mTORC2 (Rictor) in Alzheimer’s Disease and Reversal of Amyloid-β Expression-Induced Insulin Resistance and Toxicity in Rat Primary Cortical Neurons

Article type: Research Article

Authors: Lee, Han-Kyu^a | Kwon, Bumsup^a | Lemere, Cynthia A.^b | de la Monte, Suzanne^c | Itamura, Kyohei^a | Ha, Austin Y.^a | Querfurth, Henry W.^{a; 1; *}

Affiliations: [a] Department of Neurology, Rhode Island Hospital and Brown University Warren Alpert Medical School, Providence, RI, USA | [b] Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA | [c] Department of Pathology, Rhode Island Hospital and Brown University Warren Alpert Medical School, Providence, RI, USA

Correspondence: [*] Correspondence to: Henry Querfurth, MD, PhD, Department of Neurology, Rhode Island Hospital and Brown University Warren Alpert Medical School, 593 Eddy St., Providence, RI 02903, USA. Tel.: +1 617 667 5553; Fax: +1 617 667 7981; E-mail: henry_querfurth@brown.edu.

Note: [1] Current address: Department Neurology, Beth Israel Deaconess Medical Center, 330 Brookline Ave. Boston, MA 02215, USA. E-mail: hquerfur@bidmc.harvard.edu.

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.

Keywords: Akt, Alzheimer’s disease, AMPK, autophagy, insulin resistance, mTOR, mTORC2, Rictor

DOI: 10.3233/JAD-161029

Journal: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1015-1036, 2017