TY  - JOUR
AU  - Aillaud, Isabelle
AU  - Kaniyappan, Senthilvelrajan
AU  - Chandupatla, Ram Reddy
AU  - Ramirez, Lisa-Marie
AU  - Alkhashrom, Sewar
AU  - Eichler, Jutta
AU  - Horn, Anselm H C
AU  - Zweckstetter, Markus
AU  - Mandelkow, Eckhard
AU  - Sticht, Heinrich
AU  - Funke, Susanne Aileen
TI  - A novel D-amino acid peptide with therapeutic potential (ISAD1) inhibits aggregation of neurotoxic disease-relevant mutant Tau and prevents Tau toxicity in vitro.
JO  - Alzheimer's research & therapy
VL  - 14
IS  - 1
SN  - 1758-9193
CY  - London
PB  - BioMed Central
M1  - DZNE-2022-00383
SP  - 15
PY  - 2022
AB  - 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.
KW  - Aged
KW  - Alzheimer Disease: drug therapy
KW  - Alzheimer Disease: pathology
KW  - Amino Acids: therapeutic use
KW  - Cells, Cultured
KW  - Humans
KW  - Peptides: therapeutic use
KW  - Protein Conformation, beta-Strand
KW  - tau Proteins: metabolism
KW  - tau Proteins: toxicity
KW  - Alzheimer’s disease (Other)
KW  - D-amino acid peptides (Other)
KW  - Phage display (Other)
KW  - Tau aggregation inhibitors (Other)
KW  - Therapy (Other)
KW  - Amino Acids (NLM Chemicals)
KW  - Peptides (NLM Chemicals)
KW  - tau Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:35063014
C2  - pmc:PMC8783508
DO  - DOI:10.1186/s13195-022-00959-z
UR  - https://pub.dzne.de/record/163637
ER  -