Ghrelin inhibits NLRP3 inflammasome activation by upregulating autophagy to improve Alzheimer's disease

Nod-like receptor protein 3 (NLRP3) inflammasome, autophagy, and the aggregation of beta-amyloid (A beta) are key factors in Alzheimer's disease (AD) development. Ghrelin has shown promise in providing neuroprotection for AD. However, the mechanism underlying ghrelin's ability to improve AD by modulating autophagy and the NLRP3 inflammasome requires further clarification. Primary hippocampus neurons and mice were stimulated with A beta 1-42 to create an in vitro and in vivo AD model, followed by ghrelin administration for intervention. Additionally, we subjected the cells to 3-methyladenine (3-MA) treatment. Neuron morphology, microtubule-associated protein 2 (MAP-2) expression, apoptosis, cytokine levels, and protein expression were measured using various techniques. The escape latency of mice was assessed using the Morris water maze (MWM) test, and histopathology of the hippocampus was determined using hematoxylin-eosin staining. At 1-100 nM, ghrelin increased neuron/synapse numbers and MAP-2 expression dose-dependently while blocking apoptosis in A beta 1-42-treated cells. Moreover, ghrelin reduced the expression of A beta 1-42, p-Tau/Tau, p62, NLRP3, ASC, and cleaved Caspase-1, while increasing the expression of LC3II/LC3I and Beclin1 in AD cells. Furthermore, ghrelin treatment also decreased the levels of A beta 1-42, IL-1 beta, and IL-18 in the cells. The effects of ghrelin were reversed by 3-MA. Our in vivo experiments provided further confirmation of the above effect of ghrelin on AD. Additionally, the injection of A beta 1-42 induced increased escape latency in mice and histopathological changes in hippocampal neurons. All of these abnormalities were significantly improved following administration of ghrelin. Ghrelin mitigated A beta 1-42-induced neurotoxicity and relieved neuronal damage by upregulating autophagy to inactivate NLRP3, thus showing promising potential in treating AD.