TY - JOUR

T1 - 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

AU - Pupyshev, Alexander B.

AU - Belichenko, Victor M.

AU - Tenditnik, Michael V.

AU - Bashirzade, Alim A.

AU - Dubrovina, Nina I.

AU - Ovsyukova, Marina V.

AU - Akopyan, Anna A.

AU - Fedoseeva, Larisa A.

AU - Korolenko, Tatiana A.

AU - Amstislavskaya, Tamara G.

AU - Tikhonova, Maria A.

N1 - Funding Information: The study was supported by budgetary funding for basic scientific research of the Federal State Budgetary Scientific Institution Scientific Research Institute of Neurosciences and Medicine (theme No. 122042700001-9 (2021-2025)). Publisher Copyright: © 2022 Elsevier Inc.

PY - 2022/6

Y1 - 2022/6

N2 - 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.

AB - 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.

KW - Amyloid-beta

KW - Autophagy

KW - Brain

KW - Neuroprotection

KW - Rapamycin

KW - Trehalose

KW - Therapies, Investigational

KW - Mice, Transgenic

KW - Sirolimus/pharmacology

KW - Trehalose/pharmacology

KW - Animals

KW - Mice

KW - TOR Serine-Threonine Kinases/metabolism

KW - Alzheimer Disease/metabolism

KW - Amyloid beta-Peptides/metabolism

KW - Disease Models, Animal

UR - http://www.scopus.com/inward/record.url?scp=85131601482&partnerID=8YFLogxK

UR - https://www.mendeley.com/catalogue/57d60b1e-d113-3848-8dd3-ba66263845f3/

U2 - 10.1016/j.pbb.2022.173406

DO - 10.1016/j.pbb.2022.173406

M3 - Article

C2 - 35609863

AN - SCOPUS:85131601482

VL - 217

JO - Pharmacology Biochemistry and Behavior

JF - Pharmacology Biochemistry and Behavior

SN - 0091-3057

M1 - 173406

ER -