Microglia are innate immune cells of the brain, similar to macrophages elsewhere in the body. A growing body of evidence points to maladaptive inflammatory behavior of microglia in the aging brain as an important contribution to the onset and progression of neurodegenerative conditions such as Alzheimer’s disease. Some microglia become inflammatory in response to the damaged environment of aged brain tissue, but others have become senescent. Senescent cells cease replication and instead turn their efforts to secreting disruptive inflammatory signals, harmful to tissue structure and function when sustained over the long term.
Emerging evidence suggests that senescent microglia play a role in β-amyloid (Aβ) pathology and neuroinflammation in Alzheimer’s disease (AD). Targeting senescent cells with naturally derived compounds exhibiting minimal cytotoxicity represents a promising therapeutic strategy. This study aimed to investigate whether delphinidin, a naturally occurring anthocyanin, can alleviate AD-related pathologies by mitigating microglial senescence and to elucidate the underlying molecular mechanisms.
We employed APP/PS1 mice and naturally aged mice. Delphinidin treatment significantly alleviated cognitive deficits, synapse loss, amyloid-β peptides plaques of APP/PS1 mice via downregulated senescent microglia gene signature, prevented cell senescence, including senescence-associated β-galactosidase activity, senescence-associated secretory phenotype (SASP), oxidative stress, p21, and p16. And delphinidin treatment also prevented microglial senescence in naturally aged mice. Further research indicated that delphinidin treatment enhanced the AMPK/SIRT1 signaling pathway. Additionally, delphinidin was found to directly interact with SIRT1. It’s noteworthy that AMPK inhibitor Compound C inversed the protective effect of delphinidin against microglial senescence.
These findings highlight delphinidin as a promising natural anti-aging agent against the development of aging and age-related diseases.