Novel Drug Blocks Activity of Toxic Alzheimer's Disease Peptides

Drug developers have identified a compound that in a worm model blocks the action of the type of toxic peptide plaques that characterize human neurodegenerative diseases such as Alzheimer's and Huntington's.

Aging manipulation is an emerging strategy aimed to postpone the manifestation of late-onset neurodegenerative disorders such as Alzheimer's (AD) and Huntington's diseases (HD) and to slow their progression once emerged. Investigators at the Hebrew University of Jerusalem (Israel) and their colleagues at the biopharmaceutical start-up company TyrNovo (Herzliya, Israel) had shown previously that reducing the activity of the insulin/IGF signaling cascade (IIS), a prominent aging-regulating pathway, protected nematode worms (Caenorhabditis elegans) from the toxicity of various aggregative proteins, including the AD-associated peptide, A-beta and the HD-linked peptide, polyQ40.

In the current study the investigators worked with an AD model based on a variant of C. elegans that expresses the highly aggregative, human AD-associated peptide, A-beta-42, in their body wall muscles. The expression of A-beta in these animals leads to a progressive paralysis within the worm population. The investigators treated the A-beta-42 worms with TyrNovo's novel compound NT219. NT219 possesses a unique mechanism, which leads to the elimination of IRS 1/2 and the long-term blockage of all signals they transmit.

Results published in the November 22, 2013, online edition of the journal Aging Cell revealed that NT219 mediated a long-lasting, highly efficient inhibition of the IIS signaling cascade by a dual mechanism. It reduced the autophosphorylation of the IGF1 receptor and directed the insulin receptor substrates 1 and 2 (IRS 1/2) for degradation. NT219 treatment promoted stress resistance and protected nematodes from the toxicity of AD- and HD-associated peptides without affecting the lifespan of the organism.

"The findings of the study reinforces the claim that blocking the signaling pathway of insulin and the growth hormone IGF1, a pathway known to be a central controller of the aging process in worms and mammals, can potentially be used as a treatment for degenerative brain diseases," said senior author Dr. Ehud Cohen, professor of biochemistry and molecular biology at the Hebrew University of Jerusalem. "The new findings are the first evidence that a pharmacological substance can effectively protect against toxicity of proteins associated with neurodegenerative diseases, through selective inhibition of the aging process."

The investigators have filed a patent application based on this study that includes the rights for use of NT219 as a therapeutic agent.

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