Novel mouse model of mixed dementia using chronic cerebral hypoperfusion induced by bilateral carotid artery stenosis

Abstract

Abstract Background Alzheimer’s disease (AD) and vascular dementia (VaD) have distinguishable pathognomonic findings, but they are common among older adults with similar clinical manifestations. Clinically, a mixed form of dementia (MD), VaD combined with AD, is frequent in older adults accounting for approximately 50% of all patients with dementia. Owing to the clinical importance and emerging changes in MD, a representative animal model is necessary for future dementia research. Aims To develop a novel MD mouse model using bilateral carotid artery stenosis (BCAS) in 5× familial AD (FAD) transgenic mice and establish their behavioral and histological characteristics Methods Thirteen C57BL/6 and sixteen 5× FAD transgenic mice were prepared. Six C57BL/6 and seven 5× FAD transgenic mice underwent BCAS surgery, and all mice were raised for 3 months. The mice were divided into four groups: wild-type (n = 7), VaD (n = 6), AD (n = 9), and MD (n = 7). Neurobehavioral tests, including the Y-maze test (YMT), passive avoidance test (PAT), and immunohistochemical confirmation, including mouse monoclonal amyloid-β antibody (MOAB-2) in the cortex/hippocampus and myelin basic protein (MBP) in the corpus callosum, were performed. Results Newly developed MD mice demonstrated poor results in YMT, similar to AD and VaD mice, and worse results for PAT compared to the other groups. Immunohistochemical analyses demonstrated that MD mice exhibited amyloid-β protein accumulation in the cortex/hippocampus (MOAB-2) and axonal degeneration in the corpus callosum (MBP). Conclusion A novel MD animal model was developed with pathognomonic findings of both AD and VaD. The neurobehavioral spectra of MD mice displayed characteristic deficits in intermediate-term memory and learning ability (PAT).