Hippocampal vascular injury and cognitive impairment in a mixed mouse models of Alzheimer's disease and type 2 diabetes mellitus / 解剖学报

ABSTRACT

Objective To study the effect of type 2 diabetes mellitus (T2DM) on the cerebral blood vessels in Alzheimer's disease (AD), and to explore its mechanism of influence on the pathogenesis of Alzheimer's disease. Methods To generate a mouse model with AD complicated with long-term T2DM, forty 6-month-old APP/PS1 transgenic mice were fed with high-sugar and high-fat diet for 6 months, that was, when mice at 12 months of age, they were intraperitoneally injected with 1% streptozotocin solution for 4 consecutive days. Then, mice were randomly divided into 4 groups the normal control group, AD model group, T2DM model group and AD complicated with T2DM model group, 10 mice were used in each group. The learning and memory ability of the mice were tested by the mouse step-down assay, and the vascular morphology of the mice's hippocampal CAI area was observed by ink perfusion. Then oil red 0 staining and immunofluorescent staining were applied to test the pathological indices of the hippocampal area in the model. Results Compared with the control group, AD combined with T2DM mice showed decreasing significantly abilities in the learning and memory (P<0.05), and the blood vessels in the hippocampus became thinner and the vascular density decreased. Moreover, T2DM promoted lipid deposits and vascular leak in the hippocampus of the model. Additionally, the expression of β-site amyloid precursor protein cleaving enzyme-1 (BACE-1), nuclear factor (NF)-κB and matrix metalloproteinase (MMP) -9 were increased compared with the controls in the hippocampal CAI region. Conclusion T2DM plays a negative regulatory role on learning and memory functions of mice, accelerates the onset of AD and result in cerebrovascular lesions. In addition, the abnormal expression of MMP-9 may also be one of the causes of AD vascular lesions.