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

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.