scholarly journals Clioquinol Decreases Levels of Phosphorylated, Truncated, and Oligomerized Tau Protein

2021 ◽  
Vol 22 (21) ◽  
pp. 12063
Author(s):  
Gaoping Lin ◽  
Feiyan Zhu ◽  
Nicholas M. Kanaan ◽  
Rei Asano ◽  
Norimichi Shirafuji ◽  
...  
Keyword(s):  
Tau Protein ◽  
Senile Plaques ◽  
Neuroblastoma Cell ◽  
Amyloid Β ◽  
Mitogen Activated Protein Kinase ◽  
Human Neuroblastoma Cell ◽  
Amyloid Β Protein ◽  
Phosphorylated Tau ◽  
Human Neuroblastoma ◽  
Phosphorylated Tau Protein

The neuropathological hallmarks of Alzheimer’s disease (AD) are senile plaques (SPs), which are composed of amyloid β protein (Aβ), and neurofibrillary tangles (NFTs), which consist of highly phosphorylated tau protein. As bio-metal imbalance may be involved in the formation of NFT and SPs, metal regulation may be a direction for AD treatment. Clioquinol (CQ) is a metal-protein attenuating compound with mild chelating effects for Zn2+ and Cu2+, and CQ can not only detach metals from SPs, but also decrease amyloid aggregation in the brain. Previous studies suggested that Cu2+ induces the hyperphosphorylation of tau. However, the effects of CQ on tau were not fully explored. To examine the effects of CQ on tau metabolism, we used a human neuroblastoma cell line, M1C cells, which express wild-type tau protein (4R0N) via tetracycline-off (TetOff) induction. In a morphological study and ATP assay, up to 10 μM CQ had no effect on cell viability; however, 100 μM CQ had cytotoxic effects. CQ decreased accumulation of Cu+ in the M1C cells (39.4% of the control), and both total and phosphorylated tau protein. It also decreased the activity of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) (37.3% and 60.7% levels of the control, respectively), which are tau kinases. Of note, activation of protein phosphatase 2A (PP2A), which is a tau phosphatase, was also observed after CQ treatment. Fractionation experiments demonstrated a reduction of oligomeric tau in the tris insoluble, sarkosyl soluble fraction by CQ treatment. CQ also decreased caspase-cleaved tau, which accelerated the aggregation of tau protein. CQ activated autophagy and proteasome pathways, which are considered important for the degradation of tau protein. Although further studies are needed to elucidate the mechanisms responsible for the effects of CQ on tau, CQ may shed light on possible AD therapeutics.

SuHeXiang Wan Essential Oil Alleviates Amyloid Beta Induced Memory Impairment Through Inhibition of Tau Protein Phosphorylation in Mice

2011 ◽  
Vol 39 (05) ◽  
pp. 917-932 ◽  
Author(s):  
Songhee Jeon ◽  
Jinyoung Hur ◽  
Ha Jin Jeong ◽  
Byung-Soo Koo ◽  
Sok Cheon Pak
Keyword(s):  
Essential Oil ◽  
Memory Impairment ◽  
Neuroblastoma Cell ◽  
Amyloid Β ◽  
Control Group ◽  
Human Neuroblastoma Cell ◽  
Amyloid Β Protein ◽  
Human Neuroblastoma ◽  
In Vitro Investigation

SuHeXiang Wan (SHXW), a traditional Chinese medicine, has been used orally for the treatment of seizures, infantile convulsions and stroke. Previously, we reported the effects of a modified SHXW essential oil in terms of sedative effect, anticonvulsant activity and antioxidative activity. The purpose of this study was to evaluate the potential beneficial effects of SHXW essential oil in neurodegenerative diseases such as Alzheimer's disease (AD). SHXW essential oil was extracted from nine herbs. The mouse AD model was induced by a single injection of amyloid β protein (Aβ1-42) into the hippocampus. The animals were divided into four groups, the negative control group injected with Aβ42-1, the Aβ group injected with Aβ1-42, the SHXW group inhaled SHXW essential oil and received Aβ1-42 injection, and the positive control group administered with docosahexaenoic acid (DHA, 10 mg/kg) and with subsequent Aβ1-42 injection. Mice were analyzed by behavioral tests and immunological examination in the hippocampus. An additional in vitro investigation was performed to examine whether SHXW essential oil inhibits Aβ1-42 induced neurotoxicity in a human neuroblastoma cell line, SH-SY5Y cells. Pre-inhalation of SHXW essential oil improved the Aβ1-42 induced memory impairment and suppressed Aβ1-42 induced JNK, p38 and Tau phosphorylation in the hippocampus. SHXW essential oil suppressed Aβ-induced apoptosis and ROS production via an up-regulation of HO-1 and Nrf2 expression in SH-SY5Y cells. The present study suggests that SHXW essential oil may have potential as a therapeutic inhalation drug for the prevention and treatment of AD.

scholarly journals In vitroscreening of neuroprotective activity of Indian medicinal plantWithania somnifera

2017 ◽  
Vol 6 ◽  
Author(s):  
Manjeet Singh ◽  
Charles Ramassamy
Keyword(s):  
Neuroblastoma Cell ◽  
Amyloid Β ◽  
Acetylcholinesterase Activity ◽  
Neuroprotective Activity ◽  
Great Promise ◽  
Human Neuroblastoma Cell ◽  
Amyloid Β Peptide ◽  
Aβ Peptide ◽  
Neuroprotective Effects ◽  
Human Neuroblastoma

AbstractCanine cognitive dysfunction (CCD) is an age-dependent neurodegenerative condition characterised by changes in decline in learning and memory patterns. The neurodegenerative features of CCD in ageing dogs and cats are similar to human ageing and Alzheimer's disease (AD). Discovering neuroprotective disease-modifying therapies against CCD and AD is a major challenge. Strong evidence supports the role of amyloid β peptide deposition and oxidative stress in the pathophysiology of CCD and AD. In both the human and canine brain, oxidative damage progressively increases with age. Dietary antioxidants from natural sources hold a great promise in halting the progression of CCD and AD.Withania somnifera(WS), an Ayurvedic tonic medicine, also known as ‘Indian ginseng’ orashwagandhahas a long history of use in memory-enhancing therapy but there is a dearth of studies on its neuroprotective effects. The objective of this study was to investigate whetherWSextract can protect against Aβ peptide- and acrolein-induced toxicity. We demonstrated that treatment withWSextract significantly protected the human neuroblastoma cell line SK-N-SH against Aβ peptide and acrolein in various cell survival assays. Furthermore, treatment withWSextract significantly reduced the generation of reactive oxygen species in SK-N-SH cells. Finally, our results showed thatWSextract is also a potent inhibitor of acetylcholinesterase activity. Thus, our initial findings indicate thatWSextract may act as an antioxidant and cholinergic modulator and may have beneficial effects in CCD and AD therapy.

scholarly journals Aluminum and Tau in Neurofibrillary Tangles in Familial Alzheimer’s Disease

2021 ◽  
pp. 1-12
Author(s):  
Matthew John Mold ◽  
Adam O’Farrell ◽  
Benjamin Morris ◽  
Christopher Exley
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurofibrillary Tangles ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Phosphorylated Tau ◽  
Familial Alzheimer’S Disease ◽  
Therapeutic Benefits ◽  
Familial Alzheimer's Disease

Background: Familial Alzheimer’s disease (fAD) is driven by genetic predispositions affecting the expression and metabolism of the amyloid-β protein precursor. Aluminum is a non-essential yet biologically-reactive metal implicated in the etiology of AD. Recent research has identified aluminum intricately and unequivocally associated with amyloid-β in senile plaques and, more tentatively, co-deposited with neuropil-like threads in the brains of a Colombian cohort of donors with fAD. Objective: Herein, we have assessed the co-localization of aluminum to immunolabelled phosphorylated tau to probe the potential preferential binding of aluminum to senile plaques or neurofibrillary tangles in the same Colombian kindred. Methods: Herein, we have performed phosphorylated tau-specific immunolabelling followed by aluminum-specific fluorescence microscopy of the identical brain tissue sections via a sequential labelling method. Results: Aluminum was co-localized with immunoreactive phosphorylated tau in the brains of donors with fAD. While aluminum was predominantly co-located to neurofibrillary tangles in the temporal cortex, aluminum was more frequently co-deposited with cortical senile plaques. Conclusion: These data suggest that the co-deposition of aluminum with amyloid-β precedes that with neurofibrillary tangles. Extracellularly deposited amyloid-β may also be more immediately available to bind aluminum versus intracellular aggregates of tau. Therapeutic approaches to reduce tau have demonstrated the amelioration of its synergistic interactions with amyloid-β, ultimately reducing tau pathology and reducing neuronal loss. These data support the intricate associations of aluminum in the neuropathology of fAD, of which its subsequent reduction may further therapeutic benefits observed in ongoing clinical trials in vivo.

The Implications of Autophagy in Alzheimer’s Disease

2018 ◽  
Vol 15 (14) ◽  
pp. 1283-1296 ◽  
Author(s):  
Tadanori Hamano ◽  
Kouji Hayashi ◽  
Norimichi Shirafuji ◽  
Yasunari Nakamoto
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Model ◽  
Tau Protein ◽  
Protective Factor ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Model Studies ◽  
Β Protein

The pathogenic mechanisms of Alzheimer’s Disease (AD) involve the deposition of abnormally misfolded proteins, amyloid β protein (Aβ) and tau protein. Aβ comprises senile plaques, and tau aggregates form Neurofibrillary Tangles (NFTs), both of which are hallmarks of AD. Autophagy is the main conserved pathway for the degeneration of aggregated proteins, Aβ, tau and dysfunctional organelles in the cell. Many animal model studies have demonstrated that autophagy normally functions as the protective factor against AD progression associated with intracytoplasmic toxic Aβ and tau aggregates. The upregulation of autophagy can also be favorable in AD treatment. An improved understanding of the signaling pathways that regulate autophagy is critical to developing AD treatments. The cellular and molecular machineries of autophagy, their function in the pathogenesis of AD, and current drug discovery strategies will be discussed in this review.

scholarly journals Autophagy and Tau Protein

2021 ◽  
Vol 22 (14) ◽  
pp. 7475
Author(s):  
Tadanori Hamano ◽  
Soichi Enomoto ◽  
Norimichi Shirafuji ◽  
Masamichi Ikawa ◽  
Osamu Yamamura ◽  
...  
Keyword(s):  
Neurofibrillary Tangles ◽  
Tau Protein ◽  
Therapeutic Strategy ◽  
Senile Plaques ◽  
Cellular Model ◽  
Phosphorylated Tau ◽  
Degradation Mechanisms ◽  
Wild Type ◽  
Lysosomal System ◽  
Phosphorylated Tau Protein

Neurofibrillary tangles, which consist of highly phosphorylated tau protein, and senile plaques (SPs) are pathological hallmarks of Alzheimer’s disease (AD). In swollen axons, many autophagic vacuoles are observed around SP in the AD brain. This suggests that autophagy function is disturbed in AD. We used a neuronal cellular model of tauopathy (M1C cells), which harbors wild type tau (4R0N), to assess the effects of the lysosomotrophic agent NH4Cl, and autophagy inhibitors chloroquine and 3 methyladenine (3MA). It was found that chloroquine, NH4Cl and 3MA markedly increased tau accumulation. Thus, autophagy lysosomal system disturbances disturbed the degradation mechanisms of tau protein. Other studies also revealed that tau protein, including aggregated tau, is degraded via the autophagy lysosome system. Phosphorylated and C terminal truncated tau were also reported to disturb autophagy function. As a therapeutic strategy, autophagy upregulation was suggested. Thus far, as autophagy modulators, rapamycin, mTOCR1 inhibitor and its analogues, lithium, metformin, clonidine, curcumin, nicotinamide, bexaroten, and torehalose have been proposed. As a therapeutic strategy, autophagic modulation may be the next target of AD therapeutics.

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