Combined induction of mTOR-dependent and mTOR-independent pathways of autophagy activation as an experimental therapy for Alzheimer's disease-like pathology in a mouse model

Pharmacology Biochemistry and Behavior. 2022. Vol. 217. Article 173406.

Pupyshev A., Belichenko V., Tenditnik M., Bashirzade A., Dubrovina N., Ovsyukova M., Akopyan A., Fedoseeva L., Korolenko T., Amstislavskaya T., Tikhonova M.

Alzheimer's disease (AD) is associated with amyloid-β (Aβ) accumulation that might be hindered by autophagy. There are two ways to induce autophagy: through mTOR-dependent and mTOR-independent pathways (here, by means of rapamycin and trehalose, respectively). The aim of this study was to evaluate the contribution of these pathways and their combination to the treatment of experimental AD. Mice were injected bilaterally intracerebroventricularly with an Aβ fragment (25–35) to set up an AD model. Treatment with rapamycin (10 mg/kg, every other day), trehalose consumption with drinking water (2 mg/mL, ad libitum), or their combination started 2 days after the surgery and lasted for 2 weeks. Open-field, plus-maze, and passive avoidance tests were used for behavioral phenotyping. Neuronal density, Aβ accumulation, and the expression of autophagy marker LC3-II and neuroinflammatory marker IBA1 were measured in the frontal cortex and hippocampus. mRNA levels of autophagy genes (Atg8, Becn1, and Park2) were assessed in the hippocampus. Trehalose but not rapamycin caused pronounced prolonged autophagy induction and transcriptional activation of autophagy genes. Both drugs effectively prevented Aβ deposition and microglia activation. Autophagy inhibitor 3-methyladenine significantly attenuated autophagy activation and disturbed the effect of the inducers on Aβ load. The inducers substantially reversed behavioral and neuronal deficits in Aβ-injected mice. In many cases, the best outcomes were achieved with the combined treatment. Thus, trehalose alone or combined autophagy activation by the two inducers may be a promising treatment approach to AD-like neurodegeneration. Some aspects of interaction between mTOR-dependent and mTOR-independent pathways of autophagy are discussed.

Keywords: Neuroprotection, Trehalose, Amyloid-beta, Rapamycin