Truncated Tau Induces Mitochondrial Transport Failure Through the Impairment of TRAK2 Protein and Bioenergetics Decline in Neuronal Cells

Quintanilla, Rodrigo A.; Tapia-Monsalves, Carola; Vergara, Erick H.; Pérez, Marı́a José; Aránguiz, Alejandra

doi:10.3389/fncel.2020.00175

Cited by 35 publications

(36 citation statements)

References 61 publications

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“…Importantly, we have demonstrated that the expression of caspase-3 cleaved tau in neuronal cell lines and primary neurons negatively affects mitochondrial health in response to calcium stress and Aβ treatment [9,11]. Furthermore, mitochondrial impairment induced by pathological modifications of tau can also affect neuronal communication [12][13][14]. Moreover, the expression of caspase-3 cleaved tau affected mitochondrial health-inducing depolarization and mitochondrial fragmentation by impairing the mitochondrial fusion regulator Opa1 [9,12,15].…”

Section: Introductionmentioning

confidence: 92%

“…Conditionally immortalized cortical neurons (CN1.4) [10,13] were cultured in 1×Dulbecco's modified Eagle's medium with high glucose (DMEM) (Mediatech CellGro, Corning, NY, USA), supplemented with 5% inactivated fetal bovine serum (Mediatech Inc., Manassas, VA, USA) with 1% penicillin/streptomycin (Mediatech Inc., CellGro, Corning, NY, USA), and incubated at 33 • C and 5% CO 2 . In addition, these cells were transiently transfected with plasmids containing GFP, GFP-full-length tau (GFP-T4), and GFP-caspase-3 cleaved tau (GFP-T4C3), and after 48 h, transfected cells were treated with 10 µm of SFN (ChemCruz, Santa Cruz Biotechnology, Dallas, TX, USA) for 24 h.…”

Section: Cell Culturementioning

confidence: 99%

“…Tau constructs tagged with GFP, GFP-full-length tau (GFP-T4), and GFP-caspase-3 cleaved tau (GFP-T4C3) were generated as previously described [9,11,13]. In addition, CN1.4 cells were transiently transfected with plasmids containing tau constructs using Lipofectamine 2000 (Thermo Fisher Scientific, Waltham, MA, USA) diluted in OptiMEM (Thermo Fisher Scientific, Waltham, MA, USA) [9,10,12].…”

Section: Tau Constructsmentioning

confidence: 99%

“…Moreover, the expression of caspase-3 cleaved tau affected mitochondrial health-inducing depolarization and mitochondrial fragmentation by impairing the mitochondrial fusion regulator Opa1 [9,12,15]. Finally, the expression of this cleaved tau form reduced mitochondrial transport in hippocampal neurons, suggesting that these actions could be relevant to the synaptic deficiency observed in AD [12,13].…”

Section: Introductionmentioning

confidence: 99%

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Activation of the Nrf2 Pathway Prevents Mitochondrial Dysfunction Induced by Caspase-3 Cleaved Tau: Implications for Alzheimer’s Disease

et al. 2022

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Alzheimer’s disease (AD) is characterized by memory and cognitive impairment, accompanied by the accumulation of extracellular deposits of amyloid β-peptide (Aβ) and the presence of neurofibrillary tangles (NFTs) composed of pathological forms of tau protein. Mitochondrial dysfunction and oxidative stress are also critical elements for AD development. We previously showed that the presence of caspase-3 cleaved tau, a relevant pathological form of tau in AD, induced mitochondrial dysfunction and oxidative damage in different neuronal models. Recent studies demonstrated that the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) plays a significant role in the antioxidant response promoting neuroprotection. Here, we studied the effects of Nrf2 activation using sulforaphane (SFN) against mitochondrial injury induced by caspase-3 cleaved tau. We used immortalized cortical neurons to evaluate mitochondrial bioenergetics and ROS levels in control and SFN-treated cells. Expression of caspase-3 cleaved tau induced mitochondrial fragmentation, depolarization, ATP loss, and increased ROS levels. Treatment with SFN for 24 h significantly prevented these mitochondrial abnormalities, and reduced ROS levels. Analysis of Western blots and rt-PCR studies showed that SFN treatment increased the expression of several Nrf2-related antioxidants genes in caspase-3 cleaved tau cells. These results indicate a potential role of the Nrf2 pathway in preventing mitochondrial dysfunction induced by pathological forms of tau in AD.

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Section: Introductionmentioning

confidence: 92%

Section: Cell Culturementioning

confidence: 99%

Section: Tau Constructsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Activation of the Nrf2 Pathway Prevents Mitochondrial Dysfunction Induced by Caspase-3 Cleaved Tau: Implications for Alzheimer’s Disease

et al. 2022

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“…Hyperphosphorylated tau causes microtubule instability, which leads to neuronal synaptic disruption, connectivity and plasticity damage, neuronal death ultimately. A study has shown that caspase-cleaved tau increases TRAK2-mitochondria binding and decreases the ATP production available for the locomotion of these organelles, resulting in adverse effects on mitochondrial transport (Quintanilla et al, 2020).…”

Section: Alzheimer's Diseasementioning

confidence: 99%

Mitochondrial Dynamics: A Key Role in Neurodegeneration and a Potential Target for Neurodegenerative Disease

et al. 2021

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In neurodegenerative diseases, neurodegeneration has been related to several mitochondrial dynamics imbalances such as excessive fragmentation of mitochondria, impaired mitophagy, and blocked mitochondria mitochondrial transport in axons. Mitochondria are dynamic organelles, and essential for energy conversion, neuron survival, and cell death. As mitochondrial dynamics have a significant influence on homeostasis, in this review, we mainly discuss the role of mitochondrial dynamics in several neurodegenerative diseases. There is evidence that several mitochondrial dynamics-associated proteins, as well as related pathways, have roles in the pathological process of neurodegenerative diseases with an impact on mitochondrial functions and metabolism. However, specific pathological mechanisms need to be better understood in order to propose new therapeutic strategies targeting mitochondrial dynamics that have shown promise in recent studies.

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Targeting Mitochondrial Dynamics as a Restorative Approach in the Treatment of Alzheimer’s Disease

Pandey,

Bisht,

Kumari

et al. 2023

Deciphering Drug Targets for Alzheimer’s Disease

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Truncated Tau Induces Mitochondrial Transport Failure Through the Impairment of TRAK2 Protein and Bioenergetics Decline in Neuronal Cells

Cited by 35 publications

References 61 publications

Activation of the Nrf2 Pathway Prevents Mitochondrial Dysfunction Induced by Caspase-3 Cleaved Tau: Implications for Alzheimer’s Disease

Activation of the Nrf2 Pathway Prevents Mitochondrial Dysfunction Induced by Caspase-3 Cleaved Tau: Implications for Alzheimer’s Disease

Mitochondrial Dynamics: A Key Role in Neurodegeneration and a Potential Target for Neurodegenerative Disease

Targeting Mitochondrial Dynamics as a Restorative Approach in the Treatment of Alzheimer’s Disease

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