MicroRNAs (miRNAs) have been recognized as possible biomarkers for Alzheimer's disease (AD). MiR-142-5p has been reported to be abnormally expressed in brain tissues. However, the role of miR-142-5p in AD pathogenesis keeps unclear. This study aimed to investigate the effect of miR-142-5p on the learning and memory of AD rats via regulation of protein tyrosine phosphatase nonreceptor type 1 (PTPN1)-mediated protein kinase B (Akt) pathway.The AD model was established by injection of Aβ1-42 oligomer once into the lateral ventricle of rats, and the spatial learning and memory ability of rats was measured. AD rats were injected with miR-142-5p or PTPN1 vectors to explore their functions in inflammation, Aβ, p-tau protein, apoptosis in brain tissues, and the effects on Akt pathway. The targeting relationship between miR-142-5p and PTPN1 was detected.Overexpressed miR-142-5p, down-regulated PTPN1 and inactivated Akt pathway were exhibited in AD. MiR-142-5p targeted PTPN1 to mediate Akt pathway. Reduced miR-142-5p and elevated PTPN1 improved the behavior of AD rats. MiR-142-5p targeted PTPN1 to effectively inhibit Aβ formation and abnormal phosphorylation of p-tau protein, suppress the inflammation in the brain tissues of AD rat, and improve the survival rate of brain tissue cells. MiR-142-5p regulated PTPN1 to activate the Akt pathway, further inhibiting the apoptosis of brain neurons in AD rats.Down-regulating miR-142-5p targets PTPN1 to activate Akt pathway, thus improving the learning and memory of AD rats and playing an anti-AD role.Copyright © 2022. Published by Elsevier Inc.