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Cited by 111Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Tau and mTOR: The Hotspots for Multifarious Diseases in Alzheimer's Development

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Mueed, Zeba, Tandon, Pallavi, Maurya, Sanjeev Kumar, Deval, Ravi, Kamal, Mohammad A., Poddar, Nitesh Kumar·2019·Frontiers in Neuroscience
DOI 10.3389/fnins.2018.01017PMC PMC6335350
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Abstract

The hyperphosphorylation of tau protein and the overexpression of mTOR are considered to be the driving force behind Aβ plaques and Neurofibrillay Tangles (NFT's), hallmarks of Alzheimer's disease (AD). It is now evident that miscellaneous diseases such as Diabetes, Autoimmune diseases, Cancer, etc. are correlated with AD. Therefore, we reviewed the literature on the causes of AD and investigated the association of tau and mTOR with other diseases. We have discussed the role of insulin deficiency in diabetes, activated microglial cells, and dysfunction of blood-brain barrier (BBB) in Autoimmune diseases, Presenilin 1 in skin cancer, increased reactive species in mitochondrial dysfunction and deregulated Cyclins/CDKs in promoting AD pathogenesis. We have also discussed the possible therapeutics for AD such as GSK3 inactivation therapy, Rechaperoning therapy, Immunotherapy, Hormonal therapy, Metal chelators, Cell cycle therapy, γ-secretase modulators, and Cholinesterase and BACE 1-inhibitors which are thought to serve a major role in combating pathological changes coupled with AD. Recent research about the relationship between mTOR and aging and hepatic Aβ degradation offers possible targets to effectively target AD. Future prospects of AD aims at developing novel drugs and modulators that can potentially improve cell to cell signaling, prevent Aβ plaques formation, promote better release of neurotransmitters and prevent hyperphosphorylation of tau.

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  • Hyperactivation of mTOR signaling seen in TSC could contribute to increased tau protein aggregation and the development of 3R/4R positive tangles.

    “In particular, the hyperactivation of mTOR signaling seen in TSC could contribute to increased tau protein aggregation and the development of 3R/4R positive tangles.”

    From Tuberous sclerosis complex is a novel, amyloid-independent tauopathy associated with elevated phosphorylated 3R/4R tau aggregation (2022) · cites this paper as [7]

    The “AMPK and mTOR” section says that inactivation of the TSC1/TSC2 complex activates an upstream regulator of mTOR, while “mTOR and Tau” links mTOR activation to tau pathology and neurofibrillary tangles. The paper does not establish this process in people with tuberous sclerosis or identify the tangles as 3R/4R positive. Page numbers are unavailable in our copy. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • The mammalian target of rapamycin is a highly conserved protein kinase implicated in cell survival, growth, proliferation, migration, and differentiation.

    “The mammalian target of rapamycin (mTOR) is a highly conserved protein kinase that is implicated in a wide array of cellular and metabolic functions, including cell survival, growth, proliferation, migration, and differentiation (Wong, 2010; Mueed et al., 2018).”

    From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Mueed et al., 2018

    The “Mammalian Target of Rapamycin, mTOR” section (page unavailable) calls mTOR a protein kinase and says it regulates cellular processes including proliferation. The copy also describes its role in metabolic processes, but the passages do not establish that it is highly conserved or specifically link it to cell survival, growth, migration, and differentiation. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Downstream targets of mTOR activation include signaling cascades involving 4EBP1, S6K1, and CDK5, all of which result in tau phosphorylation.

    “For instance, the downstream targets of mTOR activation include signaling cascades involving 4EBP1, S6K1, and CDK5, all of which result in tau phosphorylation (Mueed et al., 2018).”

    From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Mueed et al., 2018

    The figure caption and “Downstream Components of mTOR” section identify 4EBP1 and S6K1 as downstream of mTOR and link their cascades to tau hyperphosphorylation. The “mTOR and Tau” section identifies CDK5 as a kinase involved in tau phosphorylation, but the paper does not identify it as a downstream target of mTOR. No page numbers are available in our copy. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Activation of mTOR is a proposed driver of tau pathology given the involvement of tau-related kinases both upstream and downstream of mTOR signaling and the contribution of mTOR-mediated autophagy dysfunction to tau hyperphosphorylation.

    “Activation of mTOR is also a proposed driver of tau pathology given the involvement of tau-related kinases both upstream and downstream of mTOR signaling (Figure 2) and the contribution of mTOR-mediated autophagy dysfunction to tau hyperphosphorylation (Tramutola et al., 2017; Mueed et al., 2018).”

    From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Mueed et al., 2018

  • Active GSK-3β also activates mTOR.

    “Given that active GSK-3β also activates mTOR (Mueed et al., 2018), tau hyperphosphorylation resulting from seizure-associated GSK-3β upregulation may be further exacerbated by GSK-3β-mediated mTOR activation (Caccamo et al., 2013; Figure 2).”

    From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Mueed et al., 2018

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Authors
Mueed, Z., Tandon, P., Maurya, S. K., Deval, R., Kamal, M. A., & Poddar, N. K.
Affiliations
  • Invertis University (IN)
  • King Abdulaziz University (SA)
Corresponding author
Poddar, Nitesh Kumar
ORCID
Venue
Frontiers in Neuroscience
Publisher
Frontiers Media SA
Published
2019-01-10
Volume
12
Pages
1017-1017
ISSN
1662-453X (ISSN-L)
DOI
10.3389/fnins.2018.01017
PMC
PMC6335350
OpenAlex
W2910097122
Cited by
111
References
136
Citations by year
2026: 9 · 2025: 15 · 2024: 15 · 2023: 13 · 2022: 19 · 2021: 20 · 2020: 17 · 2019: 3
FWCI
1.74
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Neuroscience (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, tau hyperphosphorylation, mTOR, amyloid plaques, neurofibrillary tangles, diabetes mellitus, autoimmune disease, microglial activation, blood-brain barrier dysfunction, presenilin 1, skin cancer, mitochondrial dysfunction, reactive oxygen species, GSK3 inhibition, chaperone therapy, immunotherapy, hormone therapy, metal chelators, γ-secretase modulators, cholinesterase inhibitors, BACE1 inhibitors, aging, Alzheimer's disease therapeutics

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