Luteolin ameliorates depression-like behaviors by suppressing ER stress in a mouse model of Alzheimer's disease

Alzheimer's disease (AD) is the most common cause of dementia in the elderly population. Inflammation plays an important role in AD, as microglia respond to several pathological insults, such as Aβ, and exert protective homeostatic functions (anti-inflammatory) and detrimental inflammatory functions (proinflammatory). During the development of AD, chronic inflammation that accompanies aging causes microglial priming, a state of hyperactivation in response to stimulation, indicating that suppressing microglial priming may be a therapeutic intervention for AD. Endoplasmic reticulum (ER) stress is crucial for inflammation through NF-kB and inflammasome activation. To identify natural flavonoids that regulate ER stress, a DNA microarray was performed using the brains of AD model mice after long-term intake of quercetin, after which the connectivity map (CMap) assay was carried out. We found that luteolin suppresses lipopolysaccharide (LPS)-induced interleukin 1β (IL1β) expression by inhibiting ER stress. Immunohistochemical analyses showed that CD68 levels were reduced in the brain after intraperitoneal injection of luteolin in a mouse model of AD, suppressing IL1β production. As shown by behavioral analyses using the tail suspension test (TST) and forced swimming test (FST), depression-like behaviors were ameliorated in luteolin-treated AD model mice. These findings indicate that luteolin prevents ER stress to suppress microglial activation in the brain, improving individual activity.