Alzheimer's disease (AD) is pathologically characterized by the deposition of Aβ and tau protein. The amyloid hypothesis that Aβ accumulation is causally involved in the pathogenesis of AD is widely accepted and is a promising target for disease-modifying therapies. Since Aβ accumulation progresses decades before cognitive impairment becomes apparent, attention has recently focused on risk factors involved in the early pathogenesis of AD.
Epidemiological studies have established that diabetes is a risk factor for AD, but it is not fully understood which factors associated with diabetes contribute to the development of AD. Our research focuses on the causal relationship between diabetes and Aβ pathology using APP Tg mice that forms amyloid plaques in the brain. High-fat diet (HFD) feeding induced obesity, insulin resistance, and diabetes in APP Tg mice, resulting in a concomitant increase in brain Aβ accumulation. This exacerbation of Aβ pathology was reversible with subsequent dietary intervention, suggesting a close association between peripheral metabolic states and brain pathology. We further focused on endoplasmic reticulum stress, one of the triggers of insulin resistance, and pharmacologically showed that reducing endoplasmic reticulum stress by targeting peripheral tissues can improve brain Aβ pathology. These results underscore the importance of elucidating the pathomechanisms linking the brain and periphery.