Результаты исследований: Научные публикации в периодических изданиях › статья › Рецензирование
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. / Pupyshev, Alexander B.; Belichenko, Victor M.; Tenditnik, Michael V. и др.
в: Pharmacology Biochemistry and Behavior, Том 217, 173406, 06.2022.Результаты исследований: Научные публикации в периодических изданиях › статья › Рецензирование
}
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 -
ID: 36436713