scholarly journals Binding and neurotoxicity mitigation of toxic tau oligomers by synthetic heparin like oligosaccharides

2018 ◽  
Vol 54 (72) ◽  
pp. 10120-10123 ◽  
Author(s):  
Peng Wang ◽  
Filippa Lo Cascio ◽  
Jia Gao ◽  
Rakez Kayed ◽  
Xuefei Huang
Keyword(s):  
Neuronal Cells ◽  
Cytotoxic Effects ◽  
Tau Oligomers ◽  
Heparin Oligosaccharides

Heparin oligosaccharides can mitigate the cytotoxic effects of tau oligomers towards neuronal cells.

Mitochondrial perturbation drives tau oligomers pathology in Alzheimer’s disease

2020 ◽  
Author(s):  
Fang DU ◽  
Qing Yu ◽  
Doris Chen ◽  
Shi Fang Yan ◽  
Shirley Yan
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Ex Vivo ◽  
Neuronal Cells ◽  
Neurofibrillary Tangle ◽  
Contributing Factors ◽  
Tau Oligomers ◽  
Oligomer Formation ◽  
Underlying Mechanisms

Abstract Tau oligomers, prior to neurofibrillary tangle formation, are toxic species responsible for tau pathology, mitochondrial and synaptic damage, and memory impairment. The underlying mechanisms of abnormal tau accumulation and strategies to eliminate them remain largely unknown. The present study addresses whether mitochondrial reactive oxygen species (ROS) are major contributing factors for tau oligomer formation and, if so, whether eliminating mitochondrial ROS reduces accumulation of tau oligomers and improves mitochondrial and cognitive function in Alzheimer’s disease (AD). First, we determined whether increased oxidative stress correlates with aggregation of tau oligomers in human AD-affected brains, Aβ/tau overexpressed mouse models, human trans-mitochondrial “cybrid” (cytoplasmic hybrid) neuronal cells containing mild cognitive impairment (MCI) and AD-derived mitochondria, and Aβ/tau expressing neuronal cells. In P301S tau and AD mice, upregulation of tau oligomers correlates with ROS accumulation. Elevated tau oligomer levels are also correlated with elevated ROS levels in the AD patient hippocampus. Importantly, human cybrid cells, whose mitochondria are derived from platelets of patients with sporadic AD or MCI, displayed aggregated tau oligomers, which also correlated with upregulated ROS levels. Application of mito-Tempo, a mitochondria-targeted antioxidant, to inhibit the generation of mitochondrial and intracellular ROS in tau and AD neurons, as well as in MCI and AD cybrids ex vivo, leads to a striking decrease in tau oligomers. Finally, in AD mice, mito-Tempo inhibited tau oligomer accumulation and improved behavioral deficiency. Our work adds to the growing body of evidence that oxidative stress contributes to tau oligomer formation and that inhibition of oxidative stress ameliorates tauopathy in AD.

Targeting Pathological Amyloid Aggregates with Conformation-Sensitive Antibodies

2020 ◽  
Vol 17 (8) ◽  
pp. 722-734
Author(s):  
Alessandra Bigi ◽  
Gilda Loffredo ◽  
Roberta Cascella ◽  
Cristina Cecchi
Keyword(s):  
Senile Plaques ◽  
Neuronal Cells ◽  
Cytotoxic Effects ◽  
Specificity And Sensitivity ◽  
Amyloid Aggregates ◽  
Culture Models ◽  
Therapeutic Tools

Background: The pathogenesis of Alzheimer's disease (AD) is not directly caused by the presence of senile plaques but rather by the detrimental effects exerted on neuronal cells by toxic soluble oligomers. Such species are formed early during the aggregation process of the Aβ1-42 peptide or can be released from mature fibrils. Nowadays, efficient tools for an early diagnosis, as well as pharmaceutical treatments targeting the harmful agents in samples of AD patients, are still missing. Objective: By integrating in vitro immunochemical assay with in vivo neuronal models of toxicity, we aim to understand and target the principles that drive toxicity in AD. Methods: We evaluated the specificity and sensitivity of A11 and OC conformational antibodies to target a range of pathologically relevant amyloid conformers and rescue their cytotoxic effects in neuronal culture models using a number of cellular readouts. Results: We demonstrated the peculiar ability of conformational antibodies to label pathologically relevant Aβ1-42 oligomers and fibrils and to prevent their detrimental effects on neuronal cells. Conclusion: Our results substantially improve our knowledge on the role of toxic assemblies in neurodegenerative diseases, thus suggesting new and more effective diagnostic and therapeutic tools for AD.

Cytoprotective Effect of Tocotrienol-Rich Fraction and α-Tocopherol Vitamin E Isoforms Against Glutamate-Induced Cell Death in Neuronal Cells

2014 ◽  
Vol 84 (3-4) ◽  
pp. 0140-0151 ◽  
Author(s):  
Thilaga Rati Selvaraju ◽  
Huzwah Khaza’ai ◽  
Sharmili Vidyadaran ◽  
Mohd Sokhini Abd Mutalib ◽  
Vasudevan Ramachandran ◽  
...  
Keyword(s):  
Vitamin E ◽  
Cell Viability ◽  
Neuronal Cells ◽  
Positive Control ◽  
Post Treatment ◽  
Mitochondrial Activity ◽  
Before And After ◽  
Pre Treatment ◽  
Tocotrienol Rich Fraction ◽  
Major Mediator

Glutamate is the major mediator of excitatory signals in the mammalian central nervous system. Extreme amounts of glutamate in the extracellular spaces can lead to numerous neurodegenerative diseases. We aimed to clarify the potential of the following vitamin E isomers, tocotrienol-rich fraction (TRF) and α-tocopherol (α-TCP), as potent neuroprotective agents against glutamate-induced injury in neuronal SK-N-SH cells. Cells were treated before and after glutamate injury (pre- and post-treatment, respectively) with 100 - 300 ng/ml TRF/α-TCP. Exposure to 120 mM glutamate significantly reduced cell viability to 76 % and 79 % in the pre- and post-treatment studies, respectively; however, pre- and post-treatment with TRF/α-TCP attenuated the cytotoxic effect of glutamate. Compared to the positive control (glutamate-injured cells not treated with TRF/α-TCP), pre-treatment with 100, 200, and 300 ng/ml TRF significantly improved cell viability following glutamate injury to 95.2 %, 95.0 %, and 95.6 %, respectively (p < 0.05).The isomers not only conferred neuroprotection by enhancing mitochondrial activity and depleting free radical production, but also increased cell viability and recovery upon glutamate insult. Our results suggest that vitamin E has potent antioxidant potential for protecting against glutamate injury and recovering glutamate-injured neuronal cells. Our findings also indicate that both TRF and α-TCP could play key roles as anti-apoptotic agents with neuroprotective properties.

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