Crocin alleviates neuroinflammation and glia-associated synaptic alterations through NRF2 after chronic cerebral hypoperfusion

BackgroundChronic cerebral hypoperfusion (CCH) is common in vascular dementia, Alzheimer's disease, and related neurodegenerative disorders. It contributes to cognitive dysfunction, with synaptic loss as an important pathological event, but the underlying mechanisms remain unclear. Because chronic hypoperfusion, glial activation, and synaptic injury are increasingly implicated in Alzheimer's disease-related neurodegeneration, clarifying the mechanisms of CCH-induced synapse loss may also inform understanding of Alzheimer's disease.ObjectiveTo examine whether CCH promotes glia-associated synaptic marker accumulation and phagocytosis-related activity via damage-associated molecular patterns (DAMPs), and whether crocin can attenuate synaptic injury by suppressing this glial response.MethodsCrocin was evaluated in vascular cognitive impairment patients, in a rat model of CCH, and in oxygen-glucose deprivation-treated glial cells. Cognitive function, neuroinflammation, synaptic injury, phagocytosis-related activity, complement-associated synaptic changes, autophagy-related alterations, lipid droplet accumulation, and NRF2-related mechanisms were assessed.ResultsCrocin improved cognitive function in patients with vascular cognitive impairment and in CCH rats, and reduced neuroinflammation. In experimental models, crocin attenuated microglial- and astrocyte-associated synaptic marker accumulation, suppressed pro-inflammatory activation and phagocytosis-related activity, downregulated MERTK and MEGF10, and reduced complement-associated synaptic vulnerability. Crocin also alleviated autophagy-related imbalance, oxidative stress, and lipid droplet accumulation in an NRF2-related manner.ConclusionsCrocin may alleviate cognitive dysfunction after CCH by suppressing DAMPs-associated glial activation and glia-associated synaptic alterations, supporting its potential relevance to chronic hypoperfusion-related cognitive impairment.