The Role of α-synuclein and Tau Hyperphosphorylation-Mediated Autophagy and Apoptosis in Lead-induced Learning and Memory Injury

Zhang, Jianbin; Cai, Tongjian; Zhao, Fang; Yao, Ting; Chen, Yaoming; Liu, Xinqin; Luo, Wenjing; Chen, Jingyuan

doi:10.7150/ijbs.4499

Cited by 89 publications

(36 citation statements)

References 33 publications

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“…The present study indicated that in our animal or cell model, the manganese exposure level we set caused tested sites at Ser199, Ser202 sites, Ser396 and Ser404 phosphorylation, with Ser199, Ser396 more sentivity. Other literatures have discovered that other heavy metals, including cadmium, lead caused tau hyperphosphorylation, but showing different phosphorylated sites [33][34][35][36]. Even exposed to Mn, the sites of phosphorylation of tau were not consistent in different models.…”

Section: Abl127 Reduces Mn-induced Tau Hyperphosphorylation By Reversmentioning

confidence: 93%

The down-regulation of PP2Ac demethylation attenuates learning and memory impairment in Manganism

Cai

Tang

et al. 2020

Preprint

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Background: Protein phosphatase 2A (PP2A) is considered a potential therapeutic target for neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD), and catalytic unit methylation of PP2A that relies on methionine and its intermediate S-adenosylmethionine (SAM) regulates most of protein phosphorylation. Manganese overload caused methionine decrease and tau phosphorylation in brain. However, the relationship between PP2Ac and manganese poisoning is not fully understood. In present study, we concentrate on the ameliorative effect of PP2Ac demethylation on cognitive impairment induced by manganese. Methods: Adult male Sprague-Dawley rats (n = 80; 200-250 g) were divided into Subacute (4W) and chronic (16W) exposure groups. Each exposure group consisted of four treatment groups: control (i.p., saline), Mn, methionine, and methionine plus Mn treatment group. N2a cells with different manganese exposure concentrations were cultured with or without methionine, furthermore, ABL127 is used in follow-up studies. Morris water maze, Alamar Blue assay, flow cytometry, Western blot, liquid chromatography, 2,7-dichlorofluorescein diacetate assay were performed to assess spatial memory, cell viability and apoptosis levels，phosphorylated tau and PP2Ac pathway protein expression, SAM content in brain tissue and cells, oixidative stress related markers. Results: Manganese-exposed rats had elevated levels of phosphorylated Tau and PP2Ac demethylation accompanied by abnormal rise of PPME1 expression in cortex and hippocampus as well as restricted SAM in hippocampus and spatial memory function. Up-regulation of PP2Ac demethylation caused by SAM increase after methionine treatment or PPME1 inhibition after ABL127 treatment significantly reduced p-tau, apoptosis and ROS levels, and increased cell viability and GSH levels. In addition, methionine treatment in vivo significantly increased the number of crossings and reduced the escape latency. Conclusion: Methionine and ABL127 treatment can prevent manganese-induced tau hyperphosphorylation and oxidative stress injury, thus improve spatial memory. This improvement is mediated by down-regulation of PP2Ac demethylation. This study confirms that PP2Ac demethylation plays an important role in manganese neurotoxicity and provides a potentially powerful therapeutic strategy for such neurodegenerative diseases.

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Section: Abl127 Reduces Mn-induced Tau Hyperphosphorylation By Reversmentioning

confidence: 93%

The down-regulation of PP2Ac demethylation attenuates learning and memory impairment in Manganism

Cai

Tang

et al. 2020

Preprint

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“…Historically, neurodegenerative diseases have been categorized by which of several proteins are produced in unusually high amounts, those relevant to this section of this text being termed the synucleopathies. While the archetypal example is PD, this protein has been correlated closely with AD outcomes (Larson et al ., ; Korff et al ., ) and been described in both TBI (Mondello et al ., ; Acosta et al ., ) and Pb 2+ toxicity (Zhang et al ., ). As well as in the brain, α‐synuclein also has a predilection for forming in the gut wall (Natale et al ., ; Cersosimo et al ., ).…”

Section: New Tnf‐based Insightsmentioning

confidence: 99%

“…More contemporary reviews describe these manifestations in some detail, including negative effects of Pb 2+ on intelligence, learning, memory, executive function, processing speed, language, visuospatial skills and affect (Mason et al, 2014), glutamate release, LTP and synaptic plasticity, increased amyloid precursor protein and increased Aβ (Basha et al, 2005;White et al, 2007) in some detail. Others describe α-synuclein accumulation (Zhang et al, 2012) and increased tau phosphorylation (Li et al, 2010;Zhang et al, 2012;Gassowska et al, 2016). Publications on these topics were contemporary with others linking Pb 2+ exposure with increased TNF production, initially using peripheral cells (Guo et al, 1996;Cheng et al, 2006) but later microglia (Li et al, 2009;Kumawat et al, 2014;Li et al, 2014).…”

Section: Insights From Lead Toxicitymentioning

confidence: 99%

Therapeutic implications of how TNF links apolipoprotein E, phosphorylated tau, α‐synuclein, amyloid‐β and insulin resistance in neurodegenerative diseases

Clark

Vissel

2018

British J Pharmacology

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While cytokines such as TNF have long been recognized as essential to normal cerebral physiology, the implications of their chronic excessive production within the brain are now also increasingly appreciated. Syndromes as diverse as malaria and lead poisoning, as well as non‐infectious neurodegenerative diseases, illustrate this. These cytokines also orchestrate changes in tau, α‐synuclein, amyloid‐β levels and degree of insulin resistance in most neurodegenerative states. New data on the effects of salbutamol, an indirect anti‐TNF agent, on α‐synuclein and Parkinson's disease, APOE4 and tau add considerably to the rationale of the anti‐TNF approach to understanding, and treating, these diseases. Therapeutic advances being tested, and arguably useful for a number of the neurodegenerative diseases, include a reduction of excess cerebral TNF, whether directly, with a specific anti‐TNF biological agent such as etanercept via Batson's plexus, or indirectly via surgically implanting stem cells. Inhaled salbutamol also warrants investigating further across the neurodegenerative disease spectrum. It is now timely to integrate this range of new information across the neurodegenerative disease spectrum, rather than keep seeing it through the lens of individual disease states.

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“…COX-2 AGGRAVATES ALZHEIMER'S DISEASE cultured neurons (79,80). In contrast, tau also decreased apoptosis via inhibition of caspase-3 activity in cultured cells (81) and Sprague-Dawley (SD) rats (82). The role of tau in autophagy is controversial (83,84).…”

Section: Signaling Pathways Involved In Mediating the Effects Of Cox-mentioning

confidence: 99%

Integrated communications between cyclooxygenase‐2 and Alzheimer's disease

Guan

Wang

2018

FASEB j.

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Elevated levels of cyclooxygenase-2 (COX-2) and prostaglandins (PGs) are involved in the pathogenesis of Alzheimer's disease (AD), which is characterized by the accumulation of β-amyloid protein (Aβ) and tau hyperphosphorylation. However, the gaps in our knowledge of the roles of COX-2 and PGs in AD have not been filled. Here, we summarized the literature showing that COX-2 dysregulation obviously influences abnormal cleavage of β-amyloid precursor protein, aggregation and deposition of Aβ in β-amyloid plaques and the inclusion of phosphorylated tau in neurofibrillary tangles. Neuroinflammation, oxidative stress, synaptic plasticity, neurotoxicity, autophagy, and apoptosis have been assessed to elucidate the mechanisms of COX-2 regulation of AD. Notably, an imbalance of these factors ultimately produces cognitive decline. The current review substantiates our understanding of the mechanisms of COX-2-induced AD and establishes foundations for the design of feasible therapeutic strategies to treat AD.-Guan, P.-P. and Wang, P. Integrated communications between cyclooxygenase-2 and Alzheimer's disease.

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The Role of α-synuclein and Tau Hyperphosphorylation-Mediated Autophagy and Apoptosis in Lead-induced Learning and Memory Injury

Cited by 89 publications

References 33 publications

The down-regulation of PP2Ac demethylation attenuates learning and memory impairment in Manganism

The down-regulation of PP2Ac demethylation attenuates learning and memory impairment in Manganism

Therapeutic implications of how TNF links apolipoprotein E, phosphorylated tau, α‐synuclein, amyloid‐β and insulin resistance in neurodegenerative diseases

Integrated communications between cyclooxygenase‐2 and Alzheimer's disease

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