A Novel Mouse Model of Mixed Dementia Using Chronic Cerebral Hypoperfusion Induced by Bilateral Carotid Artery Stenosis

Alzheimer's disease (AD) and vascular dementia (VaD) have distinct pathognomonic features, but they frequently co-occur as mixed dementia (MD) in elderly adults. This study aimed to develop a novel MD mouse model using bilateral carotid artery stenosis (BCAS) in 5 times familial Alzheimer's disease (5xFAD) transgenic mice and characterize its behavioral and histological features. Thirteen C57BL/6 and sixteen 5xFAD transgenic mice were prepared. Six C57BL/6 and seven 5xFAD transgenic mice underwent BCAS surgery, and all mice were housed for 3 months. Mice were divided into wild-type (n = 7), VaD (n = 6), AD (n = 9), and MD (n = 7) groups. Neurobehavioral tests, including the Y-maze test (YMT) and passive avoidance test (PAT), along with immunohistochemical analysis of amyloid β plaque (6E10) and myelin basic protein, were performed. MD mice exhibited similar deficits in YMT as AD and VaD groups but had significantly worse performance in PAT compared to all other groups. Histologically, MD mice showed amyloid-β accumulation in the cortex/hippocampus and axonal degeneration in the corpus callosum. This novel MD model demonstrates key features of both AD and VaD, providing a valuable tool for studying the pathophysiology of mixed dementia and testing potential therapeutic interventions.