ArticleJournal of Alzheimer's disease : JAD2017
mTORC2 (Rictor) in Alzheimer's Disease and Reversal of Amyloid-β Expression-Induced Insulin Resistance and Toxicity in Rat Primary Cortical Neurons.
Article in Journal of Alzheimer's disease : JAD, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 51 citations in OpenAlex.
- Disruption of hippocampal upstream regulators of mTOR and insulin pathways in Down syndrome with Alzheimer's disease neuropathology: Preliminary observations.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- A Rapamycin Pharmacogenomic Approach for the Childhood Dementia Niemann-Pick C.Journal of inherited metabolic disease · 2026Article
- Novel Alzheimer's disease-associated variants and genetic interactions identified from UK biobank whole-exome sequencing data using IBI-DT.Scientific reports · 2026Article
- Rewiring mTOR signaling in Alzheimer's disease: emerging mTOR modulators beyond oncology.Bioscience reports · 2026Review
- Neurosteroid-Mediated Neuroprotection via mTORC1/AMPK/BDNF Signaling Pathway in Alzheimer's Disease.Molecular neurobiology · 2026Review
- Targeting the mTOR Pathway with Natural Products: A Potential Therapeutic Approach for Autism Spectrum Disorders.Current neuropharmacology · 2026Review
- Rictor/mTORC2 signaling pathway mediates Benzo[a]pyrene-induced renal injury.Scientific reports · 2025Article
- Metabolic reprogramming in neurodegenerative diseases: New insights into mTOR-mediated microglial polarization.Journal of translational internal medicine · 2025Article
- Temporal transcriptomic dynamics in rat spinal cord after tibial fracture unveil crosstalk between spinal cord and bone.Scientific reports · 2025Article
- Role of branched chain amino acid metabolism on aging.Biogerontology · 2025Review
- Insight into the Regulation of NDRG1 Expression.International journal of molecular sciences · 2025Review
- Type 2 Diabetes Mellitus Exacerbates Pathological Processes of Parkinson's Disease: Insights from Signaling Pathways Mediated by Insulin Receptors.Neuroscience bulletin · 2025Review
- Exploring cannabinoid modulation on autophagy mechanisms in Alzheimer's disease: a review.Frontiers in pharmacology · 2025Review
- Review
- mTOR Dysregulation, Insulin Resistance, and Hypertension.Biomedicines · 2024Review
- Landscape of brain myeloid cell transcriptome along the spatiotemporal progression of Alzheimer's disease reveals distinct sequential responses to Aβ and tau.Acta neuropathologica · 2024Article
- Early-Stage Moderate Alcohol Feeding Dysregulates Insulin-Related Metabolic Hormone Expression in the Brain: Potential Links to Neurodegeneration Including Alzheimer's Disease.Journal of Alzheimer's disease reports · 2024Article
- Skeletal muscle proteome differs between youngFrontiers in aging neuroscience · 2024Article
- Conquering Insulin Network Dysfunctions in Alzheimer's Disease: Where Are We Today?Journal of Alzheimer's disease : JAD · 2024Review
- Dysregulated mTOR networks in experimental sporadic Alzheimer's disease.Frontiers in cellular neuroscience · 2024Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 1 country.
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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.
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