Dihydrocaffeic acid alleviates APOE4-associated astrocyte dysfunction and cognitive impairment via LRP1/p38 MAPK signaling

Dihydrocaffeic acid (DHCA) is a phenolic acid produced through the microbial metabolism of plant-derived caffeoylquinic acids. DHCA has been detected in human plasma following oral administration of a standardized aqueous extract of Centella asiatica (L.) Urb., a medicinal plant traditionally used to improve memory and cognitive function. However, whether DHCA exerts neuroprotective effects against APOE4-associated Alzheimer's disease-like pathology remains unclear.

To investigate whether DHCA ameliorates APOE4-associated cognitive deficits and neuropathological abnormalities and to assess the role of astrocytic LRP1/p38 MAPK signaling.

Twelve-month-old APOE4 mice were administered DHCA once daily for 21 days, with age-matched APOE3 mice and vehicle-treated APOE4 mice serving as controls. Cognitive function, Alzheimer's disease-related neuropathology, neuronal and synaptic integrity, astrocyte phenotypes, and lipid metabolism were evaluated. Mechanistic studies were performed in APOE4-overexpressing U251 cells using siRNA-mediated LRP1 knockdown and pharmacological activation of p38 MAPK.

DHCA improved object recognition and spatial learning and memory, reduced amyloid deposition and tau phosphorylation, restored neuronal and synaptic markers, shifted astrocyte-reactivity markers toward a neuroprotective profile, and restored proteins involved in lipid metabolism. DHCA also increased LRP1 expression and reduced p38 MAPK phosphorylation. LRP1 knockdown or p38 MAPK activation partially reversed these cellular effects.

DHCA ameliorated APOE4-associated cognitive deficits and neuropathological alterations, at least partly through modulation of LRP1/p38 MAPK-related signaling in the APOE4-overexpressing U251 model, astrocyte reactivity, and lipid metabolism. These findings identify DHCA as a potential neuroprotective metabolite derived from plant polyphenols.