Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by progressive cognitive impairment and memory loss. The mammalian target of rapamycin (mTOR) signaling pathway could regulate learning and memory. The effect of rapamycin (Rapa) on mTOR activity could slow or prevent the progression of AD by affecting various essential cellular processes. Previously, we prepared transferrin (Tf) decorated-nanostructured lipid carriers (NLCs) for rapamycin (150 ± 9 nm) to protect the drug from chemical and enzymatic degradation and for brain targeted delivery of rapamycin. Herein, the effect of Tf-NLCs compared to untargeted anionic-NLCs and free rapamycin, were studied in amyloid beta (Aβ) induced rat model of AD. Behavioral test revealed that the Rapa Tf-NLCs were able to significantly improve the impaired spatial memory induced by Aβ. Histopathological studies of hippocampus also showed neural survival in Rapa Tf-NLCs treated group. The immunosuppressive, and delayed wound healing adverse effects in the rapamycin solution treated group were abolished by incorporating the drug into NLCs. The Aβ induced oxidative stress was also reduced by Rapa Tf-NLCs. Molecular studies on the level of Aβ, autophagy (LC3) and apoptotic (caspase-3) markers, and mTOR activity revealed that the Rapa Tf-NLCs decreased the Aβ level and suppressed the toxic effects of Aβ plaques by modulating the mTOR activity and autophagy, and decreasing the apoptosis level. As a conclusion, the designed Tf-NLCs could be an appropriate and a safe brain delivery system for rapamycin and make this drug more efficient in AD for improving memory and neuroprotection.
Keywords: Alzheimer's disease; Brain; NLCs; Rapamycin; Transferrin; mTOR.
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