Home > Publications Database > A novel D-amino acid peptide with therapeutic potential (ISAD1) inhibits aggregation of neurotoxic disease-relevant mutant Tau and prevents Tau toxicity in vitro. > print

001     163637
005     20230915090529.0
024 7 _ |a 10.1186/s13195-022-00959-z
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037 _ _ |a DZNE-2022-00383
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Aillaud, Isabelle
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245 _ _ |a A novel D-amino acid peptide with therapeutic potential (ISAD1) inhibits aggregation of neurotoxic disease-relevant mutant Tau and prevents Tau toxicity in vitro.
260 _ _ |a London
|c 2022
|b BioMed Central
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520 _ _ |a Alzheimer's disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder that mainly affects older adults. One of the pathological hallmarks of AD is abnormally aggregated Tau protein that forms fibrillar deposits in the brain. In AD, Tau pathology correlates strongly with clinical symptoms, cognitive dysfunction, and neuronal death.We aimed to develop novel therapeutic D-amino acid peptides as Tau fibrillization inhibitors. It has been previously demonstrated that D-amino acid peptides are protease stable and less immunogenic than L-peptides, and these characteristics may render them suitable for in vivo applications. Using a phage display procedure against wild type full-length Tau (TauFL), we selected a novel Tau binding L-peptide and synthesized its D-amino acid version ISAD1 and its retro inversed form, ISAD1rev, respectively.While ISAD1rev inhibited Tau aggregation only moderately, ISAD1 bound to Tau in the aggregation-prone PHF6 region and inhibited fibrillization of TauFL, disease-associated mutant full-length Tau (TauFLΔK, TauFL-A152T, TauFL-P301L), and pro-aggregant repeat domain Tau mutant (TauRDΔK). ISAD1 and ISAD1rev induced the formation of large high molecular weight TauFL and TauRDΔK oligomers that lack proper Thioflavin-positive β-sheet conformation even at lower concentrations. In silico modeling of ISAD1 Tau interaction at the PHF6 site revealed a binding mode similar to those known for other PHF6 binding peptides. Cell culture experiments demonstrated that ISAD1 and its inverse form are taken up by N2a-TauRDΔK cells efficiently and prevent cytotoxicity of externally added Tau fibrils as well as of internally expressed TauRDΔK.ISAD1 and related peptides may be suitable for therapy development of AD by promoting off-pathway assembly of Tau, thus preventing its toxicity.
536 _ _ |a 352 - Disease Mechanisms (POF4-352)
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650 _ 7 |a Alzheimer’s disease
|2 Other
650 _ 7 |a D-amino acid peptides
|2 Other
650 _ 7 |a Phage display
|2 Other
650 _ 7 |a Tau aggregation inhibitors
|2 Other
650 _ 7 |a Therapy
|2 Other
650 _ 7 |a Amino Acids
|2 NLM Chemicals
650 _ 7 |a Peptides
|2 NLM Chemicals
650 _ 7 |a tau Proteins
|2 NLM Chemicals
650 _ 2 |a Aged
|2 MeSH
650 _ 2 |a Alzheimer Disease: drug therapy
|2 MeSH
650 _ 2 |a Alzheimer Disease: pathology
|2 MeSH
650 _ 2 |a Amino Acids: therapeutic use
|2 MeSH
650 _ 2 |a Cells, Cultured
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Peptides: therapeutic use
|2 MeSH
650 _ 2 |a Protein Conformation, beta-Strand
|2 MeSH
650 _ 2 |a tau Proteins: metabolism
|2 MeSH
650 _ 2 |a tau Proteins: toxicity
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700 1 _ |a Kaniyappan, Senthilvelrajan
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700 1 _ |a Chandupatla, Ram Reddy
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700 1 _ |a Ramirez, Lisa-Marie
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700 1 _ |a Alkhashrom, Sewar
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700 1 _ |a Eichler, Jutta
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700 1 _ |a Horn, Anselm H C
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700 1 _ |a Zweckstetter, Markus
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700 1 _ |a Mandelkow, Eckhard
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700 1 _ |a Sticht, Heinrich
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700 1 _ |a Funke, Susanne Aileen
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773 _ _ |a 10.1186/s13195-022-00959-z
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856 4 _ |y OpenAccess
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910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
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