The Crosstalk Between Pathological Tau Phosphorylation and Mitochondrial Dysfunction as a Key to Understanding and Treating Alzheimer’s Disease

Guha, Sanjib; Johnson, Gail V.W.; Nehrke, Keith

doi:10.1007/s12035-020-02084-0

Cited by 33 publications

(17 citation statements)

References 159 publications

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“…Furthermore, we found reduced levels of Parkin in the mitochondrial and cytoplasmic fraction of mice with PINK1 overexpression ( Figures 7A,C ), indicating an activation of Parkin by PINK1 as activation of Parkin would induce its own ubiquitylation and degradation ( Zhang et al, 2000 ; Xiong et al, 2009 ; McWilliams et al, 2018 ). In line with previous studies ( Li et al, 2016 ; Guha et al, 2020 ; Szabo et al, 2020 ), assessment of mitochondrial function revealed mitochondrial dysfunction in hTau mice, as evidenced by reduced levels of ATP and elevated MDA levels, both of which were reversed in the context of PINK1 overexpression ( Figures 7D,E ).…”

Section: Resultssupporting

confidence: 92%

“…Our study showed that PINK1 reduced hTau accumulation in mitochondria. We observed mitochondrial dysfunction in hTau mice, which was rescued following overexpression of PINK1, possibly because of PINK1-induced reduction of intracellular tau accumulation ( Li et al, 2016 ; Guha et al, 2020 ; Szabo et al, 2020 ) and the direct protective effects of PINK1 on mitochondria ( Voigt et al, 2016 ; Arena and Valente, 2017 ).…”

Section: Discussionmentioning

confidence: 87%

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PINK1 Alleviates Cognitive Impairments via Attenuating Pathological Tau Aggregation in a Mouse Model of Tauopathy

Jiang

et al. 2022

Front. Cell Dev. Biol.

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As a primary cause of dementia and death in older people, Alzheimer’s disease (AD) has become a common problem and challenge worldwide. Abnormal accumulation of tau proteins in the brain is a hallmark pathology of AD and is closely related to the clinical progression and severity of cognitive deficits. Here, we found that overexpression of phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) effectively promoted the degradation of tau, thereby rescuing neuron loss, synaptic damage, and cognitive impairments in a mouse model of tauopathy with AAV-full-length human Tau (hTau) injected into the hippocampal CA1 area (hTau mice). Overexpression of PINK1 activated autophagy, and chloroquine but not MG132 reversed the PINK1-induced decrease in human Tau levels and cognitive improvement in hTau mice. Furthermore, PINK1 also ameliorated mitochondrial dysfunction induced by hTau. Taken together, our data revealed that PINK1 overexpression promoted degradation of abnormal accumulated tau via the autophagy–lysosome pathway, indicating that PINK1 may be a potential target for AD treatment.

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 87%

PINK1 Alleviates Cognitive Impairments via Attenuating Pathological Tau Aggregation in a Mouse Model of Tauopathy

Jiang

et al. 2022

Front. Cell Dev. Biol.

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“…In contrast, under the same condition, the tested flavones showed significant improvements in p-CREB, BCL2, and BAX, suggesting their promising therapeutic potential. As crosstalk between pathological Tau phosphorylation and mitochondrial dysfunction exists ( Guha et al, 2020 ) and BCL2 counteracts the mitochondria dysfunction-mediated apoptosis, investigation of mitochondria-related apoptotic pathways through caspase-9 and caspase-3 activation may shed light on the mechanism of how quercetin and apigenin provide antiapoptotic effect on ΔK280 Tau RD cells. There are still other TRKB downstream pathways such as phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR.…”

Section: Discussionmentioning

confidence: 99%

Flavones 7,8-DHF, Quercetin, and Apigenin Against Tau Toxicity via Activation of TRKB Signaling in ΔK280 TauRD-DsRed SH-SY5Y Cells

Chiang

Lin

Teng

et al. 2021

Front. Aging Neurosci.

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Alzheimer’s disease (AD) is a progressive neurodegenerative disease with memory loss and cognitive decline. Neurofibrillary tangles (NFTs) formed by hyperphosphorylated Tau protein are one of the pathological hallmarks of several neurodegenerative diseases including AD. Heat shock protein family B (small) member 1 (HSPB1) is a molecular chaperone that promotes the correct folding of other proteins in response to environmental stress. Nuclear factor erythroid 2-like 2 (NRF2), a redox-regulated transcription factor, is the master regulator of the cellular response to excess reactive oxygen species. Tropomyosin-related kinase B (TRKB) is a membrane-bound receptor that, upon binding brain-derived neurotrophic factor (BDNF), phosphorylates itself to initiate downstream signaling for neuronal survival and axonal growth. In this study, four natural flavones such as 7,8-dihydroxyflavone (7,8-DHF), wogonin, quercetin, and apigenin were evaluated for Tau aggregation inhibitory activity and neuroprotection in SH-SY5Y neuroblastoma. Among the tested flavones, 7,8-DHF, quercetin, and apigenin reduced Tau aggregation, oxidative stress, and caspase-1 activity as well as improved neurite outgrowth in SH-SY5Y cells expressing ΔK280 TauRD-DsRed folding reporter. Treatments with 7,8-DHF, quercetin, and apigenin rescued the reduced HSPB1 and NRF2 and activated TRKB-mediated extracellular signal-regulated kinase (ERK) signaling to upregulate cAMP-response element binding protein (CREB) and its downstream antiapoptotic BCL2 apoptosis regulator (BCL2). Knockdown of TRKB attenuated the neuroprotective effects of these three flavones. Our results suggest 7,8-DHF, quercetin, and apigenin targeting HSPB1, NRF2, and TRKB to reduce Tau aggregation and protect cells against Tau neurotoxicity and may provide new treatment strategies for AD.

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“…Decades of research have revealed many ways in which pathologically modified tau may facilitate neurodegeneration (Figure 1), yet the underlying mechanisms behind tau-induced pathology remain scattered and unclear. Toxic tau has been shown to induce inefficient transportation of intracellular cargo to distal compartments of the neuronincluding mitochondria-and hinders synaptic function [23,[36][37][38]. Not only can abnormal tau limit mitochondrial transport, it can also directly interfere with mitochondrial function, impacting energy bioavailability, creating reactive oxygen species, and generating proteostatic stress for the neuron [39].…”

Section: Tau Structure Function and Pathologymentioning

confidence: 99%

Tau Post-Translational Modifications: Potentiators of Selective Vulnerability in Sporadic Alzheimer’s Disease

Carroll

Guha

Nehrke

et al. 2021

Biology

Self Cite

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Sporadic Alzheimer’s Disease (AD) is the most common form of dementia, and its severity is characterized by the progressive formation of tau neurofibrillary tangles along a well-described path through the brain. This spatial progression provides the basis for Braak staging of the pathological progression for AD. Tau protein is a necessary component of AD pathology, and recent studies have found that soluble tau species with selectively, but not extensively, modified epitopes accumulate along the path of disease progression before AD-associated insoluble aggregates form. As such, modified tau may represent a key cellular stressing agent that potentiates selective vulnerability in susceptible neurons during AD progression. Specifically, studies have found that tau phosphorylated at sites such as T181, T231, and S396 may initiate early pathological changes in tau by disrupting proper tau localization, initiating tau oligomerization, and facilitating tau accumulation and extracellular export. Thus, this review elucidates potential mechanisms through which tau post-translational modifications (PTMs) may simultaneously serve as key modulators of the spatial progression observed in AD development and as key instigators of early pathology related to neurodegeneration-relevant cellular dysfunctions.

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The Crosstalk Between Pathological Tau Phosphorylation and Mitochondrial Dysfunction as a Key to Understanding and Treating Alzheimer’s Disease

Cited by 33 publications

References 159 publications

PINK1 Alleviates Cognitive Impairments via Attenuating Pathological Tau Aggregation in a Mouse Model of Tauopathy

PINK1 Alleviates Cognitive Impairments via Attenuating Pathological Tau Aggregation in a Mouse Model of Tauopathy

Flavones 7,8-DHF, Quercetin, and Apigenin Against Tau Toxicity via Activation of TRKB Signaling in ΔK280 TauRD-DsRed SH-SY5Y Cells

Tau Post-Translational Modifications: Potentiators of Selective Vulnerability in Sporadic Alzheimer’s Disease

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