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Abstract Sporadic Alzheimer{u2019}s disease (SAD) is a slowly progressive neurodegenerative disorder characterized by deposition of amyloid beta (AÝ) plaques, tau protein aggregation, impaired insulin signaling, and neuroinflammation. This study aimed to investigate the neuroprotective potential of tadalafil (TAD) and bergapten (BG) in SAD-induced cognitive impairment in mice. SAD was induced by a single intracerebroventricular injection of streptozotocin (STZ) (3 mg/kg). TAD or BG was administered intraperitoneally at doses of 20 and 25 mg/kg, respectively, 5 hours after STZ injection for 21 consecutive days. TAD and BG conceivably attenuated STZ-induced hippocampal insult, preserved neuronal integrity, and improved cognitive function in the Morris water maze and object recognition tests paralleled by reduced AÝ expression and phosphorylation of tau. Moreover, TAD and BG enhanced the protein expression of pAkt, pGSK-3Ý, beclin-1, and methylated protein phosphatase 2A (PP2A) and cyclin D1 gene expression and raised brain-derived neurotrophic factor immunoreactivity. In addition, both drugs boosted the hippocampal levels of cyclic guanosine monophosphate (cGMP), protein kinase G (PKG), WNT3A, and adenosine monophosphate-activated protein kinase coupled by reduced protein expression of Ý-catenin and mammalian target of rapamycin (mTOR). TAD and BG also halted neuroinflammation as evidenced by reduced IL-23 and IL-27 levels and NF-mB protein expression |