 were measured. The fluorescence intensities of MAP-2, NeuN, APP, p-Tau, GFAP, and IBA-1 were observed. The results showed that combination of HFD and STZ/I.P. could induce glucose metabolic turmoil and Alzheimer's disease (AD)-like neuropsychiatric dysfunction in mice, as indicated by the increased concentrations of fasting blood glucose and impaired learning and memory ability. Moreover, the model mice presented increased levels of APP, p-Tau, p-IRS1, TREM2, IL-1β, IL-6, TNF-α, ocln, zo-1, and clnds; decreased levels of p-AKT, p-ERK, and TREM1; and neuron damage and the hyperactivation of astrocytes and microglia in the hippocampus as compared with control mice. Only male mice were used in this study. Although AD and type 2 diabetes mellitus (T2DM) are distinct pathologies, our results suggested that combination of HFD and STZ/I.P., a widely used T2DM modeling method, could successfully induce AD-like behavioral impairments and neuropathological injuries in mice; the mechanism might be involved with neuroinflammation and its associated dysfunction of IRS1/AKT/ERK signaling pathway. Our findings further support the potential overlap between T2DM and AD pathophysiology, providing insight into the mechanisms underlying the comorbidity of these diseases.