| Summary: | Alzheimer’s disease (AD) is a neurodegenerative disorder that jeopardizes the lives of diagnosed patients at late stages. This study aimed to assess, for the first time, the efficiency of germanium dioxide nanoparticles (GeO<sub>2</sub>NPs) in mitigating AD at the in vivo level compared to cerium dioxide nanoparticles (CeO<sub>2</sub>NPs). Nanoparticles were synthesized using the co-precipitation method. Their antioxidant activity was tested. For the bio-assessment, rats were randomly assigned into four groups: AD + GeO<sub>2</sub>NPs, AD + CeO<sub>2</sub>NPs, AD, and control. Serum and brain tau protein, phosphorylated tau, neurogranin, amyloid β peptide 1-42, acetylcholinesterase, and monoamine oxidase levels were measured. Brain histopathological evaluation was conducted. Furthermore, nine AD-related microRNAs were quantified. Nanoparticles were spherical with diameters ranging from 12–27 nm. GeO<sub>2</sub>NPs exhibited a stronger antioxidant activity than CeO<sub>2</sub>NPs. Serum and tissue analyses revealed the regression of AD biomarkers to almost control values upon treatment using GeO<sub>2</sub>NPs. Histopathological observations strongly supported the biochemical outcomes. Then, miR-29a-3p was down-regulated in the GeO<sub>2</sub>NPs-treated group. This pre-clinical study substantiated the scientific evidence favoring the pharmacological application of GeO<sub>2</sub>NPs and CeO<sub>2</sub>NPs in AD treatment. Our study is the first report on the efficiency of GeO<sub>2</sub>NPs in managing AD. Further studies are needed to fully understand their mechanism of action.
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