Homocysteine fibrillar assemblies display cross-talk with Alzheimer's disease β-amyloid polypeptide

Dorin Sade Yazdi, Dana Laor Bar-Yosef, Hanaa Adsi, Topaz Kreiser, Shahaf Sigal, Santu Bera, Dor Zaguri, Shira Shaham-Niv, Damilola S. Oluwatoba, Davide Levy, Myra Gartner, Thanh D. Do, Frenkel Dan, Ehud Gazit

Research output: Contribution to journalArticlepeer-review

Abstract

High levels of homocysteine are reported as a risk factor for Alzheimer's disease (AD). Correspondingly, inborn hyperhomocysteinemia is associated with an increased predisposition to the development of dementia in later stages of life. Yet, the mechanistic link between homocysteine accumulation and the pathological neurodegenerative processes is still elusive. Furthermore, despite the clear association between protein aggregation and AD, attempts to develop therapy that specifically targets this process have not been successful. It is envisioned that the failure in the development of efficacious therapeutic intervention may lie in the metabolomic state of affected individuals. We recently demonstrated the ability of metabolites to self-assemble and cross-seed the aggregation of pathological proteins, suggesting a role for metabolite structures in the initiation of neurodegenerative diseases. Here, we provide a report of homocysteine crystal structure and self-assembly into amyloid-like toxic fibrils, their inhibition by polyphenols, and their ability to seed the aggregation of the AD-associated β-amyloid polypeptide. A yeast model of hyperhomocysteinemia indicates a toxic effect, correlated with increased intracellular amyloid staining that could be rescued by polyphenol treatment. Analysis of AD mouse model brain sections indicates the presence of homocysteine assemblies and the interplay between β-amyloid and homocysteine. This work implies a molecular basis for the association between homocysteine accumulation and AD pathology, potentially leading to a paradigm shift in the understanding of AD initial pathological processes.

Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number24
DOIs
StatePublished - 15 Jun 2021

Keywords

  • Alzheimer’s disease
  • cross-seeding
  • homocysteine
  • hyperhomocysteinemia
  • metabolite amyloids

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