title: mTORC2 (Rictor) in Alzheimer's Disease and Reversal of Amyloid-β Expression-Induced Insulin Resistance and Toxicity in Rat Primary Cortical Neurons.
abstract: Mammalian target of rapamycin complex 1 (mTORC1), a nutrient sensor and central controller of cell growth and proliferation, is altered in various models of Alzheimer's disease (AD). Even less studied or understood in AD is mammalian target of rapamycin complex 2 (mTORC2) that influences cellular metabolism, in part through the regulations of Akt/PKB and SGK. Dysregulation of insulin/PI3K/Akt signaling is another important feature of AD pathogenesis. We found that both total mTORC1 and C2 protein levels and individual C1 and C2 enzymatic activities were decreased in human AD brain samples. In two rodent AD models, mTORC1 and C2 activities were also decreased. In a neuronal culture model of AD characterized by accumulation of cellular amyloid-β (Aβ)42, mTORC1 activity was reduced. Autophagic vesicles and markers were correspondingly increased and new protein synthesis was inhibited, consistent with mTORC1 hypofunction. Interestingly, mTORC2 activity in neural culture seemed resistant to the effects of intracellular amyloid. In various cell lines, Aβ expression provoked insulin resistance, characterized by inhibition of stimulated Akt phosphorylation, and an increase in negative mTORC1 regular, p-AMPK, itself a nutrient sensor. Rapamycin decreased phospho-mTOR and to lesser degree p-Rictor. This further suppression of mTORC1 activity protected cells from Aβ-induced toxicity and insulin resistance. More striking, Rictor over-expression fully reversed the Aβ-effects on primary neuronal cultures. Finally, using in vitro assay, Rictor protein addition completely overcame oligomeric Aβ-induced inhibition of the PDK-Akt activation step. We conclude that striking a new balance by restoring mTORC2 abundance and/or inhibition of mTORC1 has therapeutic potential in AD.
authors.affiliation: Department of Neurology, Rhode Island Hospital and Brown University Warren Alpert Medical School, Providence, RI, USA.
authors.forename: Han-Kyu
authors.initials: HK
authors.lastname: Lee
authors.affiliation: Department of Neurology, Rhode Island Hospital and Brown University Warren Alpert Medical School, Providence, RI, USA.
authors.forename: Bumsup
authors.initials: B
authors.lastname: Kwon
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Lemere
authors.affiliation: Department of Pathology, Rhode Island Hospital and Brown University Warren Alpert Medical School, Providence, RI, USA.
authors.forename: Suzanne
authors.initials: S
authors.lastname: de la Monte
authors.affiliation: Department of Neurology, Rhode Island Hospital and Brown University Warren Alpert Medical School, Providence, RI, USA.
authors.forename: Kyohei
authors.initials: K
authors.lastname: Itamura
authors.affiliation: Department of Neurology, Rhode Island Hospital and Brown University Warren Alpert Medical School, Providence, RI, USA.
authors.forename: Austin Y
authors.initials: AY
authors.lastname: Ha
authors.affiliation: Department of Neurology, Rhode Island Hospital and Brown University Warren Alpert Medical School, Providence, RI, USA.
authors.forename: Henry W
authors.initials: HW
authors.lastname: Querfurth
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism; D000076225:Mechanistic Target of Rapamycin Complex 2 / Q000378:metabolism*; D008822:Mice, Transgenic; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt
keywords: AMPK; Akt; Alzheimer’s disease; Rictor; autophagy; insulin resistance; mTOR; mTORC2