AbstractBackgroundAlzheimer's disease (AD) is a multifactorial neurodegenerative condition and the most common cause of its initiation is accumulation of oligomeric amyloid beta1‐42 (Aβ1‐42). In recent past, several studies have shown autophagy deficits in AD may resulted accumulation of misfolded protein, Aβ1‐42 and phosphorylated tau (ptau). Fibroblast growth factor 21 (FGF21), a metabolic hormone, has shown strong neuroprotective efficacy via increasing autophagic flux in AD. Therefore, this study was designed to investigate the synergistic neuroprotective efficacy of lentiviral FGF21 gene (LV‐FGF21) delivery and rapamycin‐autophagy modulator in Aβ1‐42 induced AD in rats.MethodLV‐FGF21 was administered 4weeks before inducing AD by oligomeric Aβ1‐42 into the lateral cerebral ventricles. Rats were divided into control, sham group administered with PBS intracerebroventricularly (ICV), ICV‐Aβ1‐42 group, ICV‐Aβ1‐42 group pre‐treated with LV‐FGF21, and pre‐treated LV‐FGF21 group combined with rapamycin. Morris water maze (MWM), ELISA assay for measuring protein levels of Aβ1‐42, ptau, soluble amyloid precursor protein (sAPP) and beta‐site APP cleaving enzyme 1 (BACE1), oxidative stress measurement, mRNA expression and immunofluorescence analysis were performed after treatment completion.ResultAβ1‐42 oligomer formation was confirmed by FESEM analysis. After 14 days, MWM analysis showed that the combination group considerably restored the cognitive ability while attenuated the level of Aβ1‐42, ptau, sAPP, and BACE1. Moreover, oxidative stress parameters considerably improved for the combined treated group as compared with ICV‐Aβ1‐42 group. Also, mRNA expression of main autophagy mediators (beclin‐1, LAMP‐2, LC3, ATF4, p62/SQSTM1) reflected positive outcome for the combination treatment group.ConclusionThe findings of the present study confirmed the neuroprotective potential of FGF21 and rapamycin in debilitating AD pathology in rats.