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Abstract
Aggregation of amyloids, such as amyloid-β (Aβ), tau and α-synuclein appear to be the key culprit neurodegenerative diseases such as Alzheimer's and Parkinson's, respectively. Inhibiting this aggregation is thus an attractive disease-modifying therapeutic strategy for these diseases.
Earlier findings form Gazit's lab have shown that aromatic interactions (π-π stacking) greatly facilitate the self assembly of various amyloids and stabilize the resulting nano-fibrils. Based on this notion we have designed and screened various aromatic small molecules as candidate inhibitors of amyloid assembly.
One 'parent' molecule is Tryptophan-modified naphthoquinone (NQTrp) patented by Tel Aviv University. We have shown its impressive efficacy in inhibiting in vitro aggregation of various amyloids and disassembly of pre-formed aggregates, including -synuclein; we determined its mode of binding to amyloids, using amyloid-β (Aβ) as an example; we have shown its efficacy in preventing cytotoxicity of Aβ towards cultured neurons; we demonstrated its efficacy in ameliorating Aβ-caused Alzheimer's disease behavioral symptoms in transgenic model Drosophila and in transgenic model mice, accompanied by marked reduction of aggregates in their brains. Initial systematic toxicity assays showed no adverse effects, but did show limited passage through the blood-brain-barrier (BBB). In a parallel study, using the approached mentioned above for NQTrp, we showed marked efficacy of the small sugar Mannitol for inhibition of -synuclein aggregation, and for marked neuroprotection and amelioration of Parkinson's symptoms and in transgenic model Drosophila and mice. Importantly, Mannitol is available over the counter and is FDA approved for various indications, in particular for opening of the BBB but which do NOT include indications for neurodegenerative diseases.
In the context of the collaboration between Tel Aviv University and Tsinghua University we aim to chemically link NQTrp to Mannitol for generation, and testing in vitro and in vivo, of a novel hybrid molecule that is expected to facilitate BBB passage of the former and exhibit synergistic therapeutic results for Parkinson's and possibly other amyloid-caused neurodegenerative diseases.
Daniel Segal is Professor of Molecular Developmental Biology, as well as the Nathan Galston Chair for Anti-Microbial Drug Research at Tel-Aviv University. He received his B.Sc in Biology in 1974 and Ph.D in Genetics in 1980 from Hebrew University. From 1981 to 1984, he joined in Harvard University as a post doctoral fellow. Then he worked at Weizmann Institute as a Scientists in 1984. In 1987 he joined Tel-Aviv University as a Lecturer and was then promoted to Associate Professor in 1999 and Full Professor in 2008. His research interests mainly focus on developing and screening in vivo novel small molecules and natural plant compounds as amyloid-beta and tau inhibitors in Alzheimer’s disease, examining the mechanism of spreading of TDP-43 in ALS and the role of protein glycosylation in the aging and neurodegenerative brain.
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