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000163637 037__ $$aDZNE-2022-00383
000163637 041__ $$aEnglish
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000163637 1001_ $$aAillaud, Isabelle$$b0
000163637 245__ $$aA novel D-amino acid peptide with therapeutic potential (ISAD1) inhibits aggregation of neurotoxic disease-relevant mutant Tau and prevents Tau toxicity in vitro.
000163637 260__ $$aLondon$$bBioMed Central$$c2022
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000163637 520__ $$aAlzheimer's disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder that mainly affects older adults. One of the pathological hallmarks of AD is abnormally aggregated Tau protein that forms fibrillar deposits in the brain. In AD, Tau pathology correlates strongly with clinical symptoms, cognitive dysfunction, and neuronal death.We aimed to develop novel therapeutic D-amino acid peptides as Tau fibrillization inhibitors. It has been previously demonstrated that D-amino acid peptides are protease stable and less immunogenic than L-peptides, and these characteristics may render them suitable for in vivo applications. Using a phage display procedure against wild type full-length Tau (TauFL), we selected a novel Tau binding L-peptide and synthesized its D-amino acid version ISAD1 and its retro inversed form, ISAD1rev, respectively.While ISAD1rev inhibited Tau aggregation only moderately, ISAD1 bound to Tau in the aggregation-prone PHF6 region and inhibited fibrillization of TauFL, disease-associated mutant full-length Tau (TauFLΔK, TauFL-A152T, TauFL-P301L), and pro-aggregant repeat domain Tau mutant (TauRDΔK). ISAD1 and ISAD1rev induced the formation of large high molecular weight TauFL and TauRDΔK oligomers that lack proper Thioflavin-positive β-sheet conformation even at lower concentrations. In silico modeling of ISAD1 Tau interaction at the PHF6 site revealed a binding mode similar to those known for other PHF6 binding peptides. Cell culture experiments demonstrated that ISAD1 and its inverse form are taken up by N2a-TauRDΔK cells efficiently and prevent cytotoxicity of externally added Tau fibrils as well as of internally expressed TauRDΔK.ISAD1 and related peptides may be suitable for therapy development of AD by promoting off-pathway assembly of Tau, thus preventing its toxicity.
000163637 536__ $$0G:(DE-HGF)POF4-352$$a352 - Disease Mechanisms (POF4-352)$$cPOF4-352$$fPOF IV$$x0
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000163637 650_7 $$2Other$$aAlzheimer’s disease
000163637 650_7 $$2Other$$aD-amino acid peptides
000163637 650_7 $$2Other$$aPhage display
000163637 650_7 $$2Other$$aTau aggregation inhibitors
000163637 650_7 $$2Other$$aTherapy
000163637 650_7 $$2NLM Chemicals$$aAmino Acids
000163637 650_7 $$2NLM Chemicals$$aPeptides
000163637 650_7 $$2NLM Chemicals$$atau Proteins
000163637 650_2 $$2MeSH$$aAged
000163637 650_2 $$2MeSH$$aAlzheimer Disease: drug therapy
000163637 650_2 $$2MeSH$$aAlzheimer Disease: pathology
000163637 650_2 $$2MeSH$$aAmino Acids: therapeutic use
000163637 650_2 $$2MeSH$$aCells, Cultured
000163637 650_2 $$2MeSH$$aHumans
000163637 650_2 $$2MeSH$$aPeptides: therapeutic use
000163637 650_2 $$2MeSH$$aProtein Conformation, beta-Strand
000163637 650_2 $$2MeSH$$atau Proteins: metabolism
000163637 650_2 $$2MeSH$$atau Proteins: toxicity
000163637 7001_ $$0P:(DE-2719)2812350$$aKaniyappan, Senthilvelrajan$$b1$$eFirst author$$udzne
000163637 7001_ $$0P:(DE-2719)2811626$$aChandupatla, Ram Reddy$$b2$$udzne
000163637 7001_ $$0P:(DE-2719)9001275$$aRamirez, Lisa-Marie$$b3$$udzne
000163637 7001_ $$aAlkhashrom, Sewar$$b4
000163637 7001_ $$aEichler, Jutta$$b5
000163637 7001_ $$aHorn, Anselm H C$$b6
000163637 7001_ $$0P:(DE-2719)2810591$$aZweckstetter, Markus$$b7$$udzne
000163637 7001_ $$0P:(DE-2719)2541671$$aMandelkow, Eckhard$$b8$$udzne
000163637 7001_ $$aSticht, Heinrich$$b9
000163637 7001_ $$00000-0002-1160-8762$$aFunke, Susanne Aileen$$b10
000163637 773__ $$0PERI:(DE-600)2506521-X$$a10.1186/s13195-022-00959-z$$gVol. 14, no. 1, p. 15$$n1$$p15$$tAlzheimer's research & therapy$$v14$$x1758-9193$$y2022
000163637 8564_ $$uhttps://pub.dzne.de/record/163637/files/DZNE-2022-00383.pdf$$yOpenAccess
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000163637 9201_ $$0I:(DE-2719)1013015$$kAG Mandelkow 2$$lCell and Animal Models of Neurodegeneration$$x0
000163637 9201_ $$0I:(DE-2719)1013014$$kAG Mandelkow 1$$lStructural Principles of Neurodegeneration$$x1
000163637 9201_ $$0I:(DE-2719)1410001$$kAG Zweckstetter$$lStructural Biology in Dementia$$x2
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