Hypercholesterolemia accelerates intraneuronal accumulation of Aβ oligomers resulting in memory impairment in Alzheimer's disease model mice

Aims: Hypercholesterolemia is known to be a risk factor for Alzheimer's disease (AD), and diet-induced hypercholesterolemia has been shown to accelerate amyloid pathology in animals. While growing evidence has shown that synaptic and cognitive dysfunction in AD is associated with intraneuronal accumulation of Aβ, the relationships between hypercholesterolemia, memory impairment, and intraneuronal Aβ remains unclear. The present study aims to clarify this association. Main methods: Transgenic mice expressing amyloid precursor protein (APP) harboring the Osaka (E693δ) mutation (APP_OSK-Tg mice) were used. These mice exhibit intraneuronal Aβ oligomers and memory impairment from 8 months of age. Five-month-old male APP_OSK-Tg mice and non-Tg littermates were fed a high-cholesterol diet for 1 month to induce hypercholesterolemia. At 6 months of age, their cognitive function was evaluated by the Morris water maze. Intraneuronal Aβ, synaptic density, and tau phosphorylation were examined by immunohistochemistry. Key findings: Serum and brain cholesterol levels were significantly higher in APP_OSK-Tg mice and non-Tg littermates that were fed a high-cholesterol diet than in control mice that were fed normal chow, indicating that hypercholesterolemia was successfully induced. Hypercholesterolemic APP_OSK-Tg mice, but not control APP_OSK-Tg mice or hypercholesterolemic non-Tg littermates, exhibited impaired spatial reference memory, which was accompanied with intraneuronal accumulation of Aβ oligomers, reduced synaptophysin immunoreactivity, and abnormal tau phosphorylation in the hippocampus. Hypercholesterolemia-accelerated accumulation of intraneuronal Aβ oligomers was also observed in another model mouse, Tg2576. Significance: Our findings suggest that hypercholesterolemia accelerates intraneuronal accumulation of Aβ oligomers and subsequent synapse loss, resulting in memory impairment.