AD-like neuropsychiatric dysfunction in a mice model induced by a combination of high-fat diet and intraperitoneal injection of streptozotocin

Abstract

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, clnds and protein expression of APP, p-Tau, p-IRS1, p-AKT, p-ERK, 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 FBG and impaired learning and memory ability. Moreover, the model mice presented the increased level of APP, p-Tau, p-IRS1, TREM2, IL-1β, IL-6, TNF-α, ocln, zo-1 and clnds, the decreased level of p-AKT, p-ERK and TREM1, as well as the 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.

Significance Statement Alzheimer's disease (AD) is a progressive neurodegenerative disorder which prevalence is increasing with the rapidly growing global elderly population, but the accurate disease mechanisms and underlying therapeutic targets remains unclear. The aim of the present study is to investigate the behavioral performance changes and neuropathological injuries in mice challenged with the combination of a high-fat diet (HFD) and intraperitoneal injection of streptozotocin (STZ).In our study suggested that combination of HFD and STZ/I.P. could successfully induce AD-like behavioral impairments and neuropathological injuries in mice, which 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.