Activation of central Angiotensin-(1-7)/Mas receptor alleviates synaptic damage in diabetes-associated cognitive impairment via modulating AKT/FOXO1/PACAP axis

Synaptic damage is a pathological hallmark of diabetes-associated cognitive impairment (DACI). Angiotensin-(1-7)/Mas receptor has been implicated in regulating peripheral glucose homeostasis and exerting neuroprotective effects on central nervous system. This study investigated the possible roles of Angiotensin-(1-7)/Mas receptor in DACI, aiming to elucidate the molecular mechanisms underlying synaptic damage. We observed a significant reduction of Angiotensin-(1-7) levels in type 2 diabetic patients with mild cognitive impairment and diabetic cognitive impairment mice. Downregulation of Angiotensin-(1-7)/Mas receptor was associated with the decreased synaptic protein expressions in diabetic cognitive impairment mice, and high glucose-stimulated primary hippocampal neurons. Administration of the Mas agonist AVE 0991 into the hippocampus effectively ameliorated synaptic and memory dysfunctions in diabetic cognitive impairment mice. Inhibition of hippocampal neuronal Mas receptor aggravated synaptic damage. Mechanistically, we first elucidated that pituitary adenylate cyclase-activating polypeptide (PACAP) serves as a downstream synaptic function-related target gene of Mas receptor. Furthermore, we identified AKT/FOXO1 pathway as a critical downstream mediator of Mas receptor in modulating PACAP expression, with FOXO1 binding directly to the PACAP promoter region. In conclusion, Angiotensin-(1-7)/Mas receptor may modulate synaptic function-related target gene PACAP expression through AKT/FOXO1 pathway, thereby providing a deeper theoretical basis and molecular target for future DACI treatment.