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

Mueed, Zeba; Tandon, Pallavi; Maurya, Sanjeev Kumar; Deval, Ravi; Kamal, Mohammad Amjad; Poddar, Nitesh Kumar

doi:10.3389/fnins.2018.01017

Cited by 85 publications

(64 citation statements)

References 133 publications

(140 reference statements)

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“…S2). This result is in line with others, where mTOR is found to participate in memory formation and consolidation, and seems targeted by Aβ42 (Lin et al, 2014;Mueed et al, 2019;Uddin et al, 2018). Thus, mTOR inhibition may be another experimental strategy, independent from PI3K activation, to be considered in future AD studies.…”

Section: Pi3k Mechanisms In Aβ42-induced Synapse Toxicitysupporting

confidence: 91%

PI3K activation prevents Aβ42-induced synapse loss and favors insoluble amyloid deposits formation

Arnés

Romero

Casas‐Tintó

et al. 2019

Preprint

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Alzheimer's disease is, to a large extent, a disease of the synapse triggered by the unbalanced amyloidogenic cleavage of the amyloid precursor protein APP. Excess of Aβ42 peptide in particular is considered a hallmark of the disease. Here we drive the expression of the human Aβ42 peptide to assay the neuroprotective effects of PI3K in adult Drosophila melanogaster. We show that the neuronal expression of the human peptide elicits progressive toxicity in the adult. The pathological traits include reduced axonal transport, synapse loss, defective climbing ability and olfactory perception, as well as life-span reduction. The Aβ42-dependent synapse decay does not involve transcriptional changes in the core synaptic protein encoding genes: bruchpilot, liprin and synaptobrevin. All toxicity features, however, are suppressed by the co-expression of PI3K. Moreover, PI3K activation induces a significant increase of 6E10 and Thioflavin-positive amyloid deposits. Mechanistically, we suggest that Aβ42-Ser26 could be a candidate residue for direct or indirect phosphorylation by PI3K. Finally, along with these in vivo experiments we further analyze Aβ42 toxicity and its suppression by PI3K activation in in vitro assays with SH-SY5Y human neuroblastoma cell cultures, where Aβ42 aggregation into large insoluble deposits is reproduced. Taken together, these results uncover a potential novel pharmacological strategy against this disease with PI3K activation as a target.

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Section: Pi3k Mechanisms In Aβ42-induced Synapse Toxicitysupporting

confidence: 91%

PI3K activation prevents Aβ42-induced synapse loss and favors insoluble amyloid deposits formation

Arnés

Romero

Casas‐Tintó

et al. 2019

Preprint

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“…Protein misfolding and subsequent aggregation is at the heart of Alzheimer's pathophysiology (Mueed et al, 2019). The mTORC1 complex has been reported to stimulate protein synthesis (Papadopoli et al, 2019).…”

Section: Role Of Mtor In Admentioning

confidence: 99%

“…Moreover, mTOR mediates tau synthesis and phosphorylation at specific sites and is found to co-localize with NFTs (An et al, 2003;Tang et al, 2013). This results in microtubule instability as tau is an essential microtubule associated protein and its hyperphosphorylation causes it to detach from microtubules (Mueed et al, 2019).…”

Section: Role Of Mtor In Admentioning

confidence: 99%

Integrated Pathways of COX-2 and mTOR: Roles in Cell Sensing and Alzheimer’s Disease

2020

Self Cite

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Cyclooxygenases (COX) are enzymes catalyzing arachidonic acid into prostanoids. COX exists in three isoforms: COX-1, 2, and 3. COX-1 and COX-2 have been widely studied in order to explore and understand their involvement in Alzheimer's disease (AD), a progressive neuroinflammatory dementia. COX-2 was traditionally viewed to be expressed only under pathological conditions and to have detrimental effects in AD pathophysiology and neurodegeneration. However, an increasing number of reports point to much more complex roles of COX-2 in AD. Mammalian/mechanistic target of rapamycin (mTOR) has been considered as a hub which integrates multiple signaling cascades, some of which are also involved in AD progression. COX-2 and mTOR are both involved in environmental sensing, growth, and metabolic processes of the cell. They are also known to act in cooperation in many different cancers and thus, their role together in normal cellular functions as well as AD has been explored in this review. Some of the therapeutic approaches targeting COX-2 and mTOR in AD and cancer are also discussed.

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“…The mammalian target of rapamycin (mTOR) regulates autophagy. The use of rapamycin or starvation could inhibit mTOR activity and thereby increase autophagy activity [ 104 , 105 ]. In in vitro and rodent AD model studies, mTOR activity was correlated with Aβ accumulation.…”

Section: Autophagy and Nddsmentioning

confidence: 99%

Melatonin and Autophagy in Aging-Related Neurodegenerative Diseases

Luo

Sandhu

Rungratanawanich

et al. 2020

IJMS

110

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With aging, the nervous system gradually undergoes degeneration. Increased oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, and cell death are considered to be common pathophysiological mechanisms of various neurodegenerative diseases (NDDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), organophosphate-induced delayed neuropathy (OPIDN), and amyotrophic lateral sclerosis (ALS). Autophagy is a cellular basic metabolic process that degrades the aggregated or misfolded proteins and abnormal organelles in cells. The abnormal regulation of neuronal autophagy is accompanied by the accumulation and deposition of irregular proteins, leading to changes in neuron homeostasis and neurodegeneration. Autophagy exhibits both a protective mechanism and a damage pathway related to programmed cell death. Because of its “double-edged sword”, autophagy plays an important role in neurological damage and NDDs including AD, PD, HD, OPIDN, and ALS. Melatonin is a neuroendocrine hormone mainly synthesized in the pineal gland and exhibits a wide range of biological functions, such as sleep control, regulating circadian rhythm, immune enhancement, metabolism regulation, antioxidant, anti-aging, and anti-tumor effects. It can prevent cell death, reduce inflammation, block calcium channels, etc. In this review, we briefly discuss the neuroprotective role of melatonin against various NDDs via regulating autophagy, which could be a new field for future translational research and clinical studies to discover preventive or therapeutic agents for many NDDs.

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

Cited by 85 publications

References 133 publications

PI3K activation prevents Aβ42-induced synapse loss and favors insoluble amyloid deposits formation

PI3K activation prevents Aβ42-induced synapse loss and favors insoluble amyloid deposits formation

Integrated Pathways of COX-2 and mTOR: Roles in Cell Sensing and Alzheimer’s Disease

Melatonin and Autophagy in Aging-Related Neurodegenerative Diseases

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