mTOR and neuronal cell cycle reentry: how impaired brain insulin signaling promotes Alzheimer's disease
Open accessAbstract
A major obstacle to presymptomatic diagnosis and disease‐modifying therapy for Alzheimer's disease (AD) is inadequate understanding of molecular mechanisms of AD pathogenesis. For example, impaired brain insulin signaling is an AD hallmark, but whether and how it might contribute to the synaptic dysfunction and neuron death that underlie memory and cognitive impairment has been mysterious. Neuron death in AD is often caused by cell cycle reentry (CCR) mediated by amyloid‐β oligomers (AβOs) and tau, the precursors of plaques and tangles. We now report that CCR results from AβO‐induced activation of the protein kinase complex, mTORC1, at the plasma membrane and mTORC1‐dependent tau phosphorylation, and that CCR can be prevented by insulin‐stimulated activation of lysosomal mTORC1. AβOs were also shown previously to reduce neuronal insulin signaling. Our data therefore indicate that the decreased insulin signaling provoked by AβOs unleashes their toxic potential to cause neuronal CCR, and by extension, neuron death.
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Hyperactivation of the S6K proteins correlates with increased Tau pathology and dysregulation of the insulin/IGF/mTOR signaling pathway, both in individuals with DS-AD and in idiopathic AD.
“Hyperactivation of the S6K proteins correlates with increased Tau pathology and dysregulation of the insulin/IGF/mTOR signaling pathway, both in individuals with DS‐AD 55 and in idiopathic AD. 56”
From Disruption of hippocampal upstream regulators of mTOR and insulin pathways in Down syndrome with Alzheimer's disease neuropathology: Preliminary observations (2026) · cites this paper as [56]
For the idiopathic AD portion to which citation 56 is attached, Results §4.5 links mTOR activity to tau phosphorylation, probably through S6K, and Results §4.6 reports tau phosphorylation in human AD tissue. The paper does not report a correlation in those individuals between S6K hyperactivation, increased tau pathology, and dysregulation of the insulin/IGF/mTOR pathway. The DS-AD portion has a separate citation and is not assessed against this source. (LLM, conf=0.84)
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A Unique Homeostatic Signaling Pathway Links Synaptic Inactivity to Postsynaptic mTORC1
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SOD1 mediates lysosome-to-mitochondria communication and its dysregulation by amyloid-β oligomers
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Self-citationStructural and functional damage to neuronal nuclei caused by extracellular tau oligomers
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Self-citationIntraneuronal Tau Misfolding Induced by Extracellular Amyloid-β Oligomers
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Self-citationMitochondrial dysfunction: A potential target for Alzheimer’s disease intervention and treatment
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A human-based multi-gene signature enables quantitative drug repurposing for metabolic disease
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Dysregulation of mTOR by tau in Alzheimer's disease
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Self-citationEthnicity-specific and overlapping alterations of brain hydroxymethylome in Alzheimer’s disease
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A common molecular and cellular pathway in developing Alzheimer and cancer
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Tortuous Paths of Insulin Signaling and Mitochondria in Alzheimer’s Disease
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A Mutant Variant of E2F4 Triggers Multifactorial Therapeutic Effects in 5xFAD Mice
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Alzheimer’s disease as a metabolic disorder
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SNCA genetic lowering reveals differential cognitive function of alpha-synuclein dependent on sex
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Developing theragnostics for Alzheimer's disease: Insights from cancer treatment
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Transcriptome and Translatome Regulation of Pathogenesis in Alzheimer’s Disease Model Mice
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Self-citationTesting the Neuroprotective Properties of PCSO-524® Using a Neuronal Cell Cycle Suppression Assay
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A Novel Communication Pathway Between Lysosomes and Mitochondria Is Disrupted in Alzheimer’s Disease
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Mécanisme d’activation neuronale de mTORC1 et de son altération par le peptide amyloïde β
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- Authors
- Norambuena, A., Wallrabe, H., McMahon, L., Silva, A., Swanson, E., Khan, S. S., Baerthlein, D., Kodis, E., Oddo, S., Mandell, J. W., & Bloom, G. S.
- Affiliations
- University of Virginia (US)
- Department of Biology University of Virginia Charlottesville VA USA
- Arizona State University (US)
- Corresponding author
- Norambuena, Andrés
- Bloom, George S.
- ORCID
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2016-09-28
- Volume
- 13
- Issue
- 2
- Pages
- 152-167
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- PMC
- PMC5318248
- OpenAlex
- W2524820045
- Cited by
- 79
- References
- 66
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 7 · 2023: 5 · 2022: 7 · 2021: 13 · 2020: 6 · 2019: 13 · 2018: 13 · 2017: 8
- FWCI
- 9.13
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Alzheimer s & Dementia (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (F31 NS092444)
- Cure Alzheimer's Fund
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, mTORC1
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Mechanistic Target of Rapamycin Complex 2, Aged, Aged, 80 and over, Alzheimer Disease, Animals, Cell Cycle, Cell Membrane, Cells, Cultured, Cerebral Cortex, Humans, Hydrocephalus, Normal Pressure, Insulin, Lysosomes, Middle Aged, Neurons, Amyloid beta-Peptides, tau Proteins, Mice, Knockout
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