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Homocysteine fibrillar assemblies display crosstalk with Alzheimer’s disease amyloid polypeptide

High levels of homocysteine (Hcy) 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. Furthermore, despite the apparent association between protein aggregation and AD, attempts to develop a therapy that targets explicitly this process have not been successful

It is envisioned that the failure to develop 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

Detection of Hcy fibrils and colocalization with astrocytes in AD model mice. The images represent sections of (A–C) 5xFAD or (D–F) WT animals. (A and D) Sections stained with anti–Hcy-fibrils antibodies (green). (B and E) Sections stained with anti-GFAP antibodies (red). (C and F) Merge of Hcy and GFAP staining with DAPI staining. (Scale bar, 200 μm.) 

Along with AD, high levels of Hcy are involved in many other diseases, such as diabetes, neurological diseases, vascular disease, age-related macular degeneration, cancer, and hearing loss. Thus, the formation of amyloid-like fibrils by Hcy, their toxicity, and cross-seeding capability are highly relevant to many biological and medicinal fields. 

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 

Us Provisional Patent

Sade Yazdi, D., Laor Bar-Yosef, D., Adsi, H., Kreiser, T., Sigal, S., Bera, S., Zaguri, D., Shaham-Niv, S., Oluwatoba, D. S., Levy, D., Gartner, M., Do, T. D., Frenkel, D., & Gazit, E. (2021). Homocysteine fibrillar assemblies display crosstalk with Alzheimer’s disease β-amyloid polypeptide. Proceedings of the National Academy of Sciences of the United States of America, 118(24).